Funded Projects

2017 Funded Projects

Chairman’s Award
Prashant Mishra, MD, PhD
University of Texas Southwestern Medical Center
Children’s Research Institute

“Identification of SLC Family Members as Predictive Biomarkers for Mitochondrial Disease”
The development and validation of blood based biomarkers for mitochondrial disease remains a top priority in the research community.  This project investigates the potential use of specific solute carrier (SLC) family members in blood serum as novel predictive biomarkers of mitochondrial disease.  Preliminary data generated in Dr. Mishra’s lab indicates that SLC family members are not only altered in the disease setting, but could also serve as therapeutic development targets.

New and Early Principal Investigator Award
Rustum Karanjia, MD, PhD
Doheny Eye Center
University of Ottowa

“Photopic Negative Response as an Objective Biomarker in Mitochondrial Disease”
Many forms of mitochondrial disease have eye-related symptoms, including LHON, DOA, Leigh Syndrome and MELAS.  There is a significant and need for better measurements of eye function as it relates to disease progression.   Dr. Karanjia intends to measure eye cell electrical activity over 18 months in affected individuals utilizing Photopic Negative Response (PhNR).  This data will help to validate PhNR as a potential biomarker for optic nerve function in mitochondrial disease patients.

Postdoctoral Fellowship Award
Melissa Anne Walker, MD, PhD
Massachusetts General Hospital

“A Single Blood Draw Test of Mitochondrial Disease”
There are currently no consensus biomedical tests for mitochondrial disease due to its complex and diverse nature, a situation which makes effective diagnosis and treatment extremely challenging.  The goal of Dr. Walker, working in the lab of Dr. Vamsi Mootha, is to develop a rapid, facile blood test for mitochondrial activity based on a single blood draw.  Preliminary data points to a simple, inexpensive test that could be applied in any standard clinical laboratory.  The funds provided by the UMDF will allow for continued development and validation of this assay in both healthy controls as well as affected individuals with a genetically confirmed diagnosis of mitochondrial disease.

2016 Funded Projects

Brendan J. Battersby, Ph.D., Research Director

Biomedicum Helsinki, Research Programs Unit-Molecular Neurology
University of Helsinki (Finland)
Principal Investigator Award –  2 years/$70,000

Investigating the Pathogenesis of C12orf65 Deficiency in Mitochondrial Translation and Mitochondrial Disease

The goal of this research project led by Dr. Battersby is to address a significant gap in mechanistic knowledge within the mitochondrial field- ribosome function and translation. The outcome of this work could provide unique insights into the broad range of mitochondrial disease symptoms that result from mutations in the C12orf65 gene.

Alessandro Bitto, Ph.D.,

Department of Pathology, University of Washington Medical Center (USA)
Postdoctoral Fellowship Award – 2 years/$70,000

Molecular Mechanisms for Suppression of Mitochondrial Disease by Acarbose,

Dr. Bitto, under the mentorship of Dr. Matt Kaeberlein, will evaluate an FDA-approved drug called acarbose for efficacy in a translational mouse model of Leigh Syndrome. The drug impacts mTOR signaling, an important mitochondrial function pathway whose understanding could open up a broad therapeutic strategy for mitochondrial disease.


Nicola Brunetti-Pierri, MD, FACMG

Associate Investigator, Telethon Institute of Genetics and Medicine (Italy)
Small Clinical Study Award – 1 year/$25,000

Phenylbutyrate Therapy for Pyruvate Dehydrogenase Deficiency

This grant, winner of the 2016 Chairman’s Award for highest rated research proposal after peer review, is a clinical study of a new potential therapy for pyruvate dehydrogenase complex (PDHC) deficiency by lowering lactate levels. This project comes 5 years after Dr. Brunetti-Pierri received a UMDF grant to first test phenylbutarate on patient cells. Subsequent animal model studies confirmed the promising in vitro data that resulted from the first grant, and now a pilot clinical trial will be carried out across multiple centers in Italy. Positive results from the pilot study would lead to a larger study directed toward PDHC deficiency patients.

Adam Hughes, Ph.D.

Assistant Professor of Biochemistry, University of Utah School of Medicine (USA)
Principal Investigator Award – 2 years/$100,000

Quality Control of Unimported Mitochondrial Precursor Proteins

Utilizing yeast models, Dr. Hughes intends to explore the link between loss of mitochondrial membrane potential and mis-targeted mitochondrial proteins. That the accumulation of such proteins and their associated “waste disposal” is a source of mitochondrial pathology is a novel and intriguing premise that could open up many new avenues in future research.

Leo Nijtmans, Ph.D.

Radboud University Medical Centre, Nijmegen (Netherlands)
Principal Investigator Award – 1 year/$40,000

Mitochondrial Complexome Profiling Provides a Novel Tool to Diagnose and Understand Complex I Deficiency

Complex I disorders are some of the most common types of mitochondrial disease. Dr. Nijtmans will utilize a profiling technique to study protein interactions within Complex I using patient cell lines. The results will provide insight into Complex I assembly and function, and could ultimately lead to new therapeutic targets for investigation.

George A. Porter, Jr., MD, Ph.D.

Assistant Professor, Department of Pediatrics, Division of Cardiology, University of Rochester Medical Center (USA)
Principal Investigator Award – 2 years/$100,000
Manipulating the Permeability Transition Pore to Ameliorate Neonatal Heart Failure

Many types of mitochondrial disease have associated cardiomyopathies. In this translational research project Dr. Porter will test potential therapies for cardiomyopathies in a mouse model. Success in this project would initially open the possibility for treating neonates with bioenergetics disorders, and eventually have potential for more broadly treating mitochondrial disease patients with Complex I disorders.

Eric A. Shoubridge, Ph.D.

Professor and Chair, Department of Human Genetics, Montreal Neurological Institute, McGill University (Canada)
Principal Investigator Award- 2 years/$75,000
Interrogating the Mitochondrial Interactome Using BioID

Dr. Shoubridge’s project will identify functional networks within the mitochondria based on the analysis of protein-protein interactions. In addition to the potential for revealing new insights into mitochondrial disease, the availability of a mitochondrial protein interactome will be a generally useful resource for addressing basic questions regarding mitochondrial structure and function in both a normal and diseased state.

Zarazuela Zolkipli Cunningham, MBChB MRCP

Division of Neurology, The Children’s Hospital of Philadelphia (USA)
Small Clinical Study Award – 1 year/$25,000

Development and Validation of a New Outcome Measure in Mitochondrial Disease

Dr. Zolkipli Cunningham and collaborators aim to develop a new outcome measure for mitochondrial myopathy that is specifically designed for use in Phase II/III clinical trials. The patient perspective will be critical to the project, helping to ensure that meaningful measures are developed over the full range of disease state- from early ambulatory to late non-ambulatory. Recognizing the urgent need for improved clinical trial endpoints, the development of this scale will build upon existing scales and tools.

2015 Funded Projects


John Christodoulou, Ph.D.
Children’s Hospital at Westmead
New South Wales, Australia.
Grant Award $100,000

“Utility of FGF21 and GDF15 as Diagnostic and Prognostic Biomarkers
of Mitochondrial Respiratory Chain Disorders.” 

Dr. Christodoulou will validate optimal methodology in a clinical diagnostic laboratory setting to determine the utility of measuring FGF-21 and GDF-15 as biomarkers of pediatric mitochondrial disease. This has become a major question in the field, as to how potentially useful in terms of sensitivity and specificity these biomarkers are for mitochondrial disease.

Daniel F. Bogenhagen, MD
Department of Pharmacological Sciences
Stony Brook University
Grant Award – $100,000

“Kinetics of Mitochondrial Complex Assembly.” 

Dr. Bogenhagen is utilizing mass spectrometry techniques to study the assembly map of the mitoribosome as well as the mitochondrial respiratory complexes. The improved understanding of both of these mitochondrial construction projects will enhance the diagnosis and future therapy of mitochondrial disorders.

Peter W. Stacpoole, MD, Ph.D.
Department of Medicine
University of Florida

Grant Award $24,898

“Validation of an Observer Reported Outcome (ObsRO) Measure of Home Functionality in Children with Pyruvate Dehydrogenase Complex Deficiency (PDCD).” 

Dr. Stacpoole, in response to a specific request from the FDA for information from the patient or patient family to aid in regulatory decisions, has developed an innovative computer tool to track home functionality of pediatric PDCD patients. The pilot study in 10 PDCD families will test the feasibility of the survey instrument and refine it as needed for its eventual use in a planned Phase III trial of dichloroacetate (DCA). If the trial shows DCA is found safe and effective, it could lead to this drug being designated as the first FDA-approved therapy for PDCD.

Dr. Atif Towheed, Ph.D.
Department of Pathology and Laboratory Medicine
Children’s Hospital of Philadelphia
Grant Award –  $70,000

“Allotopic RNA Rescue of LHON Mouse Model.”
The goal of Dr. Towheed’s work is to develop a novel gene therapy strategy for the treatment of Leber hereditary optic neuropathy (LHON) utilizing a mouse model developed in the labs of Dr. Douglas C. Wallace. If this therapeutic approach is successful it could inhibit the onset of the optic nerve pathology.

Sara M. Nowinski, Ph.D.
Department of Biochemistry
University of Utah
Grant Award – $70,000

“Characterizing the Function of the Atypical Mitochondrial Kinase ADCK3.”

The studies in Dr. Nowinski’s grant will improve the understanding of ADCK3 function in the synthesis of coenzyme Q and cerebellar ataxia. Additionally, better treatment strategies for mitochondrial disease could be developed in the future if new roles for ADCK3 are identified.

Anu Suomalainen Wartiovaara MD, Ph.D.
University of Helsinki, Finland.
Grant Award – $100,000

“Vitamins B as Therapy for Disorders with mtDNA Instability.” 

Dr. Suomalainen Wartiovaara will utilize a mouse model to build upon preliminary results indicating that vitamins B, especially B3 (Niacin) play key metabolism regulatory roles in patients with mitochondrial myopathies. Pre-clinical data generated in mice will inform the creation of a follow-up human clinical trial on the impact of Niacin supplementation for the alleviation of symptoms due to mitochondrial disease.
Project Descriptions on this webpage are provided by Steven G. Bassett, PhD

2014 Funded Projects

Hubert Smeets, Ph.D.
Department of Genetics and Cell Biology
Maastricht University, The Netherlands
Grant Award Amount – $25,000

Dr. Smeet’s project is entitled “Development of an autologous myogenic stem cell therapy for carriers of a heteroplasmic mtDNA mutation, a proof of principle study.” Dr. Smeets  has developed a process using transplantation of a patient’s own muscle stem cells that have been freed of mitochondrial DNA mutations. The resulting formation of normal muscle fibers promises to set the stage for significant new therapies for mitochondrial disease.

Carlos Moraes, Ph.D.
Department of Neurology
University of Miami Miller School of Medicine
Grant Award Amount – $120,000

Dr. Moraes project is entitled   “Developing specific mitochondrial nucleases to eliminate mutant mtDNA.”  Dr. Moraes has developed a process for removing disease-causing mitochondrial DNA mutations from affected mitochondria.  Extension of this research seems likely to lead to the development of gene therapies for human mitochondrial disease.

Michael James Bell, M.D.
University of Pittsburgh
Grant Award Amount – $25,000

Dr. Bell’s project is entitled “Improving CNS delivery of brain antioxidants after acute metabolic decompensation in mitochondrial disease.” Dr. Bell will investigate a combination of two FDA-approved drugs for their effectiveness in treating children and young adults with Leigh’s Syndrome. This work has the potential to improve brain function in patients with a mitochondrial disease for which there are currently no proven treatments.

Francisca Diaz, Ph.D.
Department of Neurology
University of Miami Miller School of Medicine
Grant Award Amount – $80,000

Dr. Diaz’s project is entitled  “Modulation of GSK3 activity to maintain neuronal survival in complex IV deficient mouse.” Dr. Diaz is using a much studied mouse model in which a mitochondrial respiratory enzyme has been deactivated in nerve cells.  She will study the effectiveness of modulating glucose metabolism as a treatment for these mice, with the potential for extending this therapy to human mitochondrial disease patients.

Scot Leary, Ph.D.
Department of Biochemistry
University of Saskatchewan
Grant Award Amount – $120,000

Dr. Leary’s project is entitled  “Targeted delivery of copper to mitochondria: investigating its therapeutic potential for the effective treatment of patients with mutations in SCO1 and SCO2.”  Dr. Leary is investigating therapies for copper delivery to mitochondria in patients with impaired ability to synthesize a vital mitochondrial respiratory enzyme that requires copper as a building block. This research could lead to the development of early intervention therapies for mitochondrial disease.

Erin Seifert, Ph.D.
Department of Pathology
Thomas Jefferson University
Grant Award Amount – $120,000

Dr. Seifert’s project is entitled “Pathogenesis of myopathies caused by mitochondrial phosphate carrier mutations.”  Dr. Seifert is studying mutations that severely affect the delivery of phosphate for ATP synthesis in the mitochondria of skeletal muscle and the heart. This foundational research will provide new insights into important mechanisms responsible for mitochondrial disease.


Chairman’s Award
James Stewart, Ph.D., Max Planck Institute for the Biology of Ageing, Cologne, Germany $90,000 for two years.

“Using mtDNA mutator mouse-derived lineages to generate mouse models of human mitochondrial diseases.”
The connections between genetic mutations and disease symptoms in human mitochondrial disease are not always clear. Two patients with the same mutation can have very different symptoms. More animal models of mitochondrial diseases are needed in order to address this question, allowing specific genetic and biochemical changes to be correlated with disease symptoms. Having strains of mice available that possess specific mutations of mitochondrial DNA, known to be associated with specific human mitochondrial disease will be especially useful.

Dr. Stewart and colleagues in Germany are conducting UMDF-funded research with mice that are prone to mutations in their mitochondrial DNA. They are able to use this system to generate families of mice that carry specific mitochondrial DNA mutations that lead to mitochondrial disease in the mice. Studying the biology of mice with specific mutations should significantly increase the number of available mouse models for human mitochondrial disease. Research with these animals will aid the development of new genetic models of human disease and also of new drug therapies. This will be especially important in finding treatments to improve skeletal muscle and heart function in mitochondrial disease patients.
Alberto Sanz-Monterro, Ph.D., University of Tampere, Tampere, Finland
$100,000 for two years

“A Genome-wide RNAi Screening to Identify New Genes Involved in Mitochondrial Diseases.”

Mitochondrial diseases are caused by numerous mutations of DNA residing in the nucleus or in the mitochondria themselves. And yet, many mitochondrial disease patients have not had a specific genetic mutation linked with their disease. This has only been accomplished for about half of all known mitochondrial diseases. Discovery of a specific mutation could help to identify the pathological changes that are occurring, leading to potential therapeutic interventions.

Dr. Sanz-Montero and colleagues at the University of Tampere in Finland are conducting UMDF-funded research using a well-understood fruit-fly model to discover previously unknown genetic defects that can cause mitochondrial disease. Locating genes similar to those in humans will provide insights into specific genetic processes responsible for human mitochondrial disease. Understanding the metabolic roles played by these genes will aid physicians in developing new treatments.

Gerald Shadel, Ph.D., Yale University
$90,000 for two years

“Characterization of disease-specific mitochondrial stress-signaling pathways in vivoas potential therapeutic targets for mitochondrial diseases.”

While it is known that certain genetic mutations are linked to specific mitochondrial disorders, the actual mechanisms and cell signaling pathways involved often remain unclear. The study of cell signaling involves discovering how cells regulate their function through specific communication channels. These channels can be disrupted during conditions of stress and disease. Gaining a clearer understanding of how signaling changes during the course of diseases provides important insight into how they might be treated.

Dr. Gerald Shadel and colleagues at Yale University are conducting UMDF-funded research to more fully characterize these signaling pathways. Employing genetic modifications in mice that impair the activity of specific mitochondrial components, they are studying how regulation of skeletal muscle, heart, and brain functions are affected. He will then extend these findings by looking for similar changes in cells derived from mitochondrial disease patients. This improved understanding of changes in cell signaling can lead to new treatment models for mitochondrial disease.
Rajesh Ambasudhan, Ph.D., Sanford-Burnham Medical Research Institute, La Jolla, California
$84,000 for two years

“A Human Reprogrammed-Cell Model of MELAS.”

MELAS is a severe mitochondrial disease that significantly impairs nervous system function, leading to recurring seizures and other disorders. While a number of mitochondrial DNA mutations have been linked to this condition, little research has been performed on the specific changes that occur in a MELAS patient’s affected cells. It has also been a challenge to develop effective therapies for the condition.

Dr. Rajesh Ambasudhan and colleagues are performing UMDF-funded research that involves obtaining skin cells from MELAS patients and reprograming them to become nerve cells that are grown in culture. No one could have predicted a generation ago that it would be possible to cause one kind of conversion of differentiated cell into another cell type. But this technology is being used in Dr. Ambasudhan’s lab today to provide important insights into mitochondrial disease. Once the skin cells have been converted to nerve cells in culture, they will have characteristics similar to the brain cells in a MELAS patient, with similar functional impairments. This procedure results in an unlimited supply of cells in various stages of the disease. Their use will enhance our understanding of mitochondrial dysfunction in MELAS, as well as other mitochondrial diseases, and will aid the development of treatments for these challenging disorders.
Natalie Niemi, Ph.D., University of Wisconsin, Madison, Wisconsin
$75,000 for two years

“Utilizing dynamically regulated phosphorylation as a means to modulate mitochondrial metabolism.”

Phosphorylation is a well-known mechanism for activating or inactivating enzymes in cells. Mitochondrial respiratory enzymes are at the heart of the energy metabolism that cells require for normal function. Abnormal changes in phosphorylation of these mitochondrial enzymes may be an important factor in mitochondrial disease.

Dr. Niemi and colleagues in the lab of Dr. David Pagliarini at the University of Wisconsin-Madison are conducting UMDF-funded research to study how phosphorylation is regulated in mitochondria. Her goal is to discover how impaired regulation contributes to the development of mitochondrial disease. This research could lead to new therapeutic options for mitochondrial disease patients.


2013 Clinical Fellowship Training Award

Amel Karaa, M.D., Harvard Medical School and Massachusetts General Hospital
Boston, MA
$70,000 for 1 year

“Hypogonadotropic hypogonadism in mitochondrial disease: prevalence, phenotypic heterogeneity and hormonal spectrum variations in a tertiary hospital cohort.”


2013 UMDF Grant Recipients 

Chairman’s Award

James Stewart, Ph.D., Max Planck Institute for the Biology of Ageing, Cologne, Germany  $90,000 for two years

“Using mtDNA mutator mouse-derived lineages to generate mouse models of human mitochondrial diseases.”

By working with mice that are prone to mitochondrial mutations, Dr. Stewart will develop new genetic models of human disease. Once established, these mouse models can be used for the development of new drug therapies.
Alberto Sanz-Monterro, Ph.D., University of Tampere, Tampere, Finland
$100,000 for two years

“A Genome-wide RNAi Screening to Identify New Genes Involved in Mitochondrial Diseases.”

Dr. Sanz-Monterro will use a well-understood fruit-fly model to discover previously unknown genetic defects that can cause mitochondrial disease. Many mitochondrial disease patients have not had a specific genetic mutation linked with their disease, and this research will help to fill that gap.
Rajesh Ambasudhan, Ph.D., Sanford-Burnham Medical Research Institute, La Jolla, California
$84,000 for two years

“A Human Reprogrammed-Cell Model of MELAS.”

Dr. Ambasudhan will obtain skin cells from MELAS patients and reprogram them as nerve cells to be grown in culture. This “disease-in-a-dish” model will be used to gain insights into mitochondrial dysfunction in MELAS and other mitochondrial diseases.
Natalie Niemi, Ph.D., University of Wisconsin, Madison, Wisconsin
$75,000 for two years

“Utilizing dynamically regulated phosphorylation as a means to modulate mitochondrial metabolism.”

Dr. Niemi will study mechanisms that activate enzymes in the mitochondria, with the goal of understanding how this regulation is impaired in mitochondrial disease. This could lead to new therapeutic options for mitochondrial disease patients.
Alicia Pickrell, Ph.D., National Institute of Neurological Disorders and Stroke, Bethesda, Maryland
$75,000 for two years

“Therapy for mitochondrial diseases: an investigation into the potential to stimulate Parkin-mediated mitophagy.”

Dr. Pickrell is studying the effects of the drug Rapamycin on the removal of abnormal mitochondria from cells in mice. This FDA-approved drug has the potential to selectively eliminate dysfunctional mitochondria in humans, helping to restore normal energy metabolism in mitochondrial disease patients.

2012 UMDF Grant Recipients

Carla Giordano, M.D., Ph.D.
University of Rome
2012 Chairman’s Award – $108,000

“Estrogen mediated regulation of mitochondrial biogenesis and functions: possible therapeutic implications for Leber’s hereditary optic neuropathy.”

Leber’s hereditary optic neuropathy (LHON) is the most common mitochondrial disease and causes rapid onset of blindness. Patients with the specific mitochondrial DNA mutations that cause LHON experience progressive loss of optic nerve function. This cranial nerve conducts information about what we see to the brain. The first symptom a patient notices is blurred vision, which eventually leads to severe visual impairment in one eye and is followed a couple of months later by vision loss in the other eye. Effective and reliable remedies have not been developed for the treatment or prevention of this disease. Since over half of individuals with one or more of the mutations that cause LHON do not actually have the disease and are asymptomatic, it might be possible to find therapies that would prevent its ultimate development.

Dr. Giordano and associates at the University of Rome are conducting UMDF-funded research using phytoestrogens with a cell model of LHON. Phytoestrogens are plant-derived compounds with estrogenic properties that could potentially enhance mitochondrial energy metabolism in the cells. Establishing that these compounds are effective in the cell model could lead to therapies that would not only treat patients with the disease but might prevent its development in unaffected carriers. The research group is also studying a population of female LHON patients to determine how the timing of disease onset in these women correlates with their reproductive status. Taken together, their findings could contribute to the development of therapies for a mitochondrial disease that has previously been untreatable.

William James Craigen, M.D., Ph.D.
Baylor College of Medicine

“Testing Gene Therapy in an Animal Model of Mitochondrial Respiratory Chain Disorders.”

The respiratory enzymes in the mitochondria are responsible for converting energy derived from food to ATP, a form of energy that is used by the cells. Manufacture of these enzymes follows a complex set of instructions contained in DNA found in both the cell’s nucleus and in the mitochondria themselves. Different mitochondrial diseases can be caused by DNA mutations that lead to an inability to make the enzymes necessary for normal ATP synthesis. Gene therapy, in which the correct DNA sequences have been provided to cells containing mutated DNA, has proven successful in the laboratory in reversing conditions such as Type I diabetes in mice. Does it hold promise for the treatment of mitochondrial disease as well?

Dr. Craigen and colleagues at Baylor College of Medicine are conducting UMDF-funded research to investigate gene therapy as a potential treatment for mitochondrial disease. They are working with a mouse model of a specific DNA mutation that impairs the function of a mitochondrial respiratory enzyme known as Complex I. They are developing procedures in which viruses will deliver the correct genetic information to these mice with defective mitochondria, in an attempt to greatly improve their energy metabolism. The viruses they are using are especially effective at targeting cells in the brain, heart, and skeletal muscle, all organs that can be severely impaired in some mitochondrial disease patients. Positive results could ultimately lead to the development of an effective gene therapy for mitochondrial disease.

Mariana G. Rosca, M.D.
Case Western Reserve University.
“Rescuing complex I defective mitochondria and target organs with methylene blue.”

She is developing a treatment that could bypass a defective mitochondrial enzyme, enhancing energy metabolism. Improving the performance of mitochondria in this way could address a defect that is responsible for a third of all mitochondrial disease cases.

Javier Torres-Torronteras, Ph.D.
Vall d’Hebron Research Institute, Barcelona, Spain.
“Preclinical studies for the gene therapy of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Long-term follow-up and use of adeno-associated viral vectors.”

As an idea first proposed over 40 years ago, gene therapy was fairly straightforward to envision but proved difficult to implement. It was suggested that viruses could be used to transfer DNA segments into the cells of individuals who were either missing specific sets of genetic information or had incorrect information. Viruses are known to operate by inserting their own DNA into the nuclei of human cells and then redirecting their activities towards making more viruses. Why not manufacture a virus containing DNA that could replace mutated DNA in cells, restoring their normal function? And why not use this therapy to treat mitochondrial diseases?

Dr. Torres-Torronteras and colleagues at his institution’s Laboratory of Mitochondrial Disorders are doing just this by conducting UMDF-funded research to investigate the effectiveness of a gene therapy developed in his lab for use in mice with mitochondrial disease. They are especially interested in developing treatments for MNGIE, a progressive degenerative disease of the gastrointestinal tract for whichthey have developed two virus-delivery models.This research will aid in determining the best approaches for treating this and other human mitochondrial diseases with gene therapy.

David A. Sinclair, Ph.D.
Harvard Medical School.
“Ultra-high-throughput screening for mitochondrial enhancers as novel targets for treating mitochondrial diseases.”

The variety of symptoms experienced by mitochondrial disease patients have in common a decreased capacity to make energy available to their cells in the form of ATP. Low cellular energy levels can seriously impair function in a number of organ systems, notably the musculoskeletal and nervous systems. Gaining detailed insights into how mitochondrial energy production is regulated in these organs will likely lead to important new treatments that could restore ATP synthesis in patients to more normal levels. This is a complex topic that researchers are investigating in both healthy individuals and patients. Regulation of the synthesis of mitochondrial membranes, the dynamics of how mitochondria are distributed throughout the cell, the rates of mitochondrial fusion and fission, and factors that promote either the manufacture or breakdown of mitochondria are all promising areas of research.

Dr. Sinclair and colleagues at Harvard Medical School are conducting UMDF-funded research togain a wide-ranging view of how mitochondrial energy metabolism is regulated. They are currently screening over 15,000 genes for their ability to enhance production of ATP. Understanding how these genes regulate energy metabolism will prove essential in developing new approaches to the treatment of mitochondrial disease. His lab is also evaluating thepotential of a large number of molecules to enhance energy metabolism in cell culture models of certain mitochondrial diseases, such assuch as LHON and MELAS.This large-scale approach could lead to the discovery of new and effective treatments for these and other forms of mitochondrial disease.
Nuno Raimundo, Ph.D.
Yale University School of Medicine.
“Mechanisms and treatment of mitochondrial deafness.”


Aminoglycosides are powerful antibiotics that are used successfully to treat complex infections that might not respond to other more commonly prescribed antibiotics. Unfortunately, a serious side effect of these drugs is the potential to cause hearing impairment due to their ototoxic properties. Ototoxicity can result in destruction of the hair cells in the inner ear that are responsible for hearing, leading to irreversible deafness. Certain individuals possess a mitochondrial DNA mutation that makes them more susceptible to this drug-induced deafness.

Dr. Raimundo and colleagues at Yale University School of Medicine have developed a mouse model with a mitochondrial mutation that reproduces the symptoms and pathophysiology of aminoglycoside-induced deafness, causing the same progressive hearing loss experienced by humans. They are conducting UMDF-funded research with these animals to test potential therapies that might prevent or lessen hearing loss. In one part of the project, animal diets are supplemented with various antioxidant compounds, such as alpha-lipoic acid and coenzyme Q10, with follow-up assessment of hearing after several months of treatment. The development of effective therapies for this condition would not only help prevent hearing loss in patients with the mitochondrial mutation, but could also provide fundamental insights into the pathological mechanisms of other mitochondrial diseases.


 2011 UMDF Grant Recipients

Brett Kaufman, PhD
Department of Animal Biology University of Pennsylvania

2011 Chairman’s Award – $120,000
“Regulatory mechanisms governing TFAM-mediated mtDNA copy number control”

Mitochondrial DNA contains the information for making several components of the respiratory enzymes in mitochondria. Normal function of these enzymes is necessary for mitochondria to make ATP available to cells for energy-requiring processes. While normal mitochondria contain a few dozen copies of mtDNA, many mitochondrial diseases result from an abnormally low number of mtDNA copies, through a process known as depletion. Mitochondrial transcription factor A (TFAM) is a gene that controls transcription of mtDNA and regulates the number of mtDNA copies in mitochondria. It has been suggested that increased activity of TFAM may have a protective effect in certain diseases.

Using UMDF-provided research funds, Dr. Kaufman and co-workers are researching the regulation of TFAM to acquire insights into how it maintains the mtDNA copy number. Perhaps TFAM can be stimulated to augment the number of mtDNA copies in organs affected by mitochondrial disease. His research could lead to therapies that would increase the number of copies of normal mitochondrial DNA in patients with specific types of mitochondrial disease.

Nicola Brunetti-Pierri,  MD
Telethon Institute of Genetics and Medicine
Fondazione Telethon,
Rome, Italy

2011 Chairman’s Award – $120,000
“Therapeutic Interventions for Pyruvate Dehydrogenase Deficiency.”

A key step in mitochondrial energy metabolism involves the three-carbon molecule known as pyruvate. The mitochondrial enzyme pyruvate deydrogenase complex (PDHC) plays an important role in the multi-step process of deriving energy from the food that we eat and ultimately transferring it to ATP. Impaired function or lack of PDHC results in conversion of unmetabolized pyruvate to lactic acid. The resultant lactic acidemia in turn can cause a variety of progressive neurological disorders. The prognosis for individuals with PDHC deficiency is poor and effective treatments are not available.
Dr. Brunetti-Pierri and co-workers are conducting UMDF-funded research to investigate the drug phenylbuturate as a treatment with the potential for enhancing the activity of the remaining PDHC in mitochondria deficient in the enzyme. Developing safe and effective treatments for PDHC deficiency could enhance ATP production and diminish lactic acid buildup in some mitochondrial disease patients

Miguel Garcia-Diaz, PhD
Department of Pharmacological Sciences
Stony Brook University, New York

Grant Award $100,000

“Deficiencies of tRNA maturation and the pathogenesis of mitochondrial diseases.”

Manufacture of the enzymes responsible for energy metabolism in mitochondria relies upon specific transfer RNAs (tRNAs) made by the mitochondria themselves. Mitochondrial tRNAs are responsible for delivering the amino acids used as building blocks for ATP-producing respiratory enzymes. Genetic mutations in mitochondrial DNA can adversely affect the assembly of these enzymes. Mutations impacting the synthesis of just one mitochondrial tRNA cause the majority of the cases of the mitochondrial disease MELAS, impairing the ability of mitochondria in multiple organs to make ATP.

Dr. Garcia-Diaz and colleagues are conducting UMDF-funded research to study the production of mitochondrial tRNAs. Because these molecules play an essential role in the synthesis of the energy-producing enzymes in mitochondria, this research will provide fundamental insight into pathological processes responsible for mitochondrial disease.

His research could lead to therapies that would increase the number of copies of normal mitochondrial DNA in patients with specific types of mitochondrial disease.

Ying Dai, MD, PhD
Department of Neurology
Beth Israel Deaconess Medical Center, Boston, MA

2011 Grant Award – $80,000

“Driving Selection Against Heteroplasmic Mitochondrial DNA Mutations by Enhancing Mitophagy.”

While most of the genetic information required for manufacture of a cell’s mitochondria is found in the DNA of the cell’s nucleus, a small portion of that information is contained in the mitochondria themselves. Mitochondrial DNA (mtDNA) has a high mutation rate and only a single enzyme, polymerase-gamma (POLG), is available to make the necessary repairs. Mutations in POLG can impair its ability to mend damaged mtDNA, leading to accumulation of mtDNA mutations, deletions and depletion that account for a significant number of mitochondrial diseases.

Dr. Ying Dai and colleagues are conducting UMDF-funded research directed towards developing a mechanism whereby mitochondria with abnormal mutated mtDNA could be eliminated from cells, with the goal of restoring normal function. Mitophagy is a cellular process in which defective mitochondria are degraded. Their goal is to develop a means of stimulating mitophagy in their research model in order to cause preferential elimination of mitochondria harboring high levels of the mtDNA mutation due to defective POLG. This could potentially lead to therapies that would restore normal energy metabolism in mitochondrial disease patients.
Cornelius Franciscus Boerkoel, MD, PhD
Department of Medical Genetics, University of British Columbia

2010 Research Award: $130,348

“Spinocerebellar ataxia with axonal neuropathy: defining the mitochondrial component.”
Ataxia, a general term for loss of muscle coordination during voluntary movements, can have numerous causes, either temporary or permanent. An inherited disease that progressively worsens over time, spinocerebellar ataxia results in part from degeneration of the cerebellum, a brain region that functions behind the scenes to ensure that the muscles of the arms and legs are working together harmoniously. Because neurons in the cerebellum and other brain regions are lost, the patient experiences increasing clumsiness and unsteadiness.

Dr. Boekoel and associates are conducting a UMDF-funded investigation of the role played by a mutated mitochondrial DNA-repair enzyme in the development of the progressive loss of coordination and mobility in patients with a specific type of spinocerebellar ataxia. In a related project, they are also assess the effectiveness of antioxidant therapy in reversing the effects of the enzyme mutation linked to the disease.

Robert E. Jensen, PhD
Department of Cell Biology, Johns Hopkins University

2010 Research Award: $110,000

“DMCA and Barth Syndromes- similar diseases caused by defects in mitochondrial protein import?”

The mitochondrial disease known as Barth Syndrome diminishes the capacity of cardiac (heart) muscle to pump blood. Linked to abnormalities in cardiolipin, an important component of the mitochondrial inner membrane, the disease significantly impairs mitochondrial energy metabolism leading to a seriously weakened and dilated heart. DCMA (dilated cardiomyopathy with ataxia) has a similar effect on heart function and yet seems to have a completely different mechanism, impaired transport of a mitochondrial protein. The two diseases result in similar types of cardiac dysfunction resulting from abnormal mitochondrial metabolism and yet apparently have different causes.

In a UMDF-funded project, Dr. Jensen and associates are comparing the cellular disease mechanisms of Barth Syndrome and DCMA. Discovering the mitochondrial defects that the two diseases have in common will provide important insights into metabolic impairments that may be common to a number of mitochondrial diseases.

Ingrid Tein, MD

Division of Neurology, Hospital for Sick Children, Toronto, Canada

2010 Research Award: $75,000

“Pilot study to investigate the efficacy of L-arginine therapy on endothelium-dependent vasodilation & mitochondrial metabolism in MELAS syndrome.”

MELAS is a mitochondrial disease that, among other effects, severely compromises function of the nervous system. The “stroke-like episodes” experienced by patients can lead to severe headaches, seizures, and temporary weakness on one side of the body. A possible cause of these devastating symptoms is a sudden decrease in blood flow to the brain. Development of therapies to restore blood flow could greatly improve symptomatic treatment of this disease.

Dr. Tein and associates are conducting a UMDF-funded investigation to determine the underlying vascular pathology of the stroke-like episodes associated with MELAS. Using non-invasive imaging, she is developing a procedure for detecting impaired blood flow to specific brain regions. This technique will then be employed to determine whether brain circulation improves in patients given oral doses of the amino acid L-arginine, which is known to dilate blood vessels, increasing blood flow to the brain.

Christoph Handschin
University of Basel, Switzerland

2009 Research Award: $130,000

“Mitochondrial dysfunction, exercise intolerance and myopathy in skeletal muscle-specific PGC-1α-deficient mice.”
Making the genetic information contained in DNA available for use by cells requires an initial step called transcription, in which a molecule known as RNA is synthesized. RNA embodies the original DNA message in a form used by cells to direct the manufacture of proteins. PGC-1α is a regulatory molecule known to activate synthesis of RNA that will lead to proteins important for normal energy metabolism in skeletal muscle. This transcriptional activator promotes the production of proteins that enable muscle cells to respond to exercise by increasing their capacity for aerobic ATP synthesis.
Dr. Handschin and colleagues at the University of Basel in Switzerland are conducting UMDF-funded research with mice that are deficient in PGC-1α. These mice experience skeletal muscle dysfunction similar to that associated with mitochondrial diseases in humans because the mice are missing this important regulator of the formation and activity of mitochondria. Studying the ways in which muscle function is impaired when PGC-1α occurs in abnormally low levels will provide insight into its potential as a target for treatment of mitochondrial disease.

Michael P. Murphy
Medical Research Council, Dunn Human Nutrition Unit, Cambridge, UK

2009 Research Award: $110,000

“Development of a Novel Mass Spectrometric Approach to Measure Mitochondrial Oxidative Damage In Vivo.”
Mitochondria contain the enzymatic machinery for production of ATP in the presence of oxygen, the method that makes the largest amount of ATP available to cells. This aerobic energy metabolism comes at a price, however, because it also results in the generation of reactive oxygen species (ROS). Free radicals and other ROS damage cells by removing electrons from cell components. Mitochondria with impaired energy systems do not use oxygen efficiently and produce excessive amounts of ROS, which can then further damage the mitochondria.
Dr. Murphy and his colleagues are conducting UMDF-funded research to develop a method for measuring in living organisms the extent to which their mitochondria have been damaged by ROS. This vicious cycle, in which already impaired mitochondria cannot use all of the oxygen presented to them further harm themselves by producing ROS, is a hallmark of mitochondrial disease’s progressive nature. Procedures developed in Dr. Murphy’s lab could ultimately be used to monitor ongoing changes in the function of mitochondria in mitochondrial disease patients and aid in assessing the effectiveness of potential therapies.

Patrick H. O’Farrell
University of California-San Francisco

2009 Research Award: $81,857

“Selecting for Transformation with Mitochondrial DNA.”
Mitochondrial diseases such as Leber’s hereditary optic neuropathy and Kearns-Sayre syndrome are caused by defects in mitochondrial DNA (mtDNA). The genetic information contained in mtDNA provides directions for the manufacture of important components of the ATP-generating machinery of the mitochondria. When this information is defective, it can significantly impair the ability of cells to convert energy obtained from food into the ATP that they need to function. Once researchers find a reliable method for inserting the correct DNA sequences into the mitochondria of mitochondrial disease patients, an important goal towards finding a cure will have been reached.
Dr. Patrick O’Farrell and colleagues at UC-San Diego are conducting UMDF-funded research to develop procedures for introducing DNA into the mitochondria of fruit flies. They will also be able to isolate flies for whom the mtDNA introduction was successful so that they can be studied. This research will produce reliable animal models for investigations of a variety of mitochondrial diseases and could also help guide attempts to repair the mitochondrial genome in humans.

Sarika Srivastava
Harvard Medical School

2009 Research Award: $90,804

“Investigating the Rescue of Mitochondrial Dysfunction by SIRT1 and Calorie Restriction.”
Aerobic metabolism in mitochondria is the primary source of ATP, the molecule used by cells to power the numerous activities necessary for life. Because mitochondrial disease patients have a diminished capacity to produce ATP, development of treatments to enhance energy metabolism in mitochondria would be welcome. Such treatments could also potentially forestall human aging, which is associated with declining mitochondrial function. Recent research has focused on a gene known as SIRT1, which may be an important regulator of energy balance in living systems. Factors that enhance SIRT1 activity may help to restore lost mitochondrial function associated with aging and certain diseases.
Dr. Sarika Srivastava and colleagues in the Department of Pathology at Harvard Medical School are conducting UMDF-funded research to study SIRT1 activity. Their goal is to find a way to rescue dysfunctional mitochondria in mice as well as in a cellular model for the mitochondrial disease known as MELAS. Research with these models in which SIRT1 activity is modulated will help with the development of therapies which could enhance mitochondrial energy metabolism.

Rebeca Acin-Peres, PhD
Weill Medical College, Cornell University

2008 Research Award: $99,990

“OXPHOS modulation by mitochondrial protein phosphorylation in mtDNA mutant cells.”
The underlying cause of many mitochondrial disease symptoms is a greatly reduced capacity for production of ATP, the energy molecule of cells. One cause of this impaired energy metabolism is the incorrect information provided by mutated mitochondrial DNA, which prevents the cellular machinery responsible for oxidative phosphorylation from functioning properly. This results in a diminished ability to produce ATP.
Dr. Rebeca Acin-Perez of Weill Medical College at Cornell University is conducting UMDF-funded research to determine how mutations in mitochondrial DNA affect the regulation of oxidative phosphorylation. Previous studies suggested that the cyclic AMP regulatory pathway, known to control many other aspects of cell function, is also involved in the regulation of mitochondrial ATP synthesis. Her research project will investigate how mitochondrial DNA mutations affect this regulatory system and contribute to mitochondrial disease. This may lead to new drug therapy strategies to boost ATP production in abnormal mitochondria.

Elizabeth Anne Amiott, PhD
Unitersity of Utah

2008 Research Award: $98,300

“Mitochondrial Fusion Defects in Neurological Disease.”
Mitochondria are dynamic organelles that can split into the small, bean-shaped structures usually depicted in biology textbooks, or fuse together to form a more elongated network. Fusion allows normal mitochondria to merge with others containing damaged DNA or proteins in order to restore normal ATP production. This is apparently an important process because certain nervous, muscular, and visual abnormalities have been linked to mutations in mitochondrial fusion genes.
Dr. Elizabeth Anne Amiott and colleagues in the Department of Biochemistry at the University of Utah are conducting UMDF-funded research to further our understanding of the role played by mitochondrial fusion in normal cell metabolism and in disease. Using yeast as a research model, she is investigating fundamental aspects of the regulation of fusion that are applicable to the development of defective nerve function in humans. This is significant because some severe neurological diseases may be helped by treatments that enhance mitochondrial fusion.

Brendan James Battersby, PhD
University of Helsinki

2008 Research Award: $150,000

“Identifying genetic modifiers of tissue-specific mitochondrial DNA segregation.”
Human cells contain many mitochondria, each with its own set of genetic information in the form of DNA. A given cell may possess both mitochondria with normal DNA and others with a mutated abnormal information set. This condition is known as heteroplasmy. Two fundamental questions arise from our understanding of heteroplasmy: Are cells able to distinguish between the two types of mitochondria that they carry? Would it be possible to encourage cells to retain the normal mitochondria while somehow reducing the number of mitochondria with mutated DNA?
Dr. Brendan Battersby and colleagues at the Research Program of Molecular Neurology of the University of Helsinki are looking for answers to these questions by conducting a UMDF-funded research project. Their goal is to identify genes in mice that control a cell’s ability to recognize mitochondria that contain abnormal DNA and thus have an impaired ability to produce ATP. If a therapy could be developed that encouraged cells to selectively retain mitochondria with normal DNA while eliminating abnormal mitochondria, it would be of great benefit to mitochondrial disease patients.

Bridget Elizabeth Bax, PhD
St. George’s University of London

2008 Research Award: $116,428

“Evaluation of the efficacy and safety of erythrocyte encapsulated thymidine phosphorylase therapy in two patients with mitochondrial neurogastrointestional encephalomyopathy.”
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an extremely rare inherited form of mitochondrial disease that causes severe damage to the digestive, nervous, and muscular systems. Despite its rarity, research on this disease has provided insight into the dynamics of mitochondrial DNA synthesis. This is because the disease results from the absence of an enzyme called thymidine phosphorylase and loss of this enzyme causes an imbalance of DNA building blocks in the cells. This imbalance then leads to mitochondrial dysfunction because of defective mitochondrial DNA. Also, the accumulation of excess thymidine in the blood has toxic effects on the patients.
Dr. Bridgett Bax and her colleagues at St. George’s University of London are conducting clinical research funded by the UMDF to investigate potential therapies for MNGIE. They are specifically interested in developing a form of enzyme replacement therapy for these patients. Using a novel approach called erythrocyte encapsulation they are supplying the missing enzyme to patients through use of their own treated red blood cells. This is significant because there is currently no means of ridding patients of the toxic compounds that accumulate because of the absence of thymidine phophorylase.

Deepa Vinay Dabir, PhD
University of California-Los Angeles

2008 Research Award: $100,000

“Study of redox regulated pathways in the mitochondrion.”
The manufacture of mitochondria inside of cells, called mitochondrial biogenesis, is a complex process that requires the synthesis of a large number of functional and structural proteins. While mitochondria contain their own DNA, most of the genetic directions for manufacturing these mitochondrial proteins are contained in the nucleus of the cell. After the nuclear DNA has directed the manufacture of the proteins, they must then be imported into the mitochondria through specialized transport mechanisms. Much remains unknown about how this process works.
Dr. Deepa Vinay Dabir and colleagues at the University of California-Los Angeles are studying a mutated mitochondrial import protein connected with a type of deafness. Her research with yeast is directly applicable to humans because human mitochondria use the same import protein. The importance of this research is two-fold in that it will provide fundamental insights into mitochondrial biogenesis and could also lead to the use of this pathway for introduction of therapeutic agents into mitochondria for effective treatment of mitochondrial disease. Per Dr. Dabir’s request, this grant was terminated July 2009 due to subsequently receiving a larger NIH grant that overlapped with her UMDF grant.

Leo Joseph Pallanck, PhD
University of Washington

2008 Research Award: $125,000

“The role of the PINK1/Parkin pathway in mitochondrial integrity.”
He will investigate the regulation of splitting and combining of mitochondria in cells. This is important because specific diseases are linked to defects in mitochondrial processing, especially an inability to eliminate abnormal mitochondria.

Beverly A. Rzigalinski, PhD
Virginia College of Osteopathic Medicine

2008 Research Award: $101,569

“Cerium oxide nanoparticles in the treatment of mitochondrial diseases.”
Reactive oxygen species (ROS) are normal byproducts of aerobic (oxygen-requiring) energy metabolism in the human body. Free radicals are a type of ROS that are produced in mitochondria during their synthesis of ATP, the energy used by cells for life processes. While ROS have an important role in cell signaling, they can also damage mitochondria and the cells that contain them if they are produced in excess. Anti-oxidant compounds, produced both internally and available in our diets from plant-based foods, are known as free radical scavengers. They help to deactivate free radicals before they can damage the mitochondria. While mitochondrial disease patients are often encouraged to take regular doses of anti-oxidant vitamins that are available over the counter, there is still a need for more potent therapeutic agents.
Dr. Beverly Rzigalinski and her colleagues at the Virginia College of Osteopathic Medicine are conducting UMDF-funded research on a promising new class of free radical scavengers that have a potent anti-oxidant effect. They are evaluating the beneficial effects of cerium oxide nanoparticles on mitochondrial function of cells in both tissue cultures and a fruit-fly model used to study mitochondrial disease. This research promises to develop new means of preventing the free-radical oxidative stress that is a significant cause of mitochondrial dysfunction.

Timothy E. Shutt, PhD
Yale University School of Medicine

2008 Research Award: $99,998

“Selective alteration of mitochondrial gene expression via modulation of the dual-function h-mtTFB1 and B2 factors as a potential therapy for mitochondrial diseases.”
Expression of the genetic information contained in mitochondria requires copying DNA into RNA through a process called transcription. This RNA message is then “translated” into specific proteins that mitochondria must have in order to provide ATP for the energy needs of cells. In some mitochondrial diseases, there is a connection between impaired protein translation in the mitochondria and the pathology of the disease. When these mitochondrial proteins are improperly formed, a severe energy deficit may result.
Dr. Timothy Shutt and colleagues at Yale University School of Medicine have played a major role in identifying two factors that regulate translation in mitochondria. They are currently conducting UMDF-funded research that will find ways to increasing the activity of regulatory factors that promote mitochondrial protein synthesis. This is important because it may point to new therapies for enhancing mitochondrial energy metabolism in patients with mitochondrial disease.

Stuart Smith, PhD, DSc
Children’s Hospital & Research Institute at Oakland

2008 Research Award: $128,563

“Utilization of knockout mouse models to elucidate the importance of the de novo mitochondrial fatty acid synthesis pathway in mitochondrial function.”
Fatty acids are molecules that humans obtain from food and also synthesize in their bodies. As a potential fuel source, they play a vital role in the body’s energy metabolism and provide important structural molecules used to build cell membranes. One particular fatty acid is also the precursor for the formation of lipoyl moieties that are essential for the functioning of several key mitochondrial enzymes. The details of fatty acid formation inside the fluid compartment of the cell, called the cytosol, are well established. But details of the mitochondrial pathway and its importance to mitochondrial function are poorly understood.
Dr. Stuart Smith and his colleagues at Children’s Hospital & Research Center at Oakland are conducting UMDF-funded research to develop mouse models in which functionality of the pathway is compromised. Characterization of these mice will reveal the metabolic consequences that result from defects in this pathway and will provide a framework for identifying and understanding the cause of similar defects in the human population.

Sion L. Williams, PhD
University of Miami

2008 Research Award: $99,998

“Evaluation of novel zinc finger nucleases as a means to target m.3243A>G in vivo.”
DNA is composed of four different building blocks called nucleotides which are arranged in sequence to create genes. Bacteria contain enzymes that cut DNA at specific nucleotide sequences called recognition sites. These enzymes can be used to differentiate normal and mutant genes because sometimes a mutation creates a new recognition site where the DNA can be cut. In living cells if cuts are made in mitochondrial DNA it is digested and disappears. If enzymes could be modified so that mutations in mitochondrial DNA acted as their recognition sites it would be possible to stimulate cells to digest mutant mitochondrial DNA and leave normal mitochondrial DNA untouched.
Dr. Sion Williams and his colleagues at the University of Miami are conducting UMDF-funded research into the effectiveness of modified enzymes designed to selectively cut mutant mitochondrial DNA in living cells. This is important because even small increases in the ratio of normal to mutant mitochondrial DNA in tissues like muscle can improve the wellbeing of patients with mitochondrial disease.

Paul A. Cobine, Ph.D.,
University of Utah

2007 Research Award: $99,000

“Defining copper homeostasis in the mitochondria: Recruitment and distribution of copper for the assembly of cuproenzymes.”
Mitochondrial enzymes regulate the energy-providing reactions that are necessary for normal cell function in the human body. The goal of this sequence of oxidation-reduction reactions, whereby electrons are transferred along a series of enzymes, is to produce a continuous supply of the energy molecule adenosine triphosphate (ATP).The mitochondrial enzymes that catalyze ATP synthesis are arranged in clusters known as complexes. Many of these enzymes have functional components made from elements such as iron, sulfur, or copper. Specific components of the mitochondrial enzyme complex called cytochrome c oxidase contain two copper atoms that are important in the electron transport process linked to ATP production.

Dr. Paul Cobine and colleagues at the University of Utah are investigating the mechanisms that make copper available for the manufacture of cytochrome c oxidase in cells from yeast and from humans. Little is known about the mechanisms that lead to a steady supply of copper for manufacture of new enzymes. This UMDF-funded research is significant because malfunction of cytochrome c oxidase is a common cause of mitochondrial diseases and improper copper metabolism may be a contributing factor.

Brett Graham, M.D., Ph.D.
Baylor College of Medicine

2007 Research Award: $111,779

“Mutant Complex I in Drosophila melanogaster: a Novel Genetic Model for Mitochondrial Disease.”
To derive the maximum amount of energy available from the food we eat, a series of very carefully controlled chemical reactions must occur inside the mitochondria. These cell organelles contain a variety of enzymes that are involved in transferring this food energy to adenosine triphosphate (ATP). The high-energy molecule ATP is used throughout the body to fuel the numerous energy-requiring activities necessary for life. The largest amount of ATP becomes available as a result of reactions that occur along the three enzyme complexes of the mitochondria’s respiratory chain. The first of these (complex I) is often found to be deficient in patients with mitochondrial disease.

Dr. Brett Graham and colleagues at Baylor are conducting UMDF-funded research that will lead to the development of a fruit fly model for the study of mitochondrial disease due to abnormalities of complex I. The goal is to screen for genes responsible for abnormalities related to complex I deficiency, thus pointing to potential therapies for neuromuscular disorders that result from mitochondrial malfunction. This is important because of the current lack of effective treatments for human mitochondrial disease due to complex I deficiency.

Orly Elpeleg, M.D.
Hadassah Hebrew University Medical Center, Jerusalem, Israel

2007 Research Award: $60,500

“Identification of novel genes associated with isolated complex I deficiency using whole genome mapping in small consanguineous families”
Energy in the form of ATP is made available to cells through an intricate series of chemical reactions. Mitochondria contain an important collection of enzymes that keep these reactions operating at a rapid rate. One such enzyme, Complex I, is the first in a series of enzymes referred to as the electron transport chain. It is a large molecule, with 45 subunits whose structures are specified by genes in both the nucleus and in the mitochondria themselves. Because of its complicated structure, it is not surprising that Complex I is the most common site for mutations that lead to mitochondrial disorders. (I am not sure that’s the reason, but it is indeed the most common defect) Perhaps as many as one third of mitochondrial disorders are due to some type of Complex I malfunction.

Using research funds from UMDF, Dr. Elpeleg and her colleagues at Hadassah Medical Center are employing genetic mapping techniques to analyze the entire DNA information set, the human genome, in samples obtained from a large number of patients with infantile and early childhood onset neurodegenerative disorders.  Their goal is to identify previously unknown genetic abnormalities that prevent the normal assembly of the Complex I enzyme in mitochondria. Information gained from this research will extend our understanding of how this complicated component of the electron transport chain is constructed. It could also lead to insights about the pathology of many different mitochondrial diseases that have Complex I deficiencies in common.

Konstantin Khrapko, Ph.D
Beth Israel Deaconess Medical Center, Boston, MA

2007 Research Award: $110,000

“Development of high throughput mtDNA sequencing for mutation detection and heteroplasmy assessment.”
Enzymes are functional molecules manufactured by cells that greatly increase the rate at which biochemical reactions occur. In mitochondria, enzyme complexes that maintain a high rate of ATP production are manufactured according to the genetic code contained in DNA. Most of this DNA is present in the nucleus, but some is actually inside the mitochondria themselves. Mitochondrial disease can result from faulty genetic directions in mutated mitochondrial DNA. But how common are these mutations in the general population and how many mutations have yet to be identified?

Dr. Khrapko and colleagues at Beth Israel Deaconess Medical Center are conducting UMDF-funded research to develop a rapid and efficient method for processing multiple mitochondrial DNA samples in order to search for mutations. High-throughput assays are powerful tools for analyzing large numbers of samples in a relatively short period of time. Sequencing the entire mitochondrial genome from a number of individuals will not only aid in screening for mutations, but will also assess the level of heteroplasmy, in which some of the mitochondria contain mutations while others are normal. This important research has the potential to develop a cost-effective means of screening for mitochondrial disorders.

Patrice Hamel, Ph.D.
Ohio State University

2007 Research Award: $114,189

“Molecular genetic dissection of mitochondrial complex I assembly”
All mitochondrial diseases are characterized by an impaired ability to provide the energy, in the form of ATP, that is necessary for normal life activities. It has been known for decades that a series of enzymes in the mitochondria are essential for keeping ATP available at a constant rate. These enzyme complexes, known collectively as the electron transport chain, are numbered I through IV and are located within the inner membrane region of mitochondria. Humans have this chain of respiratory enzymes in common with other oxygen-dependent organisms, and yet much of what we know about it comes from studies with organisms other than humans. Algae contain mitochondria and thus provide an easily manipulated model for the study of mitochondrial genetics.

Dr. Patrice Hamel and his colleagues at Ohio State are conducting UMDF-funded research with algae to investigate the manufacture of the key electron transport chain enzyme Complex I. This highly complicated molecule has almost four dozen subunits and is the most common site for mutations that lead to mitochondrial disorders in humans. In many cases the genetic defects causing improper assembly of Complex I in human mitochondria have not been identified and thus Dr. Hamel’s research with algae will help to identify many of these. This could then lead to a clearer understanding of the underlying genetic abnormalities that result in human mitochondrial disease.

Michael Paul King, Ph.D.
Thomas Jefferson University, Philadelphia, PA

2007 Research Award: $118,648

“Development of high throughput assays for mitochondrial respiratory chain function.”
Mitochondrial disorders can result in a wide variety of illnesses that differ greatly in terms of symptoms, severity, and age of onset. Yet, they all share the feature of a diminished capacity for cells to produce the energy molecule ATP under aerobic (oxygen-requiring) conditions. This process, called cellular respiration, occurs in mitochondria and is the major means through which the chemical energy in food is made available to the cells for all of the activities necessary for life. One strategy for developing an effective treatment for mitochondrial disease would entail discovering ways to enhance respiratory chain ATP synthesis.

Dr. King and his colleagues at Thomas Jefferson University are using UMDF-provided research funds to develop a rapid screening method that searches for chemicals that can improve mitochondrial respiratory chain function in treated cells. High-throughput assays are powerful tools for analyzing large numbers of samples in a relatively short period of time. Use of this technology will allow numerous different compounds with potential therapeutic properties to be evaluated. This is important because it is difficult to conduct studies assessing drug treatment effectiveness directly in mitochondrial disease patients, who differ significantly both in terms of symptoms and responsiveness to therapies. The automated assay method employed by Dr. King will allow for preliminary evaluation of drugs in a standardized fashion and hopefully identify drugs which could subsequently be tested on patients.

Paolo Pinton, Ph.D.
University of Ferrara, Italy

2007 Research Award: $86,250

“Mitochondrial calcium signaling and organelle dysfunction in mitochondrial diseases: molecular determinants and regulatory mechanisms.”
An important topic in the study of cell biology has to do with how cells respond to a changing environment in order to keep constant certain factors necessary for their survival. At the same time, the life spans of individual cells are determined by genes that will ultimately cause apoptosis (programmed cell death). Of course, cells can also die prematurely because of disease. Biologists are interested in how these different aspects of a cell’s existence are regulated. A key insight comes from the role that ionic calcium plays as a signal to activate specific processes within the cell. It is also known that build-up of calcium within mitochondria precedes the changes that result in cell death by apoptosis and also premature death due to damage by certain toxins.

Dr. Paolo Pinton and colleagues at the University of Ferrara are conducting UMDF-funded research to investigate calcium balance in mitochondria. This important fundamental research project will increase our understanding of how calcium functions as a mitochondrial regulatory molecule. Because changes in calcium concentration have been linked to certain mitochondrial diseases, it will also help to identify cellular disease mechanisms associated with mitochondrial disorders.

Mingdong Ren, Ph.D.
New York University School of Medicine

2007 Research Award: $157,450

“Genotype-Phenotype Correlation and Genetic Modifiers in Barth Syndrome.” Barth syndrome is a rare genetic disorder that causes generalized muscle weakness, affecting both the muscles of the heart and of the musculoskeletal system. The disease also prevents normal function of a specific population of immune system cells and has a high rate of infant mortality. The effects of Barth syndrome on various organs in the human body are due to impaired mitochondria, the energy-providing organelles found in most cells. Muscles and other tissues depend upon the ready availability of mitochondrial ATP in order to function normally. Barth’s patients are thus at a significant disadvantage because they cannot convert adequate amounts of energy from their food into ATP for use by their cells. Because there are only a few patients available for research at any time, it is necessary to use animal models for detailed study of this disease.

In a UMDF-funded project, Dr. Ren and colleagues at New York University are using fruit flies as a research model for the study of Barth syndrome. Discovery in these insects of genetic modifiers that affect the syndrome’s development will shed light on its pathology and could also point to potential therapies for other mitochondrial disorders.

Ann Saada, Ph.D.
Hadassah Hebrew University Medical Center

2007 Research Award: $98,340

“Mitochondrial DNA synthesis and Krebs (tricarboxylic acid) cycle: the succinyl-CoA synthase.”
By now, many people are aware that their DNA contains the genetic information required for the cells in their body to function normally. DNA is actually a code that spells out the structure of a cell’s proteins and most of this information is housed inside the cell’s nucleus. An additional level of complexity was added to the understanding of mitochondrial function when it was discovered that mitochondria also contain DNA. Mitochondria are the primary source of ATP, the high-energy molecule used by cells to carry out a variety of activities. How this organelle is produced in the cell when the genetic instructions for its manufacture are located in two separate cell compartments makes for a complex story. It was recently discovered that mitochondrial disease in some infants is actually due to mitochondrial DNA (mtDNA) depletion, progressive loss of the DNA normally present in their mitochondria. The effects of this depletion are widespread, impairing the function of multiple organs such as the brain, liver, and heart.

Dr. Saada and her colleagues at Hadassah – Hebrew University Medical Center are conducting UMDF-funded research using cells derived from patients with mtDNA depletion. Previous research linked a type of brain mitochondrial disease with mtDNA depletion due to a specific genetic mutation. Her goal is to understand the pathophysiology of this process and to move towards identifying methods for reversing it.

Ludivine Walter, Ph.D.
Cornell University, NY

2007 Research Award: $100,000

“Determination of the nuclear transcriptional responses that affect animal physiopathology upon impaired mitochondrial respiratory chain function.”
For over forty years, biological researchers have used the roundworm Caenorhabditis elegans as a model for understanding the genetic control of development. Its size (a little more than a millimeter in length) and rapid growth (less than four days to reach maturity) makes it an ideal organism for laboratory investigations in the fields of genetics, molecular biology, and neurobiology. Like humans, C. elegans relies upon mitochondria to supply most of its ATP for energy-requiring processes. Also similar to humans, specific mutations in this roundworm’s DNA have been linked with mitochondrial disorders.

Dr. Walter and her colleagues in the Department of Molecular Biology and Genetics at Cornell are conducting UMDF-funded research that is breaking new ground in characterizing how changes in gene expression in C. elegans result in abnormal mitochondrial energy metabolism. As with humans, impaired mitochondrial function can result in a diverse array of functional outcomes and disabilities. It is thus expected that this project will uncover underlying processes that are also at work in human mitochondrial disease.

Tina Wenz, Ph.D.
University of Miami

2007 Research Award: $94,481

“Increased mitochondrial biogenesis as therapy to mitochondrial myopathies.”
A large percentage of the energy that we derive from the food we eat is used up by our skeletal muscles. These organs have a high metabolic rate that requires a constant supply of ATP, the energy currency that we spend for the many activities necessary for life. Most of this ATP is made available by aerobic (oxygen-requiring) metabolism in mitochondria, which are present in large numbers in the muscles of normal individuals. It is not surprising, then, that patients with various mitochondrial disorders often experience severe muscle weakness and also fatigue easily. What can be done to increase the number of normal mitochondria in patients whose muscles are so starved for energy?

In a UMDF-funded project, Dr. Wenz and colleagues at the University of Miami are determining whether mice with a defective mitochondrial enzyme will improve when they are provided with a gene that increases the number of mitochondria in their muscle cells. These mice, which were developed in her lab, have a progressive disorder leading to greatly impaired muscle function. Investigations with this animal model will hopefully point towards an effective therapy. This is important because of the current scarcity of treatments for mitochondrial disease in humans.

Brian H. Robinson, PhD
Hospital for Sick Children, Canada

2006 Research Award: $125,000

“High throughput screening for mitochondrial enhancers”
The human brain constantly requires an amount of energy that is far out of proportion to its size. Any factor that decreases energy metabolism in the brain, such as impairment of the mitochondria’s capacity to produce ATP, would have severe consequences both on brain development and function. Drug treatment of neurological disorders is always a challenge because of the blood-brain barrier, the purpose of which is to protect the neurons, brain functional cells, from potential toxins in the blood. The problem with developing effective treatments for brain disorders is that many drugs which might prove effective are denied access into neurons by this barrier. Development of a drug that would stimulate mitochondria to produce ATP at a maximum rate and could also successfully cross into the brain to reach neurons possessing impaired mitochondria is an ongoing challenge.

Dr. Brian Robinson and his colleagues at the Metabolism Research Programme of the Hospital for Sick Children in Toronto are conducting UMDF-funded research to identify chemicals that can cross the blood-brain barrier for their ability to increase ATP production by mitochondria. They are using a cell-based assay allowing rapid screening of a large number of drugs that might enhance the synthesis of mitochondrial respiratory enzymes. This is important because the class of compounds being studied could readily cross into the brain to potentially treat serious neurological diseases in children.

Thomas W. O’Brien, PhD
University of Florida

2006 Research Award: $125,000

“Mitochondrial ribosomal proteins: candidate genes for mitochondrial disease”
A cell’s DNA is important because of the information it carries. This genetic code contains the directions for manufacturing proteins in the cell. The sequence of events that leads to the formation of these proteins begins with transcribing the DNA into messenger RNA (mRNA). Important organelles called ribosomes direct the subsequent translation of the mRNA code into proteins. If mitochondria are going to provide adequate amounts of energy, then their own ribosomes must function correctly to direct the continued replacement of ATP-producing enzymes. While evidence suggests that incorrectly formed ribosomes may lead to certain mitochondrial diseases, little is known about their components and how these ribosomal proteins contribute to the overall process of translating mRNA into enzymes required by the mitochondria.

Dr. Thomas O’Brien and colleagues at the University of Florida are conducting UMDF-funded research to further our understanding of the functional significance of a number of ribosomal proteins in mitochondria. This research is important because their lab is especially interested in identifying proteins associated with specific mitochondrial diseases.

Håkan Westerblad, MD, PhD
Karolinska Institute, Sweden

2006 Research Award: $122,720

“Mechanisms of muscle dysfunction studied in mouse models of mitochondrial myopathies”
It is well known that cells require the organelles called mitochondria to function normally so as to maintain a constant supply of energy. When a patient’s mitochondria are defective, organs needing large amounts of energy, such as skeletal muscle, are especially affected. Because both the maintenance of healthy muscles and the regulation of their contraction are so complex, the relationships between mitochondrial disease and muscle pathology are also likely to be complex. Obtaining a detailed picture of these disease mechanisms in humans is very difficult. What is needed is a means of linking specific mitochondrial defects with specific areas of muscle dysfunction in isolated muscles obtained from individuals with known mitochondrial defects.

Dr. Håkan Westerblad and colleagues at the Department of Physiology and Pharmacology of the Karolinska Institute have developed animal models that allow them to answer such questions. Conducting UMDF-funded research, they are comparing various aspects of function in muscle from normal mice and from mice with different types of mitochondrial defects. They are investigating regulation of muscle contraction, force generation by muscles, and factors that can lead to the death of individual muscle cells. The importance of this research lies in the detailed information that will be gained about exactly how abnormal mitochondria cause muscle dysfunction. Once information concerning specific disease mechanisms has been acquired, it should provide insight into promising treatment strategies.

Haya Lorberboum-Galski, PhD
Hebrew University of Jerusalem

2006 Research Award: $115,000

“Enzymereplacement therapy: A novel approach for treating a mitochondrial disease-LAD deficiency”
The many different medical conditions that are placed under the category “mitochondrial disease” have in common the disruption of one or more components of the energy “machinery” of the mitochondria. This machinery is made up of a number of enzymes that are crucial to the production of the energy molecule ATP. If even one of these enzymes is defective or absent, then ATP production may be greatly reduced, with serious consequences for organs such as the brain and skeletal muscle that depend upon large amounts of ATP for normal development and activity. Lipoamide dehydrogenase (LAD) is an important component of three enzyme complexes in mitochondria and LAD deficiency is an inherited disease that disrupts normal mitochondrial function.

Dr. Lorberboum-Galski and colleagues at the Department of Cellular Biochemistry and Human Genetics at Hebrew University are conducting UMDF-funded research to investigate the possibility that enzyme replacement therapy can be used to treat LAD deficiency. They are developing methods for placing the normally functioning enzyme into cultured cells of mitochondrial disease patients and also into the mitochondria of laboratory mice that are afflicted with the disease. This is a promising approach because there are currently no cures for mitochondrial disease and such research could lead to therapies that would correct its fundamental causes.

Zaza Khuchua, PhD
Vanderbilt University Medical Center, Tennessee

2006 Research Award: $110,000

“Animal models of human Barth syndrome, a mitochondrial cardiolipin disorder”
Barth syndrome is a rare genetic disorder that causes generalized muscle weakness, affecting both the muscles of the heart and of the musculoskeletal system. The disease prevents normal function of a specific population of immune system cells and has a high rate of infant mortality. The similarity of effects that the disease has on very different organs in the human body can be explained by how it affects mitochondria, energy-providing organelles found in most cells. Previous studies have shown that the muscle mitochondria in Barth patients are deficient in cardiolipin, a compound that is an essential component of the mitochondrial inner membrane. Production of the energy needed for cell activity is impaired in the absence of normal cardiolipin levels.

Dr. Zaza Khuchua and colleagues at Vanderbilt University Medical Center have developed promising animal models of human Barth syndrome. Using research funds provided by the United Mitochondrial Disease foundation, they will study a previously developed fish model of Barth syndrome and will complete development of a mouse model of the same disease. These are significant developments because the use of animal models will allow extensive research on the syndrome’s basic pathology without having to rely upon human subjects.

Stephane Chiron, PhD
University of California-San Diego

2006 Research Award: $98,500

“Utilization of fission yeast as a model for mitochondrial morphology: a new approach to discover novel genes involved in animal cells”
The cells that make up the human body are packed with organelles, complex machinery responsible for virtually all life processes. These functional components are dynamic and mobile, not the static structures often suggested by pictures in biology textbooks. Mitochondria are essential organelles responsible for maintaining normal energy levels in cells and previous research has shown that specific transport systems are dedicated to moving them within the cell interior. Other research has suggested that abnormal movement and shaping of mitochondria are associated with certain muscle and nervous system diseases in humans. Detailed studies of the internal systems responsible for distributing and positioning mitochondria within cells could shed light on disease mechanisms common to some mitochondrial diseases.

Dr. Stephane Chiron and colleagues at U.C.-San Diego are conducting UMDF-funded research seeking to further understand how mitochondrial movement is regulated. They are using a species of yeast that has the same microtubule transport system for movement of mitochondria as is found in human cells. Such yeast cells are easily cultured and maintained in the lab and, because of their similarities with human cells, will yield data that is applicable to human mitochondrial disease.

Michael J. Palladino, PhD
University of Pittsburgh

2006 Research Award: $98,457

“Developing therapies for mitochondrial disease”
Mitochondrial diseases are relatively rare and a single clinician may encounter only a small number of such patients over a long period of time. Developing a profile of the “typical” patient is challenging also because any two individuals with the same disorder may follow different courses and experience signs and symptoms that differ in both type and severity. It is therefore difficult to collect a large number of similar mitochondrial disease patients for clinical research in order to assess the effectiveness of promising treatments. Fruit flies have many genetic features in common with humans and have been used for decades to uncover aspects of human disease. Using modern biotechnology to produce fruit flies with specific genetic anomalies that lead to mitochondrial disease would be very helpful in identifying underlying disease mechanisms.

Dr. Michael Palladino and his colleagues at the University of Pittsburgh are using fruit flies with mutated mitochondria to measure the effectiveness of treatments for diseases that cause progressive deterioration of the nervous and muscular systems. The mitochondrial dysfunction in these animals causes movement disorders and decreases their life spans. The importance of this UMDF-funded research is that it will allow wide-spread screening to determine the efficacy of specific drug therapies in genetically similar populations with mitochondrial disease.

Doron Rapaport, PhD
University of Tuebingen, Germany

2006 Research Award: $98,000

“Defective biogenesis of mitochondrial beta-barrel proteins as a cause for Mohr-Tranebjaerg syndrome”
Mitochondria are complex cell organelles whose manufacture is directed by the DNA code contained in genes of both the nucleus and of the mitochondria themselves. Because the majority of mitochondrial components are encoded for in nuclear DNA, their assembly involves the transport of proteins from the interior of the cell into the mitochondria. Anything that interrupts this complicated sequence of events has the potential to impair mitochondrial function, leading to impaired mitochondrial energy metabolism. The consequences of such impairment can be seen in Mohr-Tranebjaerg syndrome (MTS), a disorder of the nervous system that results in the development of deafness, blindness, mental retardation and dysfunctional movement.

Doron Rapaport and his colleagues at the University of Tuebingen are conducting UMDF-funded research to investigate the link between a mutation associated with MTS and the insertion of nuclear-encoded proteins into the mitochondrial membrane. This research is important because it will provide insights into the normal assembly of mitochondria, as well as into the pathology of a complex mitochondrial disease.

Vishal Gohil, PhD
Massachusetts General Hospital

2006 Research Award: $88,850

“Molecular signatures of mitochondrial disorders”
It should not be surprising to learn that our muscles use up a large percentage of the energy we derive from our food. Muscle cells have such a high metabolic rate that that they burn a significant number of calories even when we are asleep. It is the job of mitochondria in these muscle cells to make energy available in the form of ATP on a reliable basis. ATP is the currency that is “spent” for energy-requiring activities in the human body and therefore mitochondria are present in large numbers in normal muscle cells. Conversely, when patients have widespread energy dysfunction associated with abnormal mitochondria, the muscles are especially vulnerable.

Dr. Vishal Gohil and colleagues at the MGH Center for Human Genetic Research are conducting UMDF-funded research to investigate the effects of malfunctioning mitochondria on mammalian muscle function. They are developing research models for about a dozen different human mitochondrial diseases by interfering with the expression of DNA in a mouse muscle cell line. This approach is important because it will allow comprehensive laboratory study of a number of mitochondrial diseases and their associated defects. Their findings should provide insight into appropriate treatments for mitochondrial disease in humans.

John Gordon Lindsay, PhD
University of Glasgow, Scotland

2006 Research Award: $43,494

“Enzymatic, assembly and genetic studies on the human pyruvate dehydrogenase multi-enzyme complex”
The machinery inside living cells is very complex and includes a variety of enzymes that regulate the rates at which chemical reactions occur. The reactions that take place within mitochondria are especially important because they are crucial to maintaining normal levels of the energy molecule ATP. The process whereby the chemical energy in glucose is ultimately transferred to ATP begins in the cytosol outside of the mitochondria and results in the formation of an intermediate molecule called pyruvate. While a relatively small amount of ATP becomes available during the breakdown of a glucose molecule into two pyruvates, obtaining the maximum amount of energy available from glucose requires that the pyruvates enter the mitochondria for further processing. Once inside, the pyruvate molecules undergo a chemical reaction that is catalyzed by pyruvate dehydrogenase complex (PDC), an important mitochondrial enzyme.

Dr. Lindsay and his colleagues at the Institute of Biomedical and Life Sciences of the University of Glasgow are conducting UMDF-funded research using modified bacteria that contain mutated forms of PDC in order to determine how changes in the complex’s function can result in mitochondrial disease. If the enzyme is defective, then numerous other reactions that follow the one catalyzed by PDC will not occur and mitochondrial production of ATP will be impaired. This research is important because PDC mutations are suspected in a large number of metabolic disorders in humans.

Patrick F. Chinnery, PhD
University of Newcaslte upon Tyne, UK

2005 Research Award: $162,878

“The Population prevalence of ten mtDNA mutations”
Each of us depends upon our own mitochondria to derive energy, in the form of ATP, from the food that we eat. Because ATP has to be readily available for use by our cells the mitochondrial enzyme systems responsible for its production are constantly working. Unfortunately, this complicated machinery can malfunction, sometimes because the mitochondrial enzyme complexes were improperly assembled. What specifical