Identification of Novel Compounds to Treat Rare Mitochondrial Diseases
Mentor: Johan Auwerx
Mitochondria are the main producers of cellular energy. There are around 150 different rare mitochondrial disease that can result when mitochondria are not working properly. These energy disorders have diverse symptoms that can present in a single organ (e.g., eyes in Leber’s hereditary optic neuropathy (LHON)) or across a range of organs (brain, muscle, etc. as is the case in Leigh syndrome). Although lifestyle and nutritional changes can help to manage mitochondrial disorders, most rare mitochondrial diseases have no known effective or specific treatments, resulting in a significant and largely unmet medical need. Several research reports suggest that increasing the number of mitochondria in cells can improves mitochondrial function and at least partially correct some of the abnormalities. Recently, the Auwerx lab has identified a pathway that seems to be critical in maintaining proper mitochondrial function). When this pathway is activated a beneficial effect on mitochondrial function and health results. The goal of this research project is to identify novel compounds that increase the amount of mitochondria and/or activate the identified pathway in lab-based cell models. The compounds that work best in the cell models will be subsequently tested in animal models of mitochondrial disease. Future work with top compound candidates have the potential to pave the way towards the development of novel drugs targeting rare mitochondrial diseases.
Mitochondria are the main producers of ATP, the energy currency of the cell, via oxidative phosphorylation (OXPHOS). Around 150 rare diseases caused by impaired OXPHOS, a heterogeneous group of clinical syndromes, trigger systemic energy deficits and can affect single tissues (such as in Leber’s hereditary optic neuropathy (LHON)) or cause severe dysfunction of multiple tissues (e.g. Leigh’s syndrome). Although lifestyle and nutritional changes can help to manage mitochondrial dysfunction, no effective and specific treatments are currently available for these rare mitochondrial diseases, posing a large unmet medical need. Several reports suggest that pharmacological induction of mitochondrial biogenesis improves mitochondrial function and corrects some of the phenotypic abnormalities in mice models of OXPHOS diseases. Additionally, the Auwerx lab has recently shown that an adaptive proteotoxic stress response pathway, termed mitochondrial unfolded protein response (UPRmt) also has a beneficial effect on mitochondrial function and health. Pharmacologically targeting either mitochondrial biogenesis and/or the UPRmt pathway hence may improve mitochondrial dysfunction and favorably impact on mitochondrial diseases. The goal of this research project is to identify novel compounds that increase mitochondrial biogenesis and activate UPRmt using a multispecies and multi-scalar screening strategy in mammalian cells and in C. elegans. Compounds with drug like features that induce biogenesis/UPRmt will be subsequently tested for their efficacy to improve mitochondrial dysfunction in pre-clinical cell, worm and mouse models of mitochondrial disease. Our screening and subsequent validation of our top candidates will pave the way towards the development of new and efficient drugs for such rare mitochondrial diseases.
Thanks to two generous contributions, the UMDF is additionally funding the projects of our other accelerators finalists:
Structural and Functional Characterization of COQ9 in Facilitating Coenzyme Q Biosynthesis and Complex Q Formation
Mentor: David J Pagliarini
Mitochondrial diseases are debilitating disorders with no known cures. A set of molecules come together inside mitochondria to produce complexes that produce energy for cells, and one of the most important of those complexes is called coenzyme Q (CoQ). Many important research questions remain unanswered about how CoQ, including how it is made. Researchers have demonstrated that other molecules help to make CoQ and when these molecules don’t work properly then CoQ isn’t produced in sufficient quantity, which in turn leads to onset of disease. This proposal aims to study how two such helper molecules called CoQ7 and CoQ9 work together to produce CoQ. Understanding this process could lead to insights on how to treat forms of mitochondrial disease related to CoQ deficiency.
Mitochondrial diseases, arising from defects in mitochondrial metabolism, are debilitating disorders often with no known cures. One mitochondrial metabolic process that is frequently dysfunctional in disease is the biosynthesis of the critical redox-active lipid coenzyme Q (CoQ), yet there are many unanswered questions surrounding its basic synthesis and transport. Recent experimental evidence has demonstrated that the synthesis of CoQ requires auxiliary proteins to present CoQ precursors to enzymes in this pathway, and that these auxiliary proteins reside with core enzymes in a metabolon-like complex. Furthermore, disruption of the function of these auxiliary proteins or the formation of this biosynthetic complex results in the loss of CoQ and human disease. How exactly auxiliary proteins, such as COQ9, support CoQ biosynthesis and enable the formation of complex Q is unclear. COQ9, which is mutated in disease such as encephalopathy, interacts with the hydroxylase COQ7 within this complex and enables its activity through an unknown mechanism. Here I propose to characterize the structural and functional interaction of the COQ9/COQ7 subcomplex, as well as to more broadly define the entire molecular architecture of complex Q. Such efforts will provide a detailed understanding of the structure of this crucial complex and how it is reinforced by auxiliary proteins, potentially offering new insights that could advance the treatment of diseases related to CoQ deficiency.
Manipulating Mitochondrial Metabolism Via the Mitochondrial Derived Compartment Pathway
Mentor: Adam Hughes
Mitochondria have many roles inside cells, including energy production and the production of nutrients that are essential for healthy growth and survival. Researchers have a good general knowledge of how nutrient production in particular is performed within mitochondria, but many important details remain undiscovered. This proposal aims to study how molecules called mitochondrial transporters are produced and controlled, with a particular emphasis on how the transporter molecules are broken down and what impact that has on how well mitochondria work. Learnings from this research could help future researchers to develop treatments for mitochondrial disease that manipulate the nutrient pathway.
Mitochondria are a central hub of cellular metabolism, and as such, most mitochondrial diseases are associated with pathological alterations in key metabolic pathways. Identifying new mechanisms to alter mitochondrial metabolism may provide unique avenues to combat metabolic deficits associated with mitochondrial diseases. Most metabolic pathways hosted by mitochondria occur in the mitochondrial matrix, requiring the active transport of metabolites across the impermeable mitochondrial inner membrane by membrane-embedded nutrient carriers. As these mitochondrial nutrient carriers create a bottleneck for several metabolic reactions, they represent important targets for therapeutic manipulation. However, despite their pivotal role in cellular metabolism, we know little about the regulation of mitochondrial nutrient transporters. Our lab has begun to address this knowledge gap through our discovery of a mitochondrial protein remodeling pathway that selectively controls the levels of mitochondrial nutrient carriers. We found that in response to cellular nutrient fluctuations, mitochondria form distinct subdomains deemed the mitochondrial derived compartment (MDC) that selectively incorporates mitochondrial nutrient carriers and directs them to lysosomes for degradation. Our working hypothesis is that the MDC pathway may serve as a key regulator of mitochondrial metabolism through control of nutrient transporter levels . The goal of this proposal is to investigate fundamental aspects on the formation and function of the MDC pathway. The results of the studies proposed are expected to elucidate cellular mechanisms involved in the regulation of the mitochondrial carrier system and will provide new avenues to target mitochondrial nutrient transporters and/or changes in mitochondrial metabolism that occur in several mitochondrial diseases.
UMDF earmarks the accelerators prize
($50,000 in 2019)
Grant applications submitted by promising post-doctoral fellows
Applications reviewed and finalists selected by UMDF Scientific and Medical Advisory Board
3-5 finalists prepare “fast pitches” to be broadcast live at UMDF Symposium
Each accelerator casts one vote for the project they feel most passionate about
Prize awarded to winner
Right now… a researcher in a lab believes her theory could cure mitochondrial myopathy.
Right now… a scientist believes his innovation may bring about an end to Leigh’s Syndrome.
Right now… people affected by mitochondrial disease need energy…and YOUR energy can help….but we need to go fast.
It could be an innovation that will find the cause of mitochondrial disease. Or, it may be the research that develops an effective treatment. Now is the time to accelerate that science from bench to bedside. Our patients and families are counting on your energy to help UMDF move faster toward a cure.
Your gift = Your vote
Our accelerators are engaged philanthropists. Through our annual livestream-pitch event, our members have the opportunity to cast their vote for the project they feel the most passionate about, and ultimately see the difference their contribution makes.
In addition to the opportunity to jumpstart discovery for the next generation of mitochondrial disease researchers, our accelerators receive:
- Name listing on umdf.org
- Name listing in UMDF annual impact report
- Name recognition at the annual Symposium
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Innovation, speed and agility are key to finding effective treatments for mitochondrial disease. Your support is the beginning. Accelerating the research could lead to a cure.
Become an accelerator
When you give $500 or more (cumulatively in a year) you unlock your accelerators benefits! No matter how you give – through a special event, to a designated fund or as a tribute to a patient – when you reach the accelerators level you join a group of engaged philanthropists. You will get a first-hand look at the promising ideas being developed in mitochondrial disease research.
To promote research and education for the
diagnosis, treatment and cure of mitochondrial disorders
and to provide support to affected individuals and families.
Innovative treatments and cures are on the horizon.
We’re jumpstarting their discoveries – right now…
With your generous support, UMDF continues
our promise of accelerating the work of scientists
who are working fast toward a cure.