APPROACHES TO TREATING MTDNA-BASED MITOCHONDRIAL DISEASE There are no generalizable rational treatments for patients with mitochondrial diseases due to deficiency in oxidative phosphorylation (OxPhos). We propose here to study pharmacological approaches to treat patients with mitochondrial diseases due to mutations in mtDNA, based on our discovery that specific agents can """"""""shift"""""""" the mutation load and/or rescue mitochondrial function in cells harboring mtDNA mutations. Specifically, we have found that the mTOR inhibitor rapamycin (sirolimus;trade name Rapamune) induces mitophagy in cells carrying homoplasmic mtDNA mutations, but does not do so in wild-type cells. Remarkably, we have now found that rapamycin treatment of heteroplasmic cells containing different pathogenic mtDNA mutations elicited a dramatic improvement in bioenergetic function, as did mdivi-1, an inhibitor of mitochondrial fission, but surprisingly, with no apparent reduction in mutant load. We now propose to follow up on these exciting results, in three ways. First, we will examine in greater detail the ability of rapamycin, mdivi-1, and other agents to restore mitochondrial function in heteroplasmic cells. Second, we will try to determine the mechanism by which functional rescue occurs, using both targeted (e,g, genetic knockdown) and unbiased (e.g. microarray) approaches. Third, we will assess the possibility of treating patients with rapamycin in a small clinical trial by first treating Dr. Hirano's mouse model of TK2 deficiency, which causes mtDNA depletion (synergy with Projects 1 and 3). If successful, the use of rapamycin or similar compounds could become the basis of the first rational treatment of mtDNA-based OxPhos diseases.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
1P01HD080642-01
Application #
8741706
Study Section
Developmental Biology Subcommittee (CHHD)
Project Start
Project End
Budget Start
2014-09-30
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10032
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Siegmund, Stephanie E; Yang, Hua; Sharma, Rohit et al. (2017) Low-dose rapamycin extends lifespan in a mouse model of mtDNA depletion syndrome. Hum Mol Genet 26:4588-4605

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