There are no generalizable rational treatments for patients with mitochondrial diseases. We propose here to study two new approaches to treat patients with mitochondrial diseases due to mutations in mtDNA. First, we have found that rapamycin (Sirolimus), an FDA-approved drug that induces autophagy, selectively targets mitochondria containing mutated mtDNAs, but not those harboring normal mtDNAs, for autophagic destruction. We will therefore examine the ability of rapamycin to restore mitochondrial function in heteroplasmic cells (""""""""heteroplasmic shifting""""""""), and use biochemical, functional, and microarray-based approaches to determine how mutant mtDNAs and dysfunctional mitochondria are recognized and degraded by the cell's autophagic machinery. Second, we have found that a number of analogs of CoQ and vitamin E developed by Edison Pharmaceuticals can rescue the viability of cells from patients with MELAS (""""""""functional rescue""""""""). We will therefore study Edison compounds in patient cells harboring various pathogenic mtDNA mutations in greater detail, and will also try to determine the mechanism by which these compounds work, using biochemical and genetic approaches. If successful, use of both rapamycin and Edison compounds could be the the basis of the first rational treatments of mtDNA-based OxPhos diseases.

Public Health Relevance

There are no rational treatments for mitochondrial disorders due to mutations in mtDNA. Our finding that rapamycin can target and destroy delsctively mitochondria harboring mutated, but not wild-type, mtDNAs and that new analogs of CoQ and vitamin E developed by Edison Pharmaceuticals can improve viability of heteroplasmic cells harboring mutated mtDNAs, hold out the promise that such treatments may be possible.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD032062-20
Application #
8616078
Study Section
Special Emphasis Panel (ZHD1-MRG-C)
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
20
Fiscal Year
2014
Total Cost
$232,217
Indirect Cost
$85,069
Name
Columbia University
Department
Type
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Garone, Caterina; Garcia-Diaz, Beatriz; Emmanuele, Valentina et al. (2014) Deoxypyrimidine monophosphate bypass therapy for thymidine kinase 2 deficiency. EMBO Mol Med 6:1016-27
Yien, Yvette Y; Robledo, Raymond F; Schultz, Iman J et al. (2014) TMEM14C is required for erythroid mitochondrial heme metabolism. J Clin Invest 124:4294-304
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Quinzii, Catarina M; Hirano, Michio; DiMauro, Salvatore (2014) Mutant COQ2 in multiple-system atrophy. N Engl J Med 371:81-2
Weiduschat, Nora; Kaufmann, Petra; Mao, Xiangling et al. (2014) Cerebral metabolic abnormalities in A3243G mitochondrial DNA mutation carriers. Neurology 82:798-805

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