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 #
5P01HD032062-19
Application #
8445408
Study Section
Special Emphasis Panel (ZHD1-MRG-C)
Project Start
Project End
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
19
Fiscal Year
2013
Total Cost
$225,065
Indirect Cost
$82,258
Name
Columbia University (N.Y.)
Department
Type
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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