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J Cell Sci. 2014 May 15;127(Pt 10):2282-90. doi: 10.1242/jcs.142026. Epub 2014 Mar 7.

Rapamycin increases mitochondrial efficiency by mtDNA-dependent reprogramming of mitochondrial metabolism in Drosophila.

Author information

1
Department of Biology, Adelphi University, PO Box 701, Garden City, NY 11530-0701, USA evilla-cuesta@adelphi.edu.
2
Department of Ecology and Evolutionary Biology, Brown University, Box G-W, Providence, RI 02912, USA.

Abstract

Downregulation of the mammalian target of rapamycin (mTOR) pathway by its inhibitor rapamycin is emerging as a potential pharmacological intervention that mimics the beneficial effects of dietary restriction. Modulation of mTOR has diverse effects on mitochondrial metabolism and biogenesis, but the role of the mitochondrial genotype in mediating these effects remains unknown. Here, we use novel mitochondrial genome replacement strains in Drosophila to test the hypothesis that genes encoded in mitochondrial DNA (mtDNA) influence the mTOR pathway. We show that rapamycin increases mitochondrial respiration and succinate dehydrogenase activity, decreases H2O2 production and generates distinct shifts in the metabolite profiles of isolated mitochondria versus whole Drosophila. These effects are disabled when divergent mitochondrial genomes from D. simulans are placed into a common nuclear background, demonstrating that the benefits of rapamycin to mitochondrial metabolism depend on genes encoded in the mtDNA. Rapamycin is able to enhance mitochondrial respiration when succinate dehydrogenase activity is blocked, suggesting that the beneficial effects of rapamycin on these two processes are independent. Overall, this study provides the first evidence for a link between mitochondrial genotype and the effects of rapamycin on mitochondrial metabolic pathways.

KEYWORDS:

Metabolism; Mitochondrial genotype; Rapamycin

PMID:
24610944
PMCID:
PMC4021473
DOI:
10.1242/jcs.142026
[Indexed for MEDLINE]
Free PMC Article

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