PMID- 24610944
OWN - NLM
STAT- MEDLINE
DCOM- 20150416
LR  - 20211203
IS  - 1477-9137 (Electronic)
IS  - 0021-9533 (Print)
IS  - 0021-9533 (Linking)
VI  - 127
IP  - Pt 10
DP  - 2014 May 15
TI  - Rapamycin increases mitochondrial efficiency by mtDNA-dependent reprogramming of 
      mitochondrial metabolism in Drosophila.
PG  - 2282-90
LID - 10.1242/jcs.142026 [doi]
AB  - 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.
CI  - (c) 2014. Published by The Company of Biologists Ltd.
FAU - Villa-Cuesta, Eugenia
AU  - Villa-Cuesta E
AD  - Department of Biology, Adelphi University, PO Box 701, Garden City, NY 
      11530-0701, USA evilla-cuesta@adelphi.edu.
FAU - Holmbeck, Marissa A
AU  - Holmbeck MA
AD  - Department of Ecology and Evolutionary Biology, Brown University, Box G-W, 
      Providence, RI 02912, USA.
FAU - Rand, David M
AU  - Rand DM
AD  - Department of Ecology and Evolutionary Biology, Brown University, Box G-W, 
      Providence, RI 02912, USA.
LA  - eng
GR  - F31 AG040925/AG/NIA NIH HHS/United States
GR  - R01 GM067862/GM/NIGMS NIH HHS/United States
GR  - R01 AG027849/AG/NIA NIH HHS/United States
GR  - 5R01AG027849/AG/NIA NIH HHS/United States
GR  - R01GM067862/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20140307
PL  - England
TA  - J Cell Sci
JT  - Journal of cell science
JID - 0052457
RN  - 0 (DNA, Mitochondrial)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - DNA, Mitochondrial/*genetics/metabolism
MH  - Down-Regulation/drug effects
MH  - Drosophila melanogaster/*genetics/*metabolism
MH  - Female
MH  - Mitochondria/*drug effects/*metabolism
MH  - Oxidation-Reduction
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC4021473
OTO - NOTNLM
OT  - Metabolism
OT  - Mitochondrial genotype
OT  - Rapamycin
EDAT- 2014/03/13 06:00
MHDA- 2015/04/17 06:00
PMCR- 2015/05/15
CRDT- 2014/03/11 06:00
PHST- 2014/03/11 06:00 [entrez]
PHST- 2014/03/13 06:00 [pubmed]
PHST- 2015/04/17 06:00 [medline]
PHST- 2015/05/15 00:00 [pmc-release]
AID - jcs.142026 [pii]
AID - 10.1242/jcs.142026 [doi]
PST - ppublish
SO  - J Cell Sci. 2014 May 15;127(Pt 10):2282-90. doi: 10.1242/jcs.142026. Epub 2014 
      Mar 7.