PMID- 24101601
OWN - NLM
STAT- MEDLINE
DCOM- 20141028
LR  - 20211203
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 23
IP  - 3
DP  - 2014 Feb 1
TI  - Rapamycin drives selection against a pathogenic heteroplasmic mitochondrial DNA 
      mutation.
PG  - 637-47
LID - 10.1093/hmg/ddt450 [doi]
AB  - Mitochondrial DNA (mtDNA) mutations cause a variety of mitochondrial disorders 
      for which effective treatments are lacking. Emerging data indicate that selective 
      mitochondrial degradation through autophagy (mitophagy) plays a critical role in 
      mitochondrial quality control. Inhibition of mammalian target of rapamycin (mTOR) 
      kinase activity can activate mitophagy. To test the hypothesis that enhancing 
      mitophagy would drive selection against dysfunctional mitochondria harboring 
      higher levels of mutations, thereby decreasing mutation levels over time, we 
      examined the impact of rapamycin on mutation levels in a human cytoplasmic hybrid 
      (cybrid) cell line expressing a heteroplasmic mtDNA G11778A mutation, the most 
      common cause of Leber's hereditary optic neuropathy. Inhibition of mTORC1/S6 
      kinase signaling by rapamycin induced colocalization of mitochondria with 
      autophagosomes, and resulted in a striking progressive decrease in levels of the 
      G11778A mutation and partial restoration of ATP levels. Rapamycin-induced 
      upregulation of mitophagy was confirmed by electron microscopic evidence of 
      increased autophagic vacuoles containing mitochondria-like organelles. The 
      decreased mutational burden was not due to rapamycin-induced cell death or mtDNA 
      depletion, as there was no significant difference in cytotoxicity/apoptosis or 
      mtDNA copy number between rapamycin and vehicle-treated cells. These data 
      demonstrate the potential for pharmacological inhibition of mTOR kinase activity 
      to activate mitophagy as a strategy to drive selection against a heteroplasmic 
      mtDNA G11778A mutation and raise the exciting possibility that rapamycin may have 
      therapeutic potential for the treatment of mitochondrial disorders associated 
      with heteroplasmic mtDNA mutations, although further studies are needed to 
      determine if a similar strategy will be effective for other mutations and other 
      cell types.
FAU - Dai, Ying
AU  - Dai Y
AD  - Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical 
      School, Boston, MA 02215, USA.
FAU - Zheng, Kangni
AU  - Zheng K
FAU - Clark, Joanne
AU  - Clark J
FAU - Swerdlow, Russell H
AU  - Swerdlow RH
FAU - Pulst, Stefan M
AU  - Pulst SM
FAU - Sutton, James P
AU  - Sutton JP
FAU - Shinobu, Leslie A
AU  - Shinobu LA
FAU - Simon, David K
AU  - Simon DK
LA  - eng
GR  - 1R21NS077758/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130918
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (DNA, Mitochondrial)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adenosine Triphosphate/metabolism
MH  - Apoptosis/drug effects/genetics
MH  - Cell Line/drug effects
MH  - *DNA, Mitochondrial
MH  - Humans
MH  - Mitochondria/*drug effects/genetics
MH  - Mitophagy/drug effects
MH  - *Mutation
MH  - Optic Atrophy, Hereditary, Leber/genetics
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism
PMC - PMC3888257
EDAT- 2013/10/09 06:00
MHDA- 2014/10/29 06:00
PMCR- 2015/02/01
CRDT- 2013/10/09 06:00
PHST- 2013/10/09 06:00 [entrez]
PHST- 2013/10/09 06:00 [pubmed]
PHST- 2014/10/29 06:00 [medline]
PHST- 2015/02/01 00:00 [pmc-release]
AID - ddt450 [pii]
AID - 10.1093/hmg/ddt450 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2014 Feb 1;23(3):637-47. doi: 10.1093/hmg/ddt450. Epub 2013 Sep 
      18.