PMID- 19137259
OWN - NLM
STAT- MEDLINE
DCOM- 20090323
LR  - 20171116
IS  - 1420-9071 (Electronic)
IS  - 1420-682X (Linking)
VI  - 66
IP  - 4
DP  - 2009 Feb
TI  - Transient and constitutive repression of cytoplasmic translation signaling in 
      cells with mtDNA mutation.
PG  - 721-30
LID - 10.1007/s00018-009-8687-4 [doi]
AB  - Cytoplasmic translation is under sophisticated control but how cells adapt its 
      rate to constitutive loss of mitochondrial oxidative phosphorylation is unknown. 
      Here we show that translation is repressed in cells with the pathogenic A3243G 
      mtDNA mutation or in mtDNA-less rho(0) cells by at least two distinct pathways, 
      one transiently targeting elongation factor eEF-2 and the other initiation factor 
      eIF-2alpha constitutively. Under conditions of exponential cell growth and 
      mammalian target of rapamycin (mTOR) activation, eEF-2 becomes transiently 
      phosphorylated by an AMP-activated protein kinase (AMPK)-dependent pathway, 
      especially high in mutant cells. Independent of AMPK and mTOR, eIF-2alpha is 
      constitutively phosphorylated in mutant cells, likely a signature of endoplasmic 
      reticulum (ER)-stress response induced by the loss of oxidative phosphorylation. 
      While the AMPK/eEF-2K/eEF-2 pathway appears to function in adaptation to 
      physiological fluctuations in ATP levels in the mutant cells, the ER stress 
      signified by constitutive protein synthesis inhibition through 
      eIF-2alpha-mediated repression of translation initiation may have 
      pathobiochemical consequences.
FAU - Janssen, G M C
AU  - Janssen GM
AD  - Department of Molecular Cell Biology, Leiden University Medical Center, The 
      Netherlands. G.M.C.Janssen@lumc.nl
FAU - Schwertman, P
AU  - Schwertman P
FAU - Wanga, T A T
AU  - Wanga TA
FAU - Tafrechi, R S Jahangir
AU  - Tafrechi RS
FAU - van den Broek, P J A
AU  - van den Broek PJ
FAU - Raap, A K
AU  - Raap AK
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Switzerland
TA  - Cell Mol Life Sci
JT  - Cellular and molecular life sciences : CMLS
JID - 9705402
RN  - 0 (DNA, Mitochondrial)
RN  - 0 (Uncoupling Agents)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinases/metabolism
MH  - Cells, Cultured
MH  - Cytoplasm/*metabolism
MH  - DNA, Mitochondrial/*genetics/metabolism
MH  - Fibroblasts/cytology/physiology
MH  - Humans
MH  - *Mutation
MH  - Oxidative Phosphorylation
MH  - *Protein Biosynthesis
MH  - Signal Transduction/*physiology
MH  - Uncoupling Agents/metabolism
EDAT- 2009/01/13 09:00
MHDA- 2009/03/24 09:00
CRDT- 2009/01/13 09:00
PHST- 2009/01/13 09:00 [entrez]
PHST- 2009/01/13 09:00 [pubmed]
PHST- 2009/03/24 09:00 [medline]
AID - 10.1007/s00018-009-8687-4 [doi]
PST - ppublish
SO  - Cell Mol Life Sci. 2009 Feb;66(4):721-30. doi: 10.1007/s00018-009-8687-4.