Transient and constitutive repression of cytoplasmic translation signaling in cells with mtDNA mutation.
Cell Mol Life Sci
; 66(4): 721-30, 2009 Feb.
Article
in En
| MEDLINE
| ID: mdl-19137259
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Protein Biosynthesis
/
DNA, Mitochondrial
/
Signal Transduction
/
Cytoplasm
/
Mutation
Limits:
Humans
Language:
En
Journal:
Cell Mol Life Sci
Journal subject:
BIOLOGIA MOLECULAR
Year:
2009
Document type:
Article
Affiliation country: