Transient and constitutive repression of cytoplasmic translation signaling in cells with mtDNA mutation

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 ρ⁰ cells by at least two dist...

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Bibliographic Details
Published in:Cellular and molecular life sciences : CMLS 2009-02, Vol.66 (4), p.721-730
Main Authors: Janssen, G. M. C, Schwertman, P, Wanga, T. A. T, Tafrechi, R. S. Jahangir, van den Broek, P. J. A, Raap, A. K
Format: Article
Language:English
Subjects:
AMP-Activated Protein Kinases - metabolism
Biochemistry
Biomedical and Life Sciences
Biomedicine
Cell Biology
Cells, Cultured
Cellular biology
Cytoplasm - metabolism
cytoplasmic translation
Diabetes
DNA, Mitochondrial - genetics
DNA, Mitochondrial - metabolism
elongation
Fibroblasts - cytology
Fibroblasts - physiology
Humans
initiation
Life Sciences
Mitochondrial DNA
mtDNA disease
Mutation
Oxidative Phosphorylation
Protein Biosynthesis
Research Article
Signal Transduction - physiology
Uncoupling Agents - metabolism
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Summary: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 ρ⁰ cells by at least two distinct pathways, one transiently targeting elongation factor eEF-2 and the other initiation factor eIF-2α 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-2α 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-2α-mediated repression of translation initiation may have pathobiochemical consequences.
ISSN:1420-682X
1420-9071
DOI:10.1007/s00018-009-8687-4