Editors' ChoiceStress responses

Going nuclear with stress

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Science Signaling  18 Sep 2018:
Vol. 11, Issue 548, eaav4285
DOI: 10.1126/scisignal.aav4285

A mitochondrial-derived peptide regulates nuclear gene expression in response to metabolic stress.

Most mitochondrial proteins are encoded by nuclear genes (see Mangalhara and Shadel). Kim et al. characterized a peptide encoded by the mitochondrial genome that translocates to the nucleus and alters gene expression in response to various types of stress. MOTS-c is a 16–amino acid peptide encoded in the short open reading frame of the mitochondrial 12S rRNA that regulates cellular metabolism. Under basal conditions, the authors detected MOTS-c predominantly associated with mitochondria, although there was a small pool in the nucleus. Nuclear translocation of MOTS-c was transiently enhanced by different types of metabolic stress: glucose restriction, serum deprivation, or various oxidative stress–producing agents, including tert-butyl hydrogen peroxide (tBHP). Nuclear translocation required the activity of the kinase AMPK. In cells subjected to glucose restriction or exposed to tBHP, MOTS-c bound to NRF2, a transcription factor involved in antioxidant responses, and to the antioxidant response elements of some of its target genes. Interaction with MOTS-c enhanced the binding of NRF2 to its target genes. Cells were protected from glucose and serum deprivation upon overexpression of wild-type MOTS-c but not nuclear translocation–deficient mutants. These results demonstrate that a mitochondrial-derived peptide translocates to the nucleus in response to metabolic stress to regulate nuclear gene expression.

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