2. Academic Validation
  3. The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress

The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress

  • Cell Metab. 2018 Sep 4;28(3):516-524.e7. doi: 10.1016/j.cmet.2018.06.008.
Kyung Hwa Kim 1,  Jyung Mean Son 1,  Bérénice A Benayoun 2,  Changhan Lee 3
Affiliations

Affiliations

  • 1 Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
  • 2 Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA; USC Norris Comprehensive Cancer Center, Los Angeles, CA 90089, USA; USC Stem Cell Initiative, Los Angeles, CA 90089, USA.
  • 3 Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA; USC Norris Comprehensive Cancer Center, Los Angeles, CA 90089, USA; Biomedical Sciences, Graduate School, Ajou University, Suwon 16499, Republic of Korea. Electronic address: changhan.lee@usc.edu.
PMID: 29983246 DOI: 10.1016/j.cmet.2018.06.008
Abstract

Cellular homeostasis is coordinated through communication between mitochondria and the nucleus, organelles that each possess their own genomes. Whereas the mitochondrial genome is regulated by factors encoded in the nucleus, the nuclear genome is currently not known to be actively controlled by factors encoded in the mitochondrial DNA. Here, we show that MOTS-c, a peptide encoded in the mitochondrial genome, translocates to the nucleus and regulates nuclear gene expression following metabolic stress in a 5'-adenosine monophosphate-activated protein kinase (AMPK)-dependent manner. In the nucleus, MOTS-c regulated a broad range of genes in response to glucose restriction, including those with antioxidant response elements (ARE), and interacted with ARE-regulating stress-responsive transcription factors, such as nuclear factor erythroid 2-related factor 2 (NFE2L2/NRF2). Our findings indicate that the mitochondrial and nuclear genomes co-evolved to independently encode for factors to cross-regulate each other, suggesting that mitonuclear communication is genetically integrated.

Keywords

MOTS-c; homeostasis; metabolic stress; mitochondria; mitochondrial DNA; mitochondrial-derived peptide (MDP); mitonuclear communication; peptide; short open reading frames (sORF); stress response.

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