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Cell Metab. 2015 Mar 3;21(3):443-54. doi: 10.1016/j.cmet.2015.02.009.

The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance.

Author information

1
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: changhan.lee@usc.edu.
2
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
3
Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
4
Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
5
Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
6
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: hassy@usc.edu.

Abstract

Mitochondria are known to be functional organelles, but their role as a signaling unit is increasingly being appreciated. The identification of a short open reading frame (sORF) in the mitochondrial DNA (mtDNA) that encodes a signaling peptide, humanin, suggests the possible existence of additional sORFs in the mtDNA. Here we report a sORF within the mitochondrial 12S rRNA encoding a 16-amino-acid peptide named MOTS-c (mitochondrial open reading frame of the 12S rRNA-c) that regulates insulin sensitivity and metabolic homeostasis. Its primary target organ appears to be the skeletal muscle, and its cellular actions inhibit the folate cycle and its tethered de novo purine biosynthesis, leading to AMPK activation. MOTS-c treatment in mice prevented age-dependent and high-fat-diet-induced insulin resistance, as well as diet-induced obesity. These results suggest that mitochondria may actively regulate metabolic homeostasis at the cellular and organismal level via peptides encoded within their genome.

PMID:
25738459
PMCID:
PMC4350682
DOI:
10.1016/j.cmet.2015.02.009
[Indexed for MEDLINE]
Free PMC Article

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