The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance.
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.
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: changhan.lee@usc.edu.
Changhan
C
Lee
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
Jennifer
J
Zeng
Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Brian G
BG
Drew
Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Tamer
T
Sallam
Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
Alejandro
A
Martin-Montalvo
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
Junxiang
J
Wan
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
Su-Jeong
SJ
Kim
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
Hemal
H
Mehta
Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Andrea L
AL
Hevener
Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
Rafael
R
de Cabo
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: hassy@usc.edu.
Pinchas
P
Cohen
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D004272:DNA, Mitochondrial / Q000235:genetics; D059305:Diet, High-Fat / Q000009:adverse effects; D057809:HEK293 Cells; D006367:HeLa Cells; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
D004272:DNA, Mitochondrial; D007328:Insulin; D010455:Peptides; C050632:polypeptide C; D055372:AMP-Activated Protein Kinases