Tuesday, 10 March 2015

The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis and Reduces Obesity and Insulin Resistance

Changhan Lee, Jennifer Zeng, Brian G. Drew, Tamer Sallam, Alejandro Martin-Montalvo, Junxiang Wan, Su-Jeong Kim, Hemal Mehta, Andrea L. Hevener, Rafael de Cabo, Pinchas Cohen

Summary: A short open reading frame (sORF) encoding the signaling peptide humanin was previously identified in mitochondria, and suggested the possible existence of others. The authors identified an sORF in 12S rRNA which encodes 16-aa peptide they name MOTS-c, which regulates insulin sensitivity & metabolic homeostasis. This peptide targets skeletal muscle, inhibiting folate and purine biosynthesis, which activates AMPK.

Retrograde signalling via ROS, calcium and cytochrome C is a well-known phenomenon, however this signalling mechanism, dubbed 'mitokines' by the authors, represents a novel means of mitonuclear signalling. sORFs have recently emerged as an area of interest as techniques to study them have improved. sORFs have been found throughout mRNAs, and may be translated through leaky scanning or transcriptional re-initiation.

The authors used an in silico search to identify potential sORFs in human 12S mitochondrial rRNA, which they named MOTS-c (mitochondrial open reading frame of 12S rRNA type-c). It appears that although MOTS-c is transcribed in the mitochondrion, it must be translated in the cytoplasm. The possibility that MOTS-c has arisen from nuclear mtDNA transfer (NUMT) was ruled out as no NUMT peptides are homologous to MOTS-c. Mitochondrial depletion showed elimination of 12S rRNA and MOTS-c transcripts in HeLa cells. Fasting reduced MOTS-c in skeletal muscle, testes and plasma, but heart and brain tissues showed no change.

MOTS-c expression alters metabolite levels, as well as changing gene expression profiles. The authors assess that its target is the folate-methionine cycle, which also affects de novo purine biosynthesis. MOTS-c action leads to a significant decrease in purines. The changes to the folate cycle also have the effect of activating AMPK and causing fatty acid oxidation, as well as increasing glucose utilisation.

MOTS-c treatment in mice on a normal diet led to body weight, food intake, and blood glucose reductions, as well as a decrease in circulating signalling proteins implicated in pathogenesis of both obesity and insulin resistance. When mice were fed a high-fat diet, however, MOTS-c treatment prevented obesity without reducing caloric intake. Heat generation significantly increased, as did respiratory exchange ratio (RER). An increase in RER is indicative of a shift towards higher glucose utilisation. This suggests that MOTS-c treatment leads to avoidance of obesity through increase of energy expenditure due to heat generation. MOTS-c appears to act in skeletal muscle. Promisingly, treating mice for 7 days restored the insulin sensitivity of 12 month old mice to nearly the level of 3 month old mice.

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