MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism

Abstract

Mitochondria are ancient organelles that are thought to have emerged from once free-living α-proto-bacteria. As such, they still possess several bacterial-like qualities, including a semi-autonomous genetic system, complete with an independent genome and a unique genetic code. The bacterial-like circular mitochondrial DNA (mtDNA) has been described to encode 37 genes, including 22 tRNAs, 2 rRNAs, and 13 mRNAs. Two additional peptides reported to originate from the mtDNA, namely humanin (Hashimoto et al., 2001; Ikone et al., 2003; Guo et al., 2003) [1-3] and MOTS-c (mitochondrial ORF of the twelve S c) (Lee et al., 2015) [4], indicate a larger mitochondrial genetic repertoire (Shokolenko and Alexeyev, 2015) [5]. These mitochondrial-derived peptides (MDPs) have profound and distinct biological activities and provide a paradigm-shifting concept of active mitochondrial-encoded signals that act at the cellular and organismal level (i.e. mitochondrial hormone) (da Cunha et al., 2015; Quiros et al., 2016) [6,7]. Considering that mitochondria are the single most important metabolic organelle, it is not surprising that these MDPs have metabolic actions. MOTS-c has been shown to target the skeletal muscle and enhance glucose metabolism. As such, MOTS-c has implications in the regulation of obesity, diabetes, exercise, and longevity, representing an entirely novel mitochondrial signaling mechanism to regulate metabolism within and between cells.

Keywords: Aging; Exercise; Fat; Insulin; MOTS-c; Metabolism; Mitochondrial-derived peptides; Muscle.

Fig. 1

A model of the systemic metabolic effects of the mitochondrial-derived peptide hormone MOTS-c. Exercise, diet (pro-longevity dietary interventions), and aging may affect the production, secretion, and activity of MOTS-c. Skeletal muscle is a major target of circulating MOTS-c, but experimental evidence also points to fat cells as a potential target. Depending on the environment, MOTS-c may have dual roles as an anabolic and a lipolytic hormone.