Mitochondria not only serve as the major source of cellular energy, but also as a coordinator of the highly sophisticated metabolic system. Coordination requires communication, and thus our long-term interest is in how mitochondria transmit messages to regulate metabolic homeostasis. Mitochondrial signaling has emerged as a key regulator of aging, but signals that have been described to date are not encoded in the mitochondrial genome. The identification of Humanin, a peptide encoded in the mitochondrial DNA, provided a paradigm-shifting regulatory mechanism of mitochondrial communication. We have recently discovered a novel peptide encoded within the mitochondrial DNA and named it MOTS-c (Mitochondrial ORF within the Twelve S rRNA). MOTS-c acts on the skeletal muscle and promotes cellular glucose and fatty acid metabolism, mediated by the folate-AMPK pathway. In mice, MOTS-c regulates glucose homeostasis and prevents obesity and insulin-resistance in high-fat fed young mice. We have also obtained evidence supporting MOTS-c-dependent regulation of metabolic aging: (i) MOTS-c levels in mice decline with age in circulation and skeletal muscle concomitantly with the development of muscle insulin-resistance and (ii) systemic injection of MOTS-c for a week sufficiently reversed age-dependent muscle insulin resistance. We hypothesize that MOTS-c is a mitochondrial-encoded regulator of the folate-AMPK pathway that promotes metabolic homeostasis and that restoring the age-dependent decline of MOTS-c can reverse metabolic aging. We propose to study (i) the impact of aging on MOTS-c biology and conversely (ii) the effect of MOTS- c on aging metabolism. We will take a top-down approach with 3 aims to test our hypothesis.
Aim 1 will determine the age-dependent impact of MOTS-c on metabolic aging in mice.
Aim 2 will examine the role of MOTS-c in regulating cellular metabolism in young vs aged primary muscle cells.
Aim 3 will test the folate- AMPK pathway in mediating MOTS-c-dependent metabolism during aging. These findings will add an entirely novel 'mitochondrial-centric' mechanistic layer to the regulation of aging metabolism, and provide a new therapeutic target for age-dependent metabolic conditions.
Diet and metabolism are highly influential regulators of aging. Mitochondria are the single most important metabolic organelles that transmit messengers encoded in the mitochondrial DNA. Such mitochondrial communication system may provide an unprecedented 'mitochondrial-centric' mechanistic and therapeutic target for age-dependent metabolic conditions.
