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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG052558-03
Application #
9472988
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Fridell, Yih-Woei
Project Start
2016-08-01
Project End
2021-04-30
Budget Start
2018-06-01
Budget End
2019-04-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
Other Specialized Schools
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Kim, Kyung Hwa; Son, Jyung Mean; Benayoun, Bérénice A et al. (2018) The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress. Cell Metab 28:516-524.e7
Choi, In Young; Lee, Changhan; Longo, Valter D (2017) Nutrition and fasting mimicking diets in the prevention and treatment of autoimmune diseases and immunosenescence. Mol Cell Endocrinol 455:4-12
Di Biase, Stefano; Shim, Hong Seok; Kim, Kyung Hwa et al. (2017) Correction: Fasting regulates EGR1 and protects from glucose- and dexamethasone-dependent sensitization to chemotherapy. PLoS Biol 15:e1002603
Lee, Young-Kyoung; Lim, Jin J; Jeoun, Un-Woo et al. (2017) Lactate-mediated mitoribosomal defects impair mitochondrial oxidative phosphorylation and promote hepatoma cell invasiveness. J Biol Chem 292:20208-20217
Di Biase, Stefano; Lee, Changhan; Brandhorst, Sebastian et al. (2016) Fasting-Mimicking Diet Reduces HO-1 to Promote T Cell-Mediated Tumor Cytotoxicity. Cancer Cell 30:136-146
Lee, Changhan; Kim, Kyung Hwa; Cohen, Pinchas (2016) MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism. Free Radic Biol Med 100:182-187