Diabetes Metab J.  2022 May;46(3):402-413. 10.4093/dmj.2022.0092.

Exercise, Mitohormesis, and Mitochondrial ORF of the 12S rRNA Type-C (MOTS-c)

• Yoon TK
• Lee CH
• Kwon O
• Kim MS

• KMID: 2530179
• DOI: http://doi.org/10.4093/dmj.2022.0092

Abstract

Low levels of mitochondrial stress are beneficial for organismal health and survival through a process known as mitohormesis. Mitohormetic responses occur during or after exercise and may mediate some salutary effects of exercise on metabolism. Exercise-related mitohormesis involves reactive oxygen species production, mitochondrial unfolded protein response (UPR^mt), and release of mitochondria-derived peptides (MDPs). MDPs are a group of small peptides encoded by mitochondrial DNA with beneficial metabolic effects. Among MDPs, mitochondrial ORF of the 12S rRNA type-c (MOTS-c) is the most associated with exercise. MOTS-c expression levels increase in skeletal muscles, systemic circulation, and the hypothalamus upon exercise. Systemic MOTS-c administration increases exercise performance by boosting skeletal muscle stress responses and by enhancing metabolic adaptation to exercise. Exogenous MOTS-c also stimulates thermogenesis in subcutaneous white adipose tissues, thereby enhancing energy expenditure and contributing to the anti-obesity effects of exercise training. This review briefly summarizes the mitohormetic mechanisms of exercise with an emphasis on MOTS-c.

Keyword

Exercise; Hormesis; Mitochondria; Mitochondrial proteins; MOTS-c peptide, human; Obesity

Figure

• 

  Fig. 1. Mitochondrial changes in response to acute exercise or exercise training. Exercise induces a variety of changes in mitochondria depending on the exercise intensity, duration, and frequency. Exercise increases mitochondrial mass through increasing mitochondrial biogenesis and increases inner mitochondrial membrane surface through cristae remodeling. These changes lead to increased mitochondrial respiration and oxidative metabolism. Exercise also promotes overall mitochondrial fusion and autophagy, which may help to maintain mitochondrial function and homeostasis during exercise-induced stress. MFN1, mitofusin 1; MFN2, mitofusin 2; OPA1, optic atrophy 1; DRP1, dynamin related protein 1; OXPHOS, oxidative phosphorylation; TCA: tricarboxylic acid; NADH, nicotinamide adenine dinucleotide (reduced); FADH2, flavin adenine dinucleotide (reduced).

• 

  Fig. 2. Mitohormetic responses to exercise. Exercise induces beneficial stress responses in mitochondria in a process known as mitohormesis. Exercise increases the production of reactive oxygen species (ROS) and triggers mitochondrial unfolded protein responses (UPRmt). However, exercise-induced mitochondrial stress also stimulates the production and release of myomitokines (growth differentiation factor 15 [GDF15] and fibroblast growth factor 21 [FGF21]) as well as mitochondrial DNA (mtDNA)-derived peptides (humanin and mitochondrial ORF of the 12S rRNA type-c [MOTS-c]), all of which have beneficial metabolic effects. PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; NRF1, nuclear respiratory factor 1; mtTFA, mitochondrial transcription factor A; JNK, c-Jun N-terminal kinase; eIF2α, eukaryotic initiation factor-2α; ATF4, activating transcription factor 4; AP-1, activating protein-1; CHOP, C/EBP-homologous protein; eIF1α-P, phosphorylated eukaryotic initiation factor-1α; ISR, integrated stress response.

• 

  Fig. 3. Roles of the mitochondria-derived peptide mitochondrial ORF of the 12S rRNA type-c (MOTS-c) in exercise physiology. (A) MOTS-c production is increased in exercising skeletal muscle in a reactive oxygen species (ROS)-dependent manner. MOTSc translocates to the nucleus to modulate gene expression profiles involved in stress adaptation, mitochondrial biogenesis, and mitochondrial dynamics. This mechanism may contribute to enhanced exercise capacity induced by exercise training. (B) Exercise enhances MOTS-c expression in hypothalamic proopiomelanocortin (POMC) neurons, likely through exercise-related myokines, such as interleukin-6 (IL-6). MOTS-c stimulates POMC transcription and β-endorphin production, which in turn increases sympathetic nerve activity innervating the inguinal subcutaneous white adipose tissue, and consequently, the beiging of inguinal subcutaneous white adipose tissue (iWAT) and enhanced thermogenesis are induced. This mechanism may underlie exerciseinduced thermogenesis. AMPK, AMP activated protein kinase; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; HSF1, heat shock factor 1; HO-1, heme oxygenase-1; NRF2, nuclear respiratory factor 2; ARH, arcuate nucleus of the hypothalamus; 3V, the third cerebroventricle; SNS, sympathetic nervous system.

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