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  • Mitohormesis in Hypothalamic POMC Neurons Mediates Regular Exercise-Induced High-Turnover Metabolism.

Mitohormesis in Hypothalamic POMC Neurons Mediates Regular Exercise-Induced High-Turnover Metabolism.

Cell metabolism (2021-02-04)
Gil Myoung Kang, Se Hee Min, Chan Hee Lee, Ji Ye Kim, Hyo Sun Lim, Min Jeong Choi, Saet-Byel Jung, Jae Woo Park, Seongjun Kim, Chae Beom Park, Hong Dugu, Jong Han Choi, Won Hee Jang, Se Eun Park, Young Min Cho, Jae Geun Kim, Kyung-Gon Kim, Cheol Soo Choi, Young-Bum Kim, Changhan Lee, Minho Shong, Min-Seon Kim
ABSTRACT

Low-grade mitochondrial stress can promote health and longevity, a phenomenon termed mitohormesis. Here, we demonstrate the opposing metabolic effects of low-level and high-level mitochondrial ribosomal (mitoribosomal) stress in hypothalamic proopiomelanocortin (POMC) neurons. POMC neuron-specific severe mitoribosomal stress due to Crif1 homodeficiency causes obesity in mice. By contrast, mild mitoribosomal stress caused by Crif1 heterodeficiency in POMC neurons leads to high-turnover metabolism and resistance to obesity. These metabolic benefits are mediated by enhanced thermogenesis and mitochondrial unfolded protein responses (UPRmt) in distal adipose tissues. In POMC neurons, partial Crif1 deficiency increases the expression of β-endorphin (β-END) and mitochondrial DNA-encoded peptide MOTS-c. Central administration of MOTS-c or β-END recapitulates the adipose phenotype of Crif1 heterodeficient mice, suggesting these factors as potential mediators. Consistently, regular running exercise at moderate intensity stimulates hypothalamic MOTS-c/β-END expression and induces adipose tissue UPRmt and thermogenesis. Our findings indicate that POMC neuronal mitohormesis may underlie exercise-induced high-turnover metabolism.

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