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

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 mitochondria! ribosomal (mitoribosomal) stress in hypothalamic proopiomelanocortin (POMC) neurons. POMC neuron -specific severe mitoribosomal stress due to Crifl homodeficiency causes obesity in mice. By contrast, mild mitoribosomal stress caused by Crifl 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 Crifl deficiency increases the expression of 1i -endorphin ((i-END) and mitochondria! DNA -encoded peptide MOTS -c. Central administration of MOTS -c or ii -END recapitulates the adipose phenotype of Crifl heterodeficient mice, suggesting these factors as potential mediators. Consistently, regular running exercise at moderate intensity stimulates hypothalamic MOTS-cM-END expression and induces adipose tissue UPRmt and thermogenesis. Our findings indicate that POMC neuronal mitohormesis may underlie exercise -induced high -turnover metabolism.