The mitochondrial-encoded microprotein MOTS-c regulates interferon signaling under age-related metabolic stress in macrophages 4772

Abstract Description Mitochondria are increasingly being appreciated as regulators of immune signaling, including during age-related metabolic dysfunction. Components of the mitochondria, including mitochondrial DNA (mtDNA), can trigger immune responses. However, mtDNA is not known to encode for immune factors. Our lab previously identified a mitochondrial-encoded microprotein named MOTS-c that regulates nuclear gene expression during metabolic stress and increases healthspan in mice. Our recent findings support that MOTS-c is a novel host defense peptide with immunomodulatory functions in monocyte-derived macrophages. In macrophages, interferon signals induced the expression and nuclear translocation of MOTS-c. Macrophage function is governed in part by shifts in metabolism that occur with age. Treatment of macrophages with MOTS-c under metabolic stress led to altered mitochondrial metabolism, phagocytosis, and chemokine expression. Because MOTS-c translocates to the nucleus during metabolic stress and regulates macrophage function, we hypothesized that MOTS-c would regulate macrophage gene expression. To test our hypothesis, we performed RNA-seq on bone marrow-derived macrophages of both sexes treated with/without MOTS-c. MOTS-c-treated macrophages were enriched for expression of interferon-related genes in a stress- and sex-dependent manner. These findings support that MOTS-c is a first-in-class mitochondrial-encoded immune factor that regulates macrophage function under metabolic stress. Funding Sources Funding was provided by the USC Leonard Davis School of Gerontology, NIA (T32AG052374, F31AG082606, R56AG069955, & R01AG084214), AFAR, and Hevolution. Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)