Mitochondrial-encoded immune (micro)proteins in health and disease 4632

Abstract Description We recently identified a first-in-class immune (micro)protein encoded in the human mitochondrial genome, which we named MOTS-c. While mitochondrial DNA (mtDNA) can trigger immune responses and entrap pathogens, it has not been known to encode active immune proteins, as the immune system thought to be exclusively nuclear-encoded. MOTS-c functions as a host defense peptide (HDP) and, consistent with known HDPs, can directly target bacteria and reprogram immune cells, including myeloid cell differentiation and T cell activation in autoimmune type 1 diabetes, thereby preventing disease onset in a mouse model (NOD mice). MOTS-c is expressed by and acts on multiple cell types, and thus has been referred to as a mitochondrial-encoded cytokine (mitokine). Mitochondria presumably originate from bacteria through endosymbiosis, a unique form of infection whereby bacteria and our ancestral cell communicated to establish eukaryotic life. Today, bacteria still communicate via gene-encoded microproteins (a.k.a. bacteriocins) that regulate specific cellular functions, such as ribosomes and protein metabolism, consistent with the functions of MOTS-c in mammalian cells. Here, we will present our recent findings on the cellular mechanisms that may underlie the immunological function of MOTS-c in aging and age-related diseases. Understanding mitochondrial-encoded immune microproteins and their integration to well-described immune systems may add an entirely new layer to mammalian immunity. Funding Sources NIH (R01 AG052558, R56 AG069955, R01 GM136837, T32 AG052374, F31 AG082606), Larry L. Hillblom Foundation (LLHF), Hanson-Thorell Family, Hevolution Foundation, AFAR, and the Ellison Medical Foundation Topic Categories Immune Mechanisms of Human Disease (HUM)