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The immune system is traditionally thought to be exclusively nuclear-encoded. Here, we report the identification of a host defense peptide (HDP) encoded in the human mitochondrial genome that presumably derives from the primordial proto-mitochondrial bacteria. We demonstrate that MOTS-c (mitochondrial open reading frame from the 12 S rRNA type-c) is a mitochondrial-encoded amphipathic and cationic peptide with direct antibacterial and immunomodulatory functions, consistent with the peptide chemistry and functions of known HDPs. MOTS-c targeted\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    and methicillin-resistant\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    (MRSA), in part, by targeting their membranes using its hydrophobic and cationic domains. In a mouse model of acute peritonitis, MOTS-c fully neutralized MRSA infectivity. In human monocytes, interferon gamma (IFN\u03b3), lipopolysaccharides (LPS), and differentiation signals each induced the expression of endogenous MOTS-c. Notably, exogenous MOTS-c, applied during primary mouse monocyte differentiation, reprogrammed the cells into macrophages with distinct transcriptomic signatures related to antigen presentation and IFN signaling. MOTS-c-programmed macrophages exhibited enhanced bacterial clearance and shifted metabolism. Our findings support MOTS-c as a first-in-class mitochondrial-encoded HDP and indicate that our immune system is not only encoded by the nuclear genome but also by the co-evolved mitochondrial genome.\n                  <\/jats:p>","DOI":"10.7554\/elife.87615","type":"journal-article","created":{"date-parts":[[2023,7,26]],"date-time":"2023-07-26T10:27:59Z","timestamp":1690367279000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.87615","source":"Crossref","is-referenced-by-count":1,"title":["MOTS-c is a mitochondrial-encoded interferon-linked host defense peptide"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6452-4610","authenticated-orcid":true,"given":"Michelle C","family":"Rice","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03taz7m60","id-type":"ROR","asserted-by":"publisher"}],"name":"Leonard Davis School of Gerontology, University of Southern California","place":["Los Angeles, United 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