Longevity & AgingMitochondria Encode a Potent Immune Peptide That Fights Bacteria and Programs Macrophages
Researchers at USC have discovered that MOTS-c, a microprotein encoded in the mitochondrial genome, functions as a bona fide host defense peptide (HDP). The 16-amino-acid peptide is amphipathic and cationic—hallmarks of antimicrobial peptides—and directly kills E. coli and methicillin-resistant Staphylococcus aureus (MRSA) by disrupting bacterial membranes. In a mouse peritonitis model, MOTS-c fully neutralized MRSA infection. In human monocytes, interferon gamma, LPS, and differentiation signals each upregulated endogenous MOTS-c. When applied during primary mouse monocyte-to-macrophage differentiation, MOTS-c reprogrammed cells toward enhanced bacterial clearance, altered metabolism, and distinct antigen-presentation and interferon-signaling transcriptomes. These findings establish MOTS-c as the first mitochondrial-encoded immune factor, expanding the known genome-encoded immune repertoire beyond the nucleus.
