MOTS-c is a mitochondrial-encoded interferon-linked host defense peptide

This study identifies MOTS-c, a peptide encoded by mitochondrial DNA, as a host defense peptide with direct antibacterial and immunomodulatory functions. MOTS-c targeted E. coli and MRSA by disrupting their membranes, fully neutralized MRSA in a mouse peritonitis model, and was induced by immune signals in human monocytes and reprogrammed mouse macrophages toward enhanced bacterial clearance.

Journal article — Preclinical in vitro and mouse study. Population: Human monocytes, primary mouse monocytes/macrophages, and mice with acute peritonitis. Interventions: Exogenous MOTS-c peptide.

MOTS-c was identified as an amphipathic, cationic mitochondrial-encoded host defense peptide. It targeted E. coli and methicillin-resistant Staphylococcus aureus (MRSA), in part by interacting with their membranes through hydrophobic and cationic domains. In a mouse model of acute peritonitis, MOTS-c fully neutralized MRSA infectivity. In human monocytes, IFNγ, lipopolysaccharides, and differentiation signals each induced endogenous MOTS-c expression. Exogenous MOTS-c during primary mouse monocyte differentiation reprogrammed cells into macrophages with distinct transcriptomic signatures related to antigen presentation and IFN signaling, enhanced bacterial clearance, and shifted metabolism.

This paper is foundational for MOTS-c researchers because it provides evidence that MOTS-c is a mitochondrial-encoded host defense peptide linked to interferon signaling and macrophage function. It does not establish clinical dosing, safety, or efficacy in human disease, nor does it define a specific receptor or signaling pathway for MOTS-c's macrophage-reprogramming effects.

Key findings

• MOTS-c is an amphipathic and cationic mitochondrial-encoded peptide with properties consistent with known host defense peptides.
• MOTS-c targeted both Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA), in part by acting on their membranes.
• In a mouse model of acute peritonitis, MOTS-c fully neutralized MRSA infectivity.
• IFNγ, lipopolysaccharides, and differentiation signals each induced endogenous MOTS-c expression in human monocytes.
• Exogenous MOTS-c applied during primary mouse monocyte differentiation reprogrammed cells into macrophages with distinct transcriptomic signatures and enhanced bacterial clearance.
• MOTS-c-programmed macrophages exhibited shifted metabolism compared with unprogrammed cells.

Limitations

• Findings come from in vitro assays and a mouse model, so human clinical relevance is not established.
• The abstract reports no quantitative data such as effective doses, sample sizes, or effect magnitudes.
• Antibacterial activity was tested only against E. coli and MRSA, so the spectrum of activity is not defined.
• The abstract does not describe a mechanism for how MOTS-c reprograms macrophages or whether this occurs in human cells.

The record

• Journal: eLife 12: RP87615
• Published: 2026-08-18
• PMID: 42611943 — DOI: 10.7554/elife.87615
• MeSH terms: Monocytes, Mitochondria, Macrophages, Animals, Humans, Mice, Escherichia coli, Disease Models, Animal, Antimicrobial Cationic Peptides, Mitochondrial Proteins, DNA, Mitochondrial, Interferon-gamma, Methicillin-Resistant Staphylococcus aureus, Antimicrobial Peptides, Micropeptides
• Funding: NIA NIH HHS; NIGMS NIH HHS; Pew Charitable Trusts; NIA NIH HHS; NIA NIH HHS; NIA NIH HHS; NIA NIH HHS
• Author countries: South Korea, USA

Peptide profiles: MOTS-c.

All indexed evidence: MOTS-c trials & papers.

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