MOTS-c: How a secreted mitochondrial microprotein may become a potential treatment for inflammatory lung diseases. — VialBase Research

Summary

This narrative review synthesizes experimental and clinical evidence on MOTS-c, a mitochondrial-derived microprotein encoded within the 12S rRNA gene, as a regulator of respiratory disease. Beyond its established role in metabolic homeostasis, the authors describe how MOTS-c modulates oxidative and toxic stress, inflammation, autophagy, cell death (apoptosis, ferroptosis, pyroptosis), mitochondrial dysfunction, and immune responses — mechanisms central to acute and chronic lung disease. The review evaluates MOTS-c as both a biomarker and a candidate therapeutic in respiratory medicine.

Key Findings

• MOTS-c acts as a mitokine with intracrine, paracrine, and endocrine effects across multiple tissues
• Circulating MOTS-c is reduced in various forms of acute respiratory distress; exogenous administration attenuates lung injury in preclinical models
• Remote ischemic preconditioning appears to mediate part of its protection through MOTS-c release
• Chronic respiratory diseases — COPD, obstructive sleep apnea, and asthma — are characterized by decreased MOTS-c concentrations, reflecting severe mitochondrial dysfunction and reduced cytoprotective capacity
• Preliminary observations suggest increased MOTS-c in lung cancer, potentially linked to NRF2-mediated antioxidant responses, but these require further validation

Relevance to MOTS-c

This review extends the MOTS-c literature from its well-characterized metabolic and exercise biology into respiratory medicine, framing the peptide as a cytoprotective mitokine whose circulating levels track inversely with lung mitochondrial dysfunction. It consolidates the rationale for testing MOTS-c supplementation or modulation in inflammatory lung disease, while candidly noting that the clinical evidence is still preliminary and that well-designed translational and multicenter studies are needed. The proposed biomarker role complements mechanistic work on MOTS-c in other tissues.

Citation

Amado CA, Agüero J, García-Unzueta M, et al. MOTS-c: How a secreted mitochondrial microprotein may become a potential treatment for inflammatory lung diseases. Journal of translational medicine. 2026. doi:10.1186/s12967-026-08398-2.

See Also

• Parent compound: MOTS-c