MOTS-c emerges as promising biomarker and therapeutic target for inflammatory lung diseases

Mitochondrial dysfunction is a critical driver in the pathogenesis of acute and chronic respiratory diseases, contributing to oxidative stress, inflammation, and cell death. Current therapies often fall short in fully addressing these underlying mechanisms. MOTS-c, a mitochondrial-derived microprotein (mitokine), has garnered attention beyond its initial role in metabolic homeostasis, demonstrating broad modulatory effects on oxidative stress, inflammation, autophagy, and mitochondrial function. This positions it as a compelling candidate to address the mechanistic gaps in treating inflammatory lung diseases.

This comprehensive review synthesized findings from available experimental and clinical studies investigating MOTS-c in various respiratory diseases. Researchers analyzed evidence across diverse preclinical models and human observational studies, focusing on MOTS-c's role in modulating inflammation, oxidative stress, and mitochondrial function. The review assessed patterns of circulating MOTS-c levels in both acute respiratory distress and chronic conditions like chronic obstructive pulmonary disease (COPD), and evaluated the impact of exogenous MOTS-c administration in preclinical models of lung injury.

Across multiple studies, circulating MOTS-c levels were consistently found to be reduced in different forms of acute respiratory distress. Exogenous administration of MOTS-c attenuated lung injury in preclinical models, suggesting a protective role. Remote ischemic preconditioning, a known protective mechanism, appears to exert some of its benefits through MOTS-c release. > In chronic respiratory diseases such as chronic obstructive pulmonary disease, obstructive sleep apnea, and asthma, decreased MOTS-c concentrations were observed, correlating with severe mitochondrial dysfunction and reduced cytoprotective capacity. Preliminary observations in lung cancer suggested increased MOTS-c levels, potentially linked to NRF2-mediated antioxidant responses, though these findings require further validation.