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

MOTS-c is a mitochondrial-derived microprotein (mitokine) encoded within the 12 S rRNA gene that exerts intracrine, paracrine, and endocrine effects across multiple tissues. Although initially described as a regulator of metabolic homeostasis, growing evidence indicates that MOTS-c also modulates oxidative and toxic stress, inflammation, autophagy, cell death (apoptosis, ferroptosis, pyroptosis, among others), mitochondrial dysfunction, and immune responses-key mechanisms involved in acute and chronic respiratory diseases.

Available experimental and clinical studies suggest that circulating MOTS-c levels are reduced in different forms of acute respiratory distress, while exogenous administration attenuates lung injury in preclinical models. Remote ischemic preconditioning appears to exert part of its protective effects through MOTS-c release. In contrast, chronic respiratory diseases such as chronic obstructive pulmonary disease, 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 levels in lung cancer, potentially related to NRF2-mediated antioxidant responses, although these findings require further validation.

Current evidence positions MOTS-c as a promising biomarker and potential therapeutic candidate in respiratory medicine. Well-designed translational and multicenter clinical studies are needed to determine whether modulation or supplementation of MOTS-c can influence disease progression and clinical outcomes in inflammatory lung diseases.