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

This review paper examines MOTS-c, a mitochondrial-derived microprotein (mitokine) encoded within the 12S rRNA gene, and its potential role in inflammatory lung diseases. The authors synthesize available experimental and clinical literature to explore how MOTS-c influences metabolic homeostasis, oxidative stress, inflammation, autophagy, cell death pathways (including apoptosis, ferroptosis, and pyroptosis), mitochondrial dysfunction, and immune responses. Key findings reported across the reviewed studies include: reduced circulating MOTS-c levels in various forms of acute respiratory distress; attenuation of lung injury following exogenous MOTS-c administration in preclinical models; a partial mechanistic link between remote ischemic preconditioning and MOTS-c release; decreased MOTS-c concentrations in chronic conditions such as COPD, obstructive sleep apnea, and asthma; and preliminary observations of elevated MOTS-c in lung cancer, tentatively attributed to NRF2-mediated antioxidant responses. The authors conclude that MOTS-c holds promise as both a biomarker and therapeutic candidate in respiratory medicine, while acknowledging that current evidence is largely preclinical and that well-designed translational and multicenter clinical trials are needed to confirm any clinical utility. Limitations include the heterogeneity of reviewed study designs and the early-stage, preliminary nature of much of the evidence.

Why this grade: This is a narrative review synthesizing preclinical and limited clinical studies; it does not itself generate primary human trial data, so evidence grading reflects the review design rather than direct experimental findings.