The Mitophagy Vortex: Bridging Inflammatory, Oxidative, Hypoxic, and Aging Insults to Drive COPD Skeletal Muscle...

Skeletal muscle dysfunction is a frequent extrapulmonary complication of chronic obstructive pulmonary disease (COPD) that limits physical capacity and increases mortality. Systemic inflammation, oxidative stress, hypoxia, and aging are distinct in origin and signaling, yet each has been implicated in COPD muscle deterioration. Whether these four drivers converge on a common pathway remains unclear. This review proposes that mitophagy, the selective elimination of damaged mitochondria, serves as this hub. Rather than acting in isolation, the four drivers converge through two functionally distinct amplification axes. The inflammatory-oxidative axis escalates mitochondrial injury, while the hypoxic-aging axis progressively erodes lysosomal disposal capacity, lowering the threshold for quality-control failure. Once injury load outruns clearance capacity, retained damaged mitochondria release mtDNA and overproduce ROS, which amplify upstream inflammatory signals and further impair lysosomal function, a self-reinforcing disequilibrium in which each iteration amplifies the next. This architecture, which we term the mitophagy vortex, implies that the four factors do not add linearly but multiply through a common quality-control node, explaining why single-target interventions have consistently failed. The framework predicts that restoring lysosomal acidification or autophagic flux, rather than neutralizing individual cytokines or ROS, may carry greater therapeutic weight once the vortex is established. Targeting the mitophagy machinery at multiple levels, including its receptors, enzymes, and lysosomal function, represents a mechanistically coherent strategy for breaking the pathological cycle.