Mitochondrial Quality Control Links Exercise to Sterile Inflammation in the Cardiovascular System: A Narrative Review

Abstract

Preservation of mitochondrial integrity has emerged as a central hub in the anti-inflammatory effect of exercise. This narrative review advances a framework in which mitochondrial damage-associated molecular patterns (mtDAMPs) serve as the mechanistic bridge between exercise and inflammation. Mitochondrial dysfunction releases mtDAMPs, including mitochondrial DNA (mtDNA), reactive oxygen species, cardiolipin, N-formyl peptides, and ATP, which activate cGAS–STING, the NLRP3 inflammasome, TLR9, AIM2, ZBP1, and NF-κB signaling. Crosstalk among these pathways allows mild mitochondrial damage to escalate into chronic inflammation. Exercise opposes this cascade through the AMPK–PGC-1α axis, which coordinately activates four mitochondrial quality control (MQC) modules: biogenesis, antioxidant defense, dynamics, and mitophagy. The cardiovascular system illustrates this framework, as myocardial inflammation runs mainly through mtDNA–cGAS–STING signaling and vascular inflammation through oxidized mtDNA–NLRP3 signaling, while cardiovascular aging engages both axes at once. Throughout, exercise refers to repeated training rather than to a single bout, and the framework targets middle-aged and older adults with, or at risk of, cardiovascular disease. The upstream half of the sequence, in which training raises mitochondrial content and antioxidant capacity, rests on human muscle biopsy data; the downstream half remains largely preclinical. MQC is therefore proposed as a testable target rather than an established one.