Myocardial ischemia/reperfusion injury (MI/RI) remains an unresolved problem despite reperfusion therapies, including percutaneous coronary intervention. Mitochondria are central mediators of reperfusion-associated cardiomyocyte injury, with excessive fission implicated as a potentially important mechanism linking acute metabolic stress to fragmentation, bioenergetic failure, and cell death. Reactive oxygen species, Ca2+ overload, mitochondrial permeability transition pore opening and membrane-potential loss promote dynamin-related protein 1-centered (Drp1-centered) fission, often involving mitochondrial fission factor, mitochondrial fission 1 protein and site-specific Drp1 phosphorylation. By disrupting mitochondrial networks and oxidative phosphorylation, this process contributes to cytochrome c release, apoptosis, microvascular dysfunction and impaired recovery. Impaired mitofusin 1/2-mediated and optic atrophy 1-mediated fusion limits repair and quality control, supporting investigation of this fission-dominant imbalance as a target for cardioprotection. Preclinical studies suggest plant-derived natural products, multi-component botanical preparations and electroacupuncture may influence this imbalance. Reported effects include attenuated Drp1 signaling, altered fusion-protein expression, preserved membrane potential, inhibited permeability transition, reduced oxidative stress and apoptosis, and modulated upstream metabolic/stress-responsive pathways. However, hypoxia/reoxygenation, oxygen-glucose deprivation/reoxygenation, non-reperfused ischemia/infarction and stress models provide surrogate or supportive evidence rather than direct evidence of MI/RI. Heterogeneity in models, timing, dosage, readouts, causal validation and botanical quality control limits interpretation. This review examines these mechanisms, interventions and translational priorities. Clinical efficacy and safety of these interventions in MI/RI have not been established.
