Strategic targeting of mitochondria in ischemic heart disease: mechanisms and emerging therapies

Ischemic heart disease (IHD) remains a leading cause of global morbidity and mortality. Mitochondrial dysfunction is central to ischemia - reperfusion injury, contributing to bioenergetic failure, oxidative stress, calcium overload, and impaired adaptive responses, making mitochondria an important therapeutic target.

This review integrates mechanistic and translational evidence linking mitochondrial dysfunction, structural injury, and adaptive-response failure in IHD. Key pathways discussed include reverse electron transport - driven reactive oxygen species generation, mitochondrial permeability transition pore activation, disrupted fusion - fission dynamics, mitophagy imbalance, and proteostasis collapse. Emerging therapeutic strategies such as mitochondria-targeted antioxidants, cardiolipin-stabilizing peptides, metabolic modulators, mitochondrial transplantation, and genome-directed approaches are evaluated alongside diagnostic innovations, including circulating mitochondrial DNA, mitomiRs, and molecular imaging. A structured literature search was conducted using PubMed/MEDLINE, Scopus, and Web of Science for English-language studies published between January 2000 and March 2025.

Precision targeting of mitochondrial injury and adaptive failure offers stage-specific therapeutic opportunities in IHD; however, successful translation requires biomarker-guided stratification, optimized delivery systems, and temporally aligned clinical trial design.