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

Abstract

Introduction: 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.

Areas covered: 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.

Expert opinion: 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.