Mitochondrial oxidative stress, calcium and dynamics in cardiac ischaemia-reperfusion injury.

Abstract

Ischaemia-reperfusion injury (IRI) is a major cause of cardiomyocyte damage and death from myocardial infarction. Oxidative stress, dysregulated calcium (Ca²⁺) handling and disrupted mitochondrial dynamics are all key factors in IRI and can play a role in cell death. Mitochondria are a primary source of oxidative stress, which is generated by electron leak from the respiratory chain complexes and the oxidation of accumulated succinate upon reperfusion. The mitochondrial permeability transition pore (mPTP), a high conductance channel that forms following reperfusion of ischaemic mitochondria, has been implicated in reperfusion-induced cell death. Although factors including mitochondrial Ca²⁺ overload and oxidative stress that regulate mPTP opening have been well characterized, the composition of the mPTP is still actively investigated. Clinically, mPTP opening and IRI complicate treatment of myocardial infarction. Therefore, many possible therapeutics to reduce the damaging effects of reperfusion are under investigation. Antioxidants, pharmaceutical approaches, postconditioning and synthetic polymers have all been investigated for use in IRI. Still, many of these therapeutics of interest have shown mixed evidence underlying their use in preclinical and clinical research. In this review we discuss our current understanding of the contributions of mitochondrial oxidative stress, mitochondrial Ca²⁺ and mitochondrial dynamics to cardiomyocyte damage and death in IRI, and where further clarification of these mechanisms is needed to identify potential therapeutic targets.