Ischemic heart disease (IHD) remains the leading cause of death and disability worldwide. For patients presenting with an acute
myocardial infarction, the most effective treatment for limiting
myocardial infarct (MI) size is timely reperfusion. However, in addition to the injury incurred during acute
myocardial ischemia, the process of reperfusion can itself induce myocardial injury and cardiomyocyte death, termed '
myocardial reperfusion injury', the combination of which can be referred to as acute
ischemia-reperfusion injury (IRI). Crucially, there is currently no effective
therapy for preventing this form of injury, and novel cardioprotective
therapies are therefore required to protect the heart against acute IRI in order to limit MI size and preserve cardiac function. The opening of the
mitochondrial permeability transition pore (MPTP) in the first few minutes of reperfusion is known to be a critical determinant of IRI, contributing up to 50% of the final MI size. Importantly, preventing its opening at this time using
MPTP inhibitors, such as
cyclosporin-A, has been reported in experimental and clinical studies to reduce MI size and preserve cardiac function. However, more specific and novel
MPTP inhibitors are required to translate
MPTP inhibition as a cardioprotective strategy into clinical practice. In this article, we review the role of the
MPTP as a mediator of acute myocardial IRI and as a therapeutic target for cardioprotection. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to
Cardiovascular Disease".