Background— Whether alterations in mitochondrial morphology affect the susceptibility of the heart to ischemia/reperfusion injury is unknown. We hypothesized that modulating mitochondrial morphology protects the heart against ischemia/reperfusion injury. Methods and Results— In response to ischemia, mitochondria in HL-1 cells (a cardiac-derived cell line) undergo fragmentation, a process that is dependent on the mitochondrial fission protein dynamin-related protein 1 (Drp1). Transfection of HL-1 cells with the mitochondrial fusion proteins mitofusin 1 or 2 or with Drp1 _K38A , a dominant-negative mutant form of Drp1, increased the percentage of cells containing elongated mitochondria (65±4%, 69±5%, and 63±6%, respectively, versus 46±6% in control: n=80 cells per group; P <0.05), decreased mitochondrial permeability transition pore sensitivity (by 2.4±0.5-, 2.3±0.7-, and 2.4±0.3-fold, respectively; n=80 cells per group; P <0.05), and reduced cell death after simulated ischemia/reperfusion injury (11.6±3.9%, 16.2±3.9%, and 12.1±2.9%, respectively, versus 41.8±4.1% in control: n=320 cells per group; P <0.05). Treatment of HL-1 cells with mitochondrial division inhibitor-1, a pharmacological inhibitor of Drp1, replicated these beneficial effects. Interestingly, elongated interfibrillar mitochondria were identified in the adult rodent heart with confocal and electron microscopy, and in vivo treatment with mitochondrial division inhibitor-1 increased the percentage of elongated mitochondria from 3.6±0.5% to 14.5±2.8% ( P =0.023). Finally, treatment of adult murine cardiomyocytes with mitochondrial division inhibitor-1 reduced cell death and inhibited mitochondrial permeability transition pore opening after simulated ischemia/reperfusion injury, and in vivo treatment with mitochondrial division inhibitor-1 reduced myocardial infarct size in mice subject to coronary artery occlusion and reperfusion (21.0±2.2% with mitochondrial division inhibitor-1 versus 48.0±4.5% in control; n=6 animals per group; P <0.05). Conclusion— Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury, suggesting a novel pharmacological strategy for cardioprotection.

Acute myocardial infarction (AMI) and the heart failure that often follows, are major causes of death and disability worldwide. As such, new therapies are required to limit myocardial infarct (MI) size, prevent adverse left ventricular (LV) remodeling, and reduce the onset of heart failure following AMI. The inflammatory response to AMI, plays a critical role in determining MI size, and a persistent pro-inflammatory reaction can contribute to adverse post-MI LV remodeling, making inflammation an important therapeutic target for improving outcomes following AMI. In this article, we provide an overview of the multiple players (and their dynamic roles) involved in the complex inflammatory response to AMI and subsequent LV remodeling, and highlight future opportunities for targeting inflammation as a therapeutic strategy for limiting MI size, preventing adverse LV remodeling, and reducing heart failure in AMI patients.

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".

Mitochondria are dynamic and are able to interchange their morphology between elongated interconnected mitochondrial networks and a fragmented disconnected arrangement by the processes of mitochondrial fusion and fission, respectively. Changes in mitochondrial morphology are regulated by the mitochondrial fusion proteins (mitofusins 1 and 2, and optic atrophy 1) and the mitochondrial fission proteins (dynamin-related peptide 1 and mitochondrial fission protein 1) and have been implicated in a variety of biological processes including embryonic development, metabolism, apoptosis, and autophagy, although the majority of studies have been largely confined to non-cardiac cells. Despite the unique arrangement of mitochondria in the adult heart, emerging data suggest that changes in mitochondrial morphology may be relevant to various aspects of cardiovascular biology—these include cardiac development, the response to ischaemia–reperfusion injury, heart failure, diabetes mellitus, and apoptosis. Interestingly, the machinery required for altering mitochondrial shape in terms of the mitochondrial fusion and fission proteins are all present in the adult heart, but their physiological function remains unclear. In this article, we review the current developments in this exciting new field of mitochondrial biology, the implications for cardiovascular physiology, and the potential for discovering novel therapeutic strategies for treating cardiovascular disease.

Mitochondria are dynamic organelles capable of changing their shape and distribution by undergoing either fission or fusion. Changes in mitochondrial dynamics, which is under the control of specific mitochondrial fission and fusion proteins, have been implicated in cell division, embryonic development, apoptosis, autophagy, and metabolism. Although the machinery for modulating mitochondrial dynamics is present in the cardiovascular system, its function there has only recently been investigated. In this article, we review the emerging role of mitochondrial dynamics in cardiovascular health and disease. Changes in mitochondrial dynamics have been implicated in vascular smooth cell proliferation, cardiac development and differentiation, cardiomyocyte hypertrophy, myocardial ischemia-reperfusion injury, cardioprotection, and heart failure. Many of the experimental studies investigating mitochondrial dynamics in the cardiovascular system have been confined to cardiac cell lines, vascular cells, or neonatal cardiomyocytes, in which mitochondria are distributed throughout the cytoplasm and are free to move. However, in the adult heart where mitochondrial movements are restricted by their tightly-packed distribution along myofibrils or beneath the subsarcolemma, the relevance of mitochondrial dynamics is less obvious. The investigation of transgenic mice deficient in cardiac mitochondrial fission or fusion proteins should help elucidate the role of mitochondrial dynamics in the adult heart. Investigating the role of mitochondrial dynamics in cardiovascular health and disease should result in the identification of novel therapeutic targets for treating patients with cardiovascular disease, the leading cause of death and disability globally.