This study investigates the protective effects of modulating mitochondrial morphology against ischemia/reperfusion (IR) injury in the heart. The researchers hypothesized that altering mitochondrial morphology could protect the heart from IR injury. They used HL-1 cells, a cardiac-derived cell line, to test this hypothesis. By transfecting HL-1 cells with mitochondrial fusion proteins (mitofusin 2 or Drp1K38A, a dominant-negative mutant of the mitochondrial fission protein Drp1), they increased the percentage of cells containing elongated mitochondria, reduced mitochondrial permeability transition pore (mPTP) sensitivity, and decreased cell death after simulated ischemia/reperfusion injury (SIRI). The beneficial effects were replicated using the pharmacological inhibitor of Drp1, mitochondrial division inhibitor-1 (mdvi-1). Confocal and electron microscopy revealed elongated mitochondria in adult rodent hearts, and in vivo treatment with mdvi-1 increased the percentage of elongated mitochondria. Additionally, mdvi-1 reduced cell death and inhibited mPTP opening in adult murine cardiomyocytes after SIRI, and decreased myocardial infarct size in a murine model of IR injury. These findings suggest that inhibiting mitochondrial fission through pharmacological means may provide a novel therapeutic strategy for cardioprotection against IR injury.This study investigates the protective effects of modulating mitochondrial morphology against ischemia/reperfusion (IR) injury in the heart. The researchers hypothesized that altering mitochondrial morphology could protect the heart from IR injury. They used HL-1 cells, a cardiac-derived cell line, to test this hypothesis. By transfecting HL-1 cells with mitochondrial fusion proteins (mitofusin 2 or Drp1K38A, a dominant-negative mutant of the mitochondrial fission protein Drp1), they increased the percentage of cells containing elongated mitochondria, reduced mitochondrial permeability transition pore (mPTP) sensitivity, and decreased cell death after simulated ischemia/reperfusion injury (SIRI). The beneficial effects were replicated using the pharmacological inhibitor of Drp1, mitochondrial division inhibitor-1 (mdvi-1). Confocal and electron microscopy revealed elongated mitochondria in adult rodent hearts, and in vivo treatment with mdvi-1 increased the percentage of elongated mitochondria. Additionally, mdvi-1 reduced cell death and inhibited mPTP opening in adult murine cardiomyocytes after SIRI, and decreased myocardial infarct size in a murine model of IR injury. These findings suggest that inhibiting mitochondrial fission through pharmacological means may provide a novel therapeutic strategy for cardioprotection against IR injury.