Mff-dependent mitochondrial fission contributes to the pathogenesis of cardiac microvasculature ischemia/reperfusion injury via induction of mROS-mediated cardiolipin oxidation and HK2/VDAC1 disassociation-involved mPTP opening

Background-the cardiac microvascular system ischemia/reperfusion injury following percutaneous coronary intervention is a clinical thorny problem. this study explores the mechanisms by which ischemia/reperfusion injury induces cardiac microcirculation collapse. methods and results-in wild-type mice,mitochondrial fission factor (mff) expression increased in response to acute microvascular ischemia/reperfusion injury. compared with wild-type mice,homozygous mff-deficient (mffgt) mice exhibited a smaller infarcted area,restored cardiac function,improved blood flow,and reduced microcirculation perfusion defects. histopathology analysis demonstrated that cardiac microcirculation endothelial cells (cmecs) in mffgt mice had an intact endothelial barrier,recovered phospho-endothelial nitric oxide synthase production,opened lumen,undivided mitochondrial structures,and less cmec death. in vitro,mff-deficient cmecs (derived from mffgt mice or mff small interfering rna-treated) demonstrated less mitochondrial fission and mitochondrial-dependent apoptosis compared with cells derived from wild-type mice. the loss of mff inhibited mitochondrial permeability transition pore opening via blocking the oligomerization of voltage-dependent anion channel 1 and subsequent hexokinase 2 separation from mitochondria. moreover,mff deficiency reduced the cyt-c leakage into the cytoplasm by alleviating cardiolipin oxidation resulting from damage to the electron transport chain complexes and mitochondrial reactive oxygen species overproduction. conclusions-this evidence clearly illustrates that microcirculatory ischemia/reperfusion injury can be attributed to mffdependent mitochondrial fission via voltage-dependent anion channel 1/hexokinase 2-mediated mitochondrial permeability transition pore opening and mitochondrial reactive oxygen species/cardiolipin involved cyt-c release. © 2017 the authors.