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

Abstract

BackgroundThe 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 ResultsIn 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.ConclusionsThis evidence clearly illustrates that microcirculatory ischemia/reperfusion injury can be attributed to Mff‐dependent 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.

YAP Inhibits the Apoptosis and Migration of Human Rectal Cancer Cells via Suppression of JNK-Drp1-Mitochondrial Fission-HtrA2/Omi Pathways

“…Scrambled shRNA control or shRNA specific to Yap was constructed using a lentiviral shRNA technique (GeneChem), as described previously [10, 11]. The shRNA was used to generate the stable cell line SW837 without expression of Yap.…”

“…The mitochondrial functions were evaluated by ΔΨm, mPTP opening, mitochondrial OCR and respiratory chain complex activities as previously described [10]. The mitochondrial transmembrane potential was analyzed using a JC-1 Kit (Beyotime, China).…”

“…Previous studies [10, 11] have found that mitochondria also act as messengers to transmit or amplify damage signals via mitochondrial dynamics, a process that balances mitochondrial fusion and fission events to regulate the structure and function of the mitochondrion. Normally, mitochondrial fusion enables the exchange of proteins, lipids, and mitochondrial DNA and ATP across distances within the cell, which is essential to meet the metabolic demands of the cell [12].…”

“…However, mitochondrial fission (fragmentation) is essential for intrinsic apoptosis–it is necessary for cytochrome c (cyt-c) release and subsequent caspase activation [13]. Inhibition of dynamin-related protein 1 (Drp1)-dependent mitochondrial fission impairs and partially inhibits intrinsic apoptosis [10]. However, it is still unclear whether mitochondrial dynamics, especially fission, are vital for the RC phenotype related to RC survival and migration.…”

Effect of Mst1 on Endometriosis Apoptosis and Migration: Role of Drp1-Related Mitochondrial Fission and Parkin-Required Mitophagy

“…State 3 respiration was initiated by adding ADP (150 nmol/L); state 4 was measured as the rate of oxygen consumption after ADP phosphorylation. The respiratory control ratio (state 3/state 4) and the ADP/O ratio (number of nmol ADP phosphorylated to atoms of oxygen consumed) were calculated as previously described [35,36]. ]c was imaged with Fluo-2 (Molecular Probes).…”