title: 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: 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.
  
  
  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 Mffgtmice 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 Mffgtmice 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 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.
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Shunying
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Qinhua
authors.initials: Q
authors.lastname: Jin
authors.affiliation: Department of Radiation Oncology, Peking University Cancer Hospital and Institute, Beijing, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Shi
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Pingjun
authors.initials: P
authors.lastname: Zhu
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Tian
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing, China yundaic@163.com cyundai@vip.163.com.
authors.forename: Yundai
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002308:Cardiolipins / Q000096:biosynthesis / Q000235:genetics*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004272:DNA, Mitochondrial / Q000235:genetics; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D006593:Hexokinase / Q000096:biosynthesis / Q000235:genetics*; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008833:Microcirculation / Q000187:drug effects*; D055806:Microvessels / Q000503:physiopathology; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D063154:Mitochondrial Dynamics / Q000187:drug effects / Q000235:genetics; D033681:Mitochondrial Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics*; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000648:ultrastructure; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D050995:Voltage-Dependent Anion Channel 1 / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D002308:Cardiolipins; D004272:DNA, Mitochondrial; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C494763:Vdac1 protein, mouse; C000603499:mitochondrial fission factor, mouse; D050995:Voltage-Dependent Anion Channel 1; D006593:Hexokinase; C000598049:hexokinase 2, mouse
keywords: apoptosis; endothelial cell; ischemia/reperfusion injury; mitochondria