Elucidating Mitochondrial Electron Transport Chain Supercomplexes in the Heart During Ischemia-Reperfusion.
Mitochondrial supercomplexes (SCs) are the large supramolecular assembly of individual electron transport chain (ETC) complexes that apparently provide highly efficient ATP synthesis and reduce electron leakage and reactive oxygen species (ROS) production. Oxidative stress during cardiac ischemia-reperfusion (IR) can result in degradation of SCs through oxidation of cardiolipin (CL). Also, IR induces calcium overload and enhances reactive oxygen species (mitROS) in mitochondria that result in the opening of the nonselective permeability transition pores (PTP). The opening of the PTP further compromises cellular energetics and increases mitROS ultimately leading to cell death. Here, we examined the role of PTP-induced mitROS in disintegration of SCs during cardiac IR. The relationship between mitochondrial PTP, ROS, and SCs was investigated using Langendorff-perfused rat hearts subjected to global ischemia (25 min) followed by short-time (5 min) or long-time (60 min) reperfusion in the presence or absence of the PTP inhibitor, sanglifehrin A (SfA), and the mitochondrial targeted ROS and electron scavenger, XJB-5-131. Also, the effects of CL deficiency on SC degradation, PTP, and mitROS were investigated in tafazzin knockdown (TazKD) mice.



Cardiac IR induced PTP opening and mitROS generation, inhibited by SfA. Percent distributions of SCs were significantly affected by IR, and the effects were dependent on the reperfusion time and reversed by SfA and XJB-5-131. TazKD mice demonstrated a 40% lower SC I + III+IV with reduced basal mitochondrial PTP, ROS, and ETC complex activity. Innovation and Conclusion: Sustained reperfusion after cardiac ischemia induces disintegration of mitochondrial SCs, and PTP-induced ROS presumably play a causal role in SC disassembly. Antioxid. Redox Signal. 27, 57-69.
1 Department of Physiology, University of Puerto Rico School of Medicine , San Juan, Puerto Rico .
Sehwan
S
Jang
2 Department of Chemistry, University of Pittsburgh , Pittsburgh, Pennsylvania.
Taber S
TS
Lewis
3 The Heart Institute, Cincinnati Children's Medical Center and University of Cincinnati , Cincinnati, Ohio.
Corey
C
Powers
3 The Heart Institute, Cincinnati Children's Medical Center and University of Cincinnati , Cincinnati, Ohio.
Zaza
Z
Khuchua
4 Department of Biomedical Sciences, University of Missouri-Columbia , Columbia, Missouri.
Christopher P
CP
Baines
2 Department of Chemistry, University of Pittsburgh , Pittsburgh, Pennsylvania.
Peter
P
Wipf
1 Department of Physiology, University of Puerto Rico School of Medicine , San Juan, Puerto Rico .
Sabzali
S
Javadov
D000818:Animals; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004195:Disease Models, Animal; D004579:Electron Transport; D005260:Female; D007783:Lactones / Q000494:pharmacology; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D018384:Oxidative Stress; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013141:Spiro Compounds / Q000494:pharmacology
D003497:Cyclic N-Oxides; D007783:Lactones; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D013141:Spiro Compounds; C523959:XJB-5-131; C121329:sanglifehrin A
ETC supercomplexes; cardiac ischemia–reperfusion; cardiolipin; cyclophilin D; mitochondria; permeability transition pore