title: SOD1 and MitoTEMPO partially prevent mitochondrial permeability transition pore opening, necrosis, and mitochondrial apoptosis after ATP depletion recovery.
abstract: Generation of excessive reactive oxygen species (ROS) leads to mitochondrial dysfunction, apoptosis, and necrosis in renal ischemia-reperfusion (IR) injury. Previously we showed that lentiviral vector-mediated overexpression of superoxide dismutase-1 (SOD1) in proximal tubular epithelial cells (LLC-PK(1)) reduced cytotoxicity in an in vitro model of IR injury. Here, we examined the effects of SOD1 overexpression on mitochondrial signaling after ATP depletion-recovery (ATP-DR). To examine the role of mitochondrial ROS, a subset of cells was treated with the mitochondrial antioxidant MitoTEMPO. ATP-DR-mediated increase in mitochondrial calcium, loss of mitochondrial membrane potential, and increase in mitochondrial permeability transition pore (MPTP) were attenuated by SOD1 and MitoTEMPO (P<0.01). SOD1 prevented ATP-DR-induced mitochondrial Bax translocation, although the release of proapoptotic proteins from mitochondria was not prevented by SOD1 alone and required the presence of both SOD1 and MitoTEMPO. SOD1 suppressed the increase in c-jun phosphorylation, suggesting that JNK signaling regulates Bax translocation to mitochondria via ROS. ATP-DR-mediated changes in MPTP and mitochondrial signaling increased necrosis and apoptosis, both of which were partially attenuated by SOD1 and MitoTEMPO. These studies show that SOD1 and MitoTEMPO preserve mitochondrial integrity and attenuate ATP-DR-mediated necrosis and apoptosis.
authors.affiliation: Division of Transplant Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Huan Ling
authors.initials: HL
authors.lastname: Liang
authors.forename: Filip
authors.initials: F
authors.lastname: Sedlic
authors.forename: Zeljko
authors.initials: Z
authors.lastname: Bosnjak
authors.forename: Vani
authors.initials: V
authors.lastname: Nilakantan
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D009336:Necrosis; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000502:physiology*; D000072105:Superoxide Dismutase-1; D013552:Swine
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; C555916:MitoTEMPO; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins; D009943:Organophosphorus Compounds; D010880:Piperidines; D016755:Proto-Oncogene Proteins c-jun; D000255:Adenosine Triphosphate; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D048055:Mitogen-Activated Protein Kinase 8; C003959:TEMPO