title: OMA1 mediates OPA1 proteolysis and mitochondrial fragmentation in experimental models of ischemic kidney injury.
abstract: Acute kidney injury (AKI) is associated with mitochondrial fragmentation, which contributes to mitochondrial damage and tubular cell apoptosis. Mitochondrial fragmentation involves the cleavage of both mitochondrial outer and inner membranes. Cleavage of the outer membrane results from Drp-1-mediated fission activation and Bak-promoted fusion arrest, but the molecular mechanism of inner membrane cleavage remains elusive. OMA1-mediated proteolysis of OPA1, a key inner membrane fusion protein, was recently suggested to account for inner membrane cleavage during cell stress. In this study, we determined the role of OMA1 in OPA1 proteolysis and mitochondrial fragmentation in experimental models of ischemic AKI. In ATP-depletion injury, knockdown of OMA1 suppressed OPA1 proteolysis, mitochondrial fragmentation, cytochrome c release, and consequent apoptosis in renal proximal tubular cells. In mice, OMA1 deficiency prevented ischemic AKI as indicated by better renal function, less tubular damage, and lower apoptosis. OPA1 proteolysis and mitochondrial injury during ischemic AKI were ameliorated in OMA1-deficient mice. Thus, OMA1-mediated OPA1 proteolysis plays an important role in the disruption of mitochondrial dynamics in ischemic AKI.
authors.affiliation: Department of Cellular Biology and Anatomy, Medical College of Georgia at Georgia Reagents University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia; Wuhan University, Wuhan, China; and.
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Department of Cell Biology and Genetics, Henan University School of Medicine, Kaifeng, Henan, China;
authors.forename: Yanzhong
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Quirós
authors.affiliation: Department of Cellular Biology and Anatomy, Medical College of Georgia at Georgia Reagents University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia;
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
authors.affiliation: Department of Cellular Biology and Anatomy, Medical College of Georgia at Georgia Reagents University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia; Department of Cell Biology and Genetics, Henan University School of Medicine, Kaifeng, Henan, China; zdong@gru.edu.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D007511:Ischemia / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply / Q000378:metabolism*; D008297:Male; D045726:Metalloproteases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D051381:Rats
chemical_list: D024101:Mitochondrial Proteins; D045726:Metalloproteases; C572960:OMA1 protein, mouse; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse
keywords: acute kidney injury; apoptosis; ischemia-reperfusion; mitochondria