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Am J Physiol Renal Physiol. 2014 Jun 1;306(11):F1318-26. doi: 10.1152/ajprenal.00036.2014. Epub 2014 Mar 26.

OMA1 mediates OPA1 proteolysis and mitochondrial fragmentation in experimental models of ischemic kidney injury.

Author information

1
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.
2
Department of Cell Biology and Genetics, Henan University School of Medicine, Kaifeng, Henan, China;
3
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain.
4
Department of Cellular Biology and Anatomy, Medical College of Georgia at Georgia Reagents University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia;
5
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.

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.

KEYWORDS:

acute kidney injury; apoptosis; ischemia-reperfusion; mitochondria

PMID:
24671334
PMCID:
PMC4042105
DOI:
10.1152/ajprenal.00036.2014
[Indexed for MEDLINE]
Free PMC Article
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