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

Xiao Xiao, Yanzhong Hu, Pedro M. Quirós, Qingqing Wei, Carlos López-Otín, Zheng Dong

Research output: Contribution to journalArticle

51 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)F1318-F1326
JournalAmerican Journal of Physiology - Renal Physiology
Volume306
Issue number11
DOIs
StatePublished - Jun 1 2014

Keywords

  • Acute kidney injury
  • Apoptosis
  • Ischemia-reperfusion
  • Mitochondria

ASJC Scopus subject areas

  • Physiology
  • Urology

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