Journal
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
Volume 306, Issue 11, Pages F1318-F1326Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00036.2014
Keywords
acute kidney injury; ischemia-reperfusion; mitochondria; apoptosis
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Funding
- National Natural Science Foundation of China [81370791]
- National Basic Research Program of China 973 Program [2012CB517600]
- National Institutes of Health and Department of Veterans Administration of USA
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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-1mediated 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, OMA1mediated OPA1 proteolysis plays an important role in the disruption of mitochondrial dynamics in ischemic AKI.
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