TY - JOUR
T1 - OMA1 mediates OPA1 proteolysis and mitochondrial fragmentation in experimental models of ischemic kidney injury
AU - Xiao, Xiao
AU - Hu, Yanzhong
AU - Quirós, Pedro M.
AU - Wei, Qingqing
AU - López-Otín, Carlos
AU - Dong, Zheng
PY - 2014/6/1
Y1 - 2014/6/1
N2 - 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.
AB - 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.
KW - Acute kidney injury
KW - Apoptosis
KW - Ischemia-reperfusion
KW - Mitochondria
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U2 - 10.1152/ajprenal.00036.2014
DO - 10.1152/ajprenal.00036.2014
M3 - Article
C2 - 24671334
AN - SCOPUS:84901712100
SN - 0363-6127
VL - 306
SP - F1318-F1326
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 11
ER -