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Craig Brooks, Qingqing Wei, Sung-Gyu Cho, Zheng Dong
J Clin Invest. 2009;
119(5):1275
doi:10.1172/JCI37829
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T
he mechanism of mitochondrial damage, a key contributor to renal tubular cell death
during acute kidney injury, remains largely unknown. Here, we have demonstrated a
striking morphological change of mitochondria in experimental models of renal
ischemia/reperfusion and cisplatin-induced nephrotoxicity. This change contributed to
mitochondrial outer membrane permeabilization, release of apoptogenic factors, and
consequent apoptosis. Following either ATP depletion or cisplatin treatment of rat
renal tubular cells, mitochondrial fragmentation was observed prior to cytochrome
c release and apoptosis. This mitochondrial fragmentation was
inhibited by Bcl2 but not by caspase inhibitors. Dynamin-related protein 1 (Drp1), a
critical mitochondrial fission protein, translocated to mitochondria early during
tubular cell injury, and both siRNA knockdown of Drp1 and expression of a
dominant-negative Drp1 attenuated mitochondrial fragmentation, cytochrome
c release, caspase activation, and apoptosis. Further in vivo
analysis revealed that mitochondrial fragmentation also occurred in proximal tubular
cells in mice during renal ischemia/reperfusion and cisplatin-induced nephrotoxicity.
Notably, both tubular cell apoptosis and acute kidney injury were attenuated by
mdivi-1, a newly identified pharmacological inhibitor of Drp1. This study
demonstrates a rapid regulation of mitochondrial dynamics during acute kidney injury
and identifies mitochondrial fragmentation as what we believe to be a novel mechanism
contributing to mitochondrial damage and apoptosis in vivo in mouse models of
disease.
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