Craig brooks
Faculty Member
Last active: 3/14/2019

Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models.

Brooks C, Wei Q, Cho SG, Dong Z
J Clin Invest. 2009 119 (5): 1275-85

PMID: 19349686 · PMCID: PMC2673870 · DOI:10.1172/JCI37829

The 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.

MeSH Terms (24)

Adenosine Triphosphate Animals Apoptosis Caspase Inhibitors Cell Line Cells, Cultured Cisplatin Cytochromes c Dynamins Enzyme Inhibitors GTP Phosphohydrolases Imaging, Three-Dimensional Kidney Tubular Necrosis, Acute Kidney Tubules, Proximal Male Mice Mice, Inbred C57BL Microtubule-Associated Proteins Mitochondria Proto-Oncogene Proteins c-bcl-2 Rats Reperfusion Injury RNA, Small Interfering Sodium Azide

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