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

Craig Brooks, QingQing Wei, Sung Gyu Cho, Zheng Dong

Research output: Contribution to journalArticle

360 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1275-1285
Number of pages11
JournalJournal of Clinical Investigation
Volume119
Issue number5
DOIs
StatePublished - May 1 2009

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Mitochondrial Dynamics
Dynamins
Acute Kidney Injury
Rodentia
Cell Culture Techniques
Apoptosis
Cisplatin
Kidney
Cytochromes c
Reperfusion
Mitochondria
Proteins
Ischemia
Caspase Inhibitors
Mitochondrial Proteins
Mitochondrial Membranes
Caspases
Small Interfering RNA
Cell Death
Theoretical Models

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models. / Brooks, Craig; Wei, QingQing; Cho, Sung Gyu; Dong, Zheng.

In: Journal of Clinical Investigation, Vol. 119, No. 5, 01.05.2009, p. 1275-1285.

Research output: Contribution to journalArticle

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