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

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.

myo-Inositol Oxygenase Overexpression Accentuates Generation of Reactive Oxygen Species and Exacerbates Cellular Injury following High Glucose Ambience

“…Ten cells/variable were photographed at a magnification of ϫ5,000, and 25 mitochondria were measured along the long axis. We designated intactness of mitochondria based on the morphology of a majority of mitochondria (Ͼ70%) that were more than 1 m in length along the long axis in control cells, as described previously (45).…”

Inhibition of Drp1 provides neuroprotection in vitro and in vivo

“…[24][25][26] In addition, mdiviA was efficacious in rodent models of cisplatin-induced renal damage, 24 suggesting a therapeutic potential for Drp1 inhibitors in tissue damage caused by different insults. Earlier studies using dominant negative mutant Drp1K38A validated Drp1 as a potential therapeutic target in neurodegenerative diseases.…”

Mitochondrial Morphology in Metabolic Diseases

“…Given the recent reports of Mff (103), MiD49/50 (104), and MIEF1 (158) targeting DLP1 to the mitochondria, hFis1 may not serve as the bona fide receptor of DLP1, but rather works downstream in the fission process. This may help reconcile the observed delay in the induction of apoptosis with hFis1 and mitochondrial fission disruption under apoptotic stimuli (3,12,13,54,81), and its reported expendability in mitochondrial fission (103). Conceivably, the two receptor proteins Mff and hFis1 may function in varied capacities in the promotion of mitochondrial fission dependent upon environmental cues and normal network maintenance, but dissection of this will require further investigation.…”