Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models.
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.
Department of Cellular Biology and Anatomy, Medical College of Georgia, and Charlie Norwood VA Medical Center, Augusta, 30912, USA.
Craig
C
Brooks
Qingqing
Q
Wei
Sung-Gyu
SG
Cho
Zheng
Z
Dong
D000255:Adenosine Triphosphate / Q000172:deficiency; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors; D002460:Cell Line; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D034281:Dynamins / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000235:genetics; D021621:Imaging, Three-Dimensional; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control; D007687:Kidney Tubules, Proximal / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control; D019810:Sodium Azide / Q000494:pharmacology
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D019810:Sodium Azide; D020558:GTP Phosphohydrolases; C486391:Dnm1l protein, mouse; C519851:Dnm1l protein, rat; D034281:Dynamins; D002945:Cisplatin