p66SHC-mediated mitochondrial dysfunction in renal proximal tubule cells during oxidative injury.
Mitochondrial dysfunction is involved in pathopysiology of ischemia-reperfusion-induced acute kidney injury (AKI). The p66shc adaptor protein is a newly recognized mediator of mitochondrial dysfunction, which might play a role in AKI-induced renal tubular injury. Oxidative stress-mediated Serine36 phosphorylation of p66shc facilitates its transportation to the mitochondria where it oxidizes cytochrome c and generates excessive amount of reactive oxygen species (ROS). The consequence is mitochondrial depolarization and injury. Earlier we determined that p66shc plays an essential role in injury of cultured mouse renal proximal tubule cells during oxidative stress. Here, we studied the role of p66shc in ROS generation and consequent mitochondrial dysfunction during oxidative injury in renal proximal tubule cells. We employed p66shc knockdown renal proximal tubule cells and cells that overexpress wild-type, Serine phosphorylation (S36A), or cytochrome c-binding (W134F) mutants of p66shc. Inhibition of the mitochondrial electron transport chain or the mitochondrial permeability transition revealed that hydrogen peroxide-induced injury is mitochondrial ROS and consequent mitochondrial depolarization dependent. We also found that through Ser36 phosphorylation and mitochondria/cytochrome c binding, p66shc mediates those effects. We propose a similar mechanism in vivo as we demonstrated mitochondrial binding of p66shc as well as its association with cytochrome c in the postischemic kidneys of mice. Thus, manipulating p66shc might offer a new therapeutic modality to ameliorate renal ischemic injury.
Arany
Istvan
I
Dept. of Pediatrics, Div. of Pediatric Nephrology, Univ. of Mississippi Medical Center, 2500 N. State St., Jackson, MS 39126, USA. iarany@ped.umsmed.edu
Faisal
Amir
A
Clark
Jeb S
JS
Vera
Trinity
T
Baliga
Radhakrishna
R
Nagamine
Yoshikuni
Y
D058186:Acute Kidney Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000502:physiology*
D017382:Reactive Oxygen Species; D055765:Shc Signaling Adaptor Proteins; D012694:Serine; D045304:Cytochromes c; D006861:Hydrogen Peroxide