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Protein kinase C- inhibits the repair of oxidative phosphorylation after S-(1,2-dichlorovinyl)-L-cysteine injury in renal cells

Xiuli Liu, Malinda L. Godwin, and Grayna Nowak

Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205

Submitted 2 June 2003 ; accepted in final form 29 February 2004

Previously, we showed that physiological functions of renal proximal tubular cells (RPTC) do not recover following S-(1,2-dichlorovinyl)-L-cysteine (DCVC)-induced injury. This study investigated the role of protein kinase C- (PKC-) in the lack of repair of mitochondrial function in DCVC-injured RPTC. After DCVC exposure, basal oxygen consumption (QO₂), uncoupled QO₂, oligomycin-sensitive QO₂, F₁F₀-ATPase activity, and ATP production decreased, respectively, to 59, 27, 27, 57, and 68% of controls. None of these functions recovered. Mitochondrial transmembrane potential decreased 53% after DCVC injury but recovered on day 4. PKC- was activated 4.3- and 2.5-fold on days 2 and 4, respectively, of the recovery period. Inhibition of PKC- activation (10 nM Go6976) did not block DCVC-induced decreases in mitochondrial functions but promoted the recovery of uncoupled QO₂, oligomycin-sensitive QO₂, F₁F₀-ATPase activity, and ATP production. Protein levels of the catalytic -subunit of F₁F₀-ATPase were not changed by DCVC or during the recovery period. Amino acid sequence analysis revealed that -, -, and -subunits of F₁F₀-ATPase have PKC consensus motifs. Recombinant PKC- phosphorylated the -subunit and decreased F₁F₀-ATPase activity in vitro. Serine but not threonine phosphorylation of the -subunit was increased during late recovery following DCVC injury, and inhibition of PKC- activation decreased this phosphorylation. We conclude that during RPTC recovery following DCVC injury, 1) PKC- activation decreases F₀F₁-ATPase activity, oxidative phosphorylation, and ATP production; 2) PKC- phosphorylates the -subunit of F₁F₀-ATPase on serine residue; and 3) PKC- does not mediate depolarization of RPTC mitochondria. This is the first report showing that PKC- phosphorylates the catalytic subunit of F₁F₀-ATPase and that PKC- plays an important role in regulating repair of mitochondrial function.

renal proximal tubular cells; mitochondria; F₁F₀-ATPase

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