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J Cell Biochem. 2018 Nov;119(11):9394-9407. doi: 10.1002/jcb.27256. Epub 2018 Aug 3.

Protein kinase Cε targets respiratory chain and mitochondrial membrane potential but not F0 F1 -ATPase in renal cells injured by oxidant.

Author information

1
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas.

Abstract

We have previously shown that protein kinase Cε (PKCε) is involved in mitochondrial dysfunction in renal proximal tubular cells (RPTC). This study examined mitochondrial targets of active PKCε in RPTC injured by the model oxidant tert-butyl hydroperoxide (TBHP). TBHP exposure augmented the levels of phosphorylated (active) PKCε in mitochondria, which suggested translocation of PKCε to mitochondria after oxidant exposure. Oxidant injury decreased state 3 respiration, adenosine triphosphate (ATP) production, ATP content, and complex I activity. Further, TBHP exposure increased ΔΨm and production of reactive oxygen species (ROS), and induced mitochondrial fragmentation and RPTC death. PKCε activation by overexpressing constitutively active PKCε exacerbated decreases in state 3 respiration, complex I activity, ATP content, and augmented RPTC death. In contrast, inhibition of PKCε by overexpressing dnPKCε mutant restored state 3 respiration, respiratory control ratio, complex I activity, ΔΨm , and ATP production and content, but did not prevent decreases in F0 F1 -ATPase activity. Inhibition of PKCε prevented oxidant-induced production of ROS and mitochondrial fragmentation, and reduced RPTC death. We conclude that activation of PKCε mediates: (a) oxidant-induced changes in ΔΨm , decreases in mitochondrial respiration, complex I activity, and ATP content; (b) mitochondrial fragmentation; and (c) RPTC death. In contrast, oxidant-induced inhibition of F0 F1 -ATPase activity is not mediated by PKCε. These results show that, in contrast to the protective effects of PKCε in the heart, PKCε activation is detrimental to mitochondrial function and viability in RPTC and mediates oxidant-induced injury.

KEYWORDS:

adenosine triphosphate synthase; mitochondria; mitochondrial membrane potential; oxidant injury; protein kinase Cε; reactive oxygen species; renal proximal tubular cells; respiratory chain

PMID:
30074270
PMCID:
PMC6298597
DOI:
10.1002/jcb.27256
[Indexed for MEDLINE]
Free PMC Article

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