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Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes
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Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes

Published on: January 7, 2013

Activation of ERK1/2 pathway mediates oxidant-induced decreases in mitochondrial function in renal cells

Grazyna Nowak1, Ginger L Clifton, Malinda L Godwin

  • 1Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, 4301 West Markham St., Little Rock, AR 72205, USA. gnowak@uams.edu

American Journal of Physiology. Renal Physiology
|May 18, 2006
PubMed

Insights

Oxidant injury in kidney cells activates ERK1/2, impairing mitochondrial function and ATP production. Inhibiting ERK1/2 restores mitochondrial respiration, suggesting independent pathways for PKC-epsilon and ERK1/2 in kidney cell injury.

Area of Science:

  • Cellular and Molecular Biology
  • Renal Physiology
  • Mitochondrial Biology

Background:

  • Oxidant exposure in renal proximal tubular cells (RPTC) previously shown to induce mitochondrial dysfunction via PKC-epsilon.
  • The role of the ERK1/2 pathway in oxidant-induced mitochondrial dysfunction requires further elucidation.
  • Investigating the interplay between PKC-epsilon and the Raf-MEK1/2-ERK1/2 pathway in mediating mitochondrial effects.

Purpose of the Study:

  • To examine the role of extracellular signal-regulated kinase 1/2 (ERK1/2) in mitochondrial dysfunction caused by oxidant injury in RPTC.
  • To determine if protein kinase C-epsilon (PKC-epsilon) mediates its effects on mitochondrial function through the Raf-MEK1/2-ERK1/2 pathway.
  • To elucidate the specific mitochondrial targets and pathways affected by ERK1/2 activation during oxidative stress.

Main Methods:

  • Sublethal injury induced in RPTC using tert-butylhydroperoxide (TBHP).
  • Assessment of ERK1/2, p38, and JNK phosphorylation levels.
  • Measurement of mitochondrial respiration (basal, uncoupled, state 3), ATP production, and specific enzyme activities (Complex I, aconitase, dehydrogenases).
  • Pharmacological inhibition and genetic activation of the ERK1/2 pathway.

Main Results:

  • TBHP exposure significantly increased ERK1/2 and p38 phosphorylation, leading to reduced mitochondrial respiration, ATP production, and Complex I activity.
  • Inhibition of ERK1/2 restored mitochondrial function and Complex I activity, but not aconitase activity.
  • Activation of ERK1/2 mimicked the effects of oxidant injury on mitochondrial respiration in non-injured cells.
  • PKC-epsilon inhibition did not affect TBHP-induced ERK1/2 phosphorylation, indicating independent pathways.

Conclusions:

  • Oxidant-induced activation of ERK1/2, but not p38 or JNK, impairs mitochondrial respiration and ATP production by reducing Complex I activity.
  • The ERK1/2 pathway's effect on mitochondrial dysfunction in oxidant-injured RPTC does not involve citric acid cycle dehydrogenases.
  • ERK1/2 and PKC-epsilon mediate oxidant-induced mitochondrial dysfunction through independent signaling pathways.

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