Reduced coupling of oxidative phosphorylation In Vivo precedes electron transport chain defects due to mild oxidative stress in mice

Michael P. Siegel, Shane E. Kruse, Gary Knowels, Adam Salmon, Richard Beyer, Hui Xie, Holly van Remmen, Steven R. Smith, David J. Marcinek

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24 Scopus citations

Abstract

Oxidative stress and mitochondrial function are at the core of many degenerative conditions. However, the interaction between oxidative stress and in vivo mitochondrial function is unclear. We used both pharmacological (2 week paraquat (PQ) treatment of wild type mice) and transgenic (mice lacking Cu, Zn-superoxide dismutase (SOD1 -/-)) models to test the effect of oxidative stress on in vivo mitochondrial function in skeletal muscle. Magnetic resonance and optical spectroscopy were used to measure mitochondrial ATP and oxygen fluxes and cell energetic state. In both models of oxidative stress, coupling of oxidative phosphorylation was significantly lower (lower P/O) at rest in vivo in skeletal muscle and was dose-dependent in the PQ model. Despite this reduction in efficiency, in vivo mitochondrial phosphorylation capacity (ATPmax) was maintained in both models, and ex vivo mitochondrial respiration in permeabilized muscle fibers was unchanged following PQ treatment. In association with the reduced P/O, PQ treatment led to a dose-dependent reduction in PCr/ATP ratio and increased phosphorylation of AMPK. These results indicate that oxidative stress uncouples oxidative phosphorylation in vivo and results in energetic stress in the absence of defects in the mitochondrial electron transport chain.

Original languageEnglish (US)
Article numbere26963
JournalPloS one
Volume6
Issue number11
DOIs
StatePublished - Nov 22 2011

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Siegel, M. P., Kruse, S. E., Knowels, G., Salmon, A., Beyer, R., Xie, H., van Remmen, H., Smith, S. R., & Marcinek, D. J. (2011). Reduced coupling of oxidative phosphorylation In Vivo precedes electron transport chain defects due to mild oxidative stress in mice. PloS one, 6(11), [e26963]. https://doi.org/10.1371/journal.pone.0026963