Reduced Coupling of Oxidative Phosphorylation In Vivo Precedes Electron Transport Chain Defects Due to Mild Oxidative Stress in Mice
Open Access
- 22 November 2011
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 6 (11), e26963
- https://doi.org/10.1371/journal.pone.0026963
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.Keywords
This publication has 54 references indexed in Scilit:
- Sucrose nonfermenting AMPK-related kinase (SNARK) mediates contraction-stimulated glucose transport in mouse skeletal muscleProceedings of the National Academy of Sciences of the United States of America, 2010
- Uncoupling protein-3 lowers reactive oxygen species production in isolated mitochondriaFree Radical Biology & Medicine, 2010
- Age‐dependent cardiomyopathy in mitochondrial mutator mice is attenuated by overexpression of catalase targeted to mitochondriaAging Cell, 2010
- Mitochondrial fission and remodelling contributes to muscle atrophyThe EMBO Journal, 2010
- Hydrogen peroxide inhibits mTOR signaling by activation of AMPKα leading to apoptosis of neuronal cellsLaboratory Investigation, 2010
- Increased superoxide in vivo accelerates age‐associated muscle atrophy through mitochondrial dysfunction and neuromuscular junction degenerationThe FASEB Journal, 2009
- Antioxidants prevent health-promoting effects of physical exercise in humansProceedings of the National Academy of Sciences of the United States of America, 2009
- Energization-dependent endogenous activation of proton conductance in skeletal muscle mitochondriaBiochemical Journal, 2008
- Mild mitochondrial uncoupling impacts cellular aging in human muscles in vivoProceedings of the National Academy of Sciences of the United States of America, 2007
- Superoxide activates mitochondrial uncoupling proteinsNature, 2002