title: Reduced coupling of oxidative phosphorylation in vivo precedes electron transport chain defects due to mild oxidative stress in mice.
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.
authors: Department of Bioengineering, University of Washington Medical School, Seattle, Washington, United States of America.
authors: Michael P
authors: MP
authors: Siegel
authors: Shane E
authors: SE
authors: Kruse
authors: Gary
authors: G
authors: Knowels
authors: Adam
authors: A
authors: Salmon
authors: Richard
authors: R
authors: Beyer
authors: Hui
authors: H
authors: Xie
authors: Holly
authors: H
authors: Van Remmen
authors: Steven R
authors: SR
authors: Smith
authors: David J
authors: DJ
authors: Marcinek
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004579:Electron Transport / Q000187:drug effects; D005260:Female; D006614:Hindlimb / Q000187:drug effects / Q000473:pathology; D007511:Ischemia / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010269:Paraquat / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D012146:Rest; D015398:Signal Transduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000172:deficiency / Q000378:metabolism
chemical_list: D000255:Adenosine Triphosphate; D013482:Superoxide Dismutase; D010269:Paraquat