title: Impaired adaptability of in vivo mitochondrial energetics to acute oxidative insult in aged skeletal muscle.
abstract: Periods of elevated reactive oxygen species (ROS) production are a normal part of mitochondrial physiology. However, little is known about age-related changes in the mitochondrial response to elevated ROS in vivo. Significantly, ROS-induced uncoupling of oxidative phosphorylation has received attention as a negative feedback mechanism to reduce mitochondrial superoxide production. Here we use a novel in vivo spectroscopy system to test the hypothesis that ROS-induced uncoupling is diminished in aged mitochondria. This system simultaneously acquires (31)P magnetic resonance and near-infrared optical spectra to non-invasively measure phosphometabolite and O(2) concentrations in mouse skeletal muscle. Using low dose paraquat to elevate intracellular ROS we assess in vivo mitochondrial function in young, middle aged, and old mice. Oxidative phosphorylation was uncoupled to the same degree in response to ROS at each age, but this uncoupling was associated with loss of phosphorylation capacity and total ATP in old mice only. Using mice lacking UCP3 we demonstrate that this in vivo uncoupling is independent of this putative uncoupler of skeletal muscle mitochondria. These data indicate that ROS-induced uncoupling persists throughout life, but that oxidative stress leads to mitochondrial deficits and loss of ATP in aged organisms that may contribute to impaired function and degeneration.
authors.affiliation: Department of Bioengineering, University of Washington, 3720 15th Ave NE, Seattle, WA 98195, USA. msiegel1@uw.edu
authors.forename: Michael P
authors.initials: MP
authors.lastname: Siegel
authors.forename: Tim
authors.initials: T
authors.lastname: Wilbur
authors.forename: Mark
authors.initials: M
authors.lastname: Mathis
authors.forename: Eric G
authors.initials: EG
authors.lastname: Shankland
authors.forename: Atlas
authors.initials: A
authors.lastname: Trieu
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Harper
authors.forename: David J
authors.initials: DJ
authors.lastname: Marcinek
mesh_terms: D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism; D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D005260:Female; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012038:Regeneration / Q000235:genetics; D000071247:Uncoupling Protein 3
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C000604393:Ucp3 protein, mouse; D000071247:Uncoupling Protein 3; D000255:Adenosine Triphosphate; D010100:Oxygen