title: Increased mitochondrial matrix-directed superoxide production by fatty acid hydroperoxides in skeletal muscle mitochondria.
abstract: Previous studies have shown that muscle atrophy is associated with mitochondrial dysfunction and an increased rate of mitochondrial reactive oxygen species production. We recently demonstrated that fatty acid hydroperoxides (FA-OOHs) are significantly elevated in mitochondria isolated from atrophied muscles. The purpose of this study was to determine whether FA-OOHs can alter skeletal muscle mitochondrial function. We found that FA-OOHs (at low-micromolar concentrations) induce mitochondrial dysfunction assessed by a decrease in the rate of ATP production, oxygen consumption, and activity of respiratory chain complexes I and III. Using methods to distinguish superoxide release toward the matrix and toward the intermembrane space, we demonstrate that FA-OOHs significantly elevate oxidative stress in the mitochondrial matrix (and not the intermembrane space), with complex I as the major site of superoxide production (most probably from a site upstream of the ubiquinone binding site but downstream from the flavin binding site-the iron sulfur clusters). Our results are the first to indicate that FA-OOHs are important modulators of mitochondrial function and oxidative stress in skeletal muscle mitochondria and may play an important role in muscle atrophies that are associated with increased generation of FA-OOHs, e.g., denervation-induced muscle atrophy.
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, TX 78229-3900, USA.
authors.forename: Arunabh
authors.initials: A
authors.lastname: Bhattacharya
authors.forename: Michael
authors.initials: M
authors.lastname: Lustgarten
authors.forename: Yun
authors.initials: Y
authors.lastname: Shi
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.forename: Youngmok C
authors.initials: YC
authors.lastname: Jang
authors.forename: Daniel
authors.initials: D
authors.lastname: Pulliam
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Jernigan
authors.forename: Holly
authors.initials: H
authors.lastname: Van Remmen
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D042967:Electron Transport Complex I / Q000502:physiology; D014450:Electron Transport Complex III / Q000502:physiology; D008054:Lipid Peroxides / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009133:Muscular Atrophy / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D010101:Oxygen Consumption / Q000502:physiology; D013481:Superoxides / Q000378:metabolism*
chemical_list: D008054:Lipid Peroxides; D013481:Superoxides; D000255:Adenosine Triphosphate; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III