Denervation induces cytosolic phospholipase A2-mediated fatty acid hydroperoxide generation by muscle mitochondria.
Previously, we demonstrated that mitochondria from denervated muscle exhibited dramatically higher Amplex Red dependent fluorescence (thought to be highly specific for hydrogen peroxide) compared with control muscle mitochondria. We now demonstrate that catalase only partially inhibits the Amplex Red signal in mitochondria from denervated muscle. In contrast, ebselen (a glutathione peroxidase mimetic and inhibitor of fatty acid hydroperoxides) significantly inhibits the Amplex Red signal. This suggests that the majority of the Amplex Red signal in mitochondria from denervated muscle is not derived from hydrogen peroxide. Because Amplex Red cannot react with substrates in the lipid environment, we hypothesize that lipid hydroperoxides formed within the mitochondrial lipid bilayer are released as fatty acid hydroperoxides and react with the Amplex Red probe. We also suggest that the release of fatty acid hydroperoxides from denervated muscle mitochondria may be an important determinant of muscle atrophy. In support of this, muscle atrophy and the Amplex Red signal are inhibited in caloric restricted mice and in transgenic mice that overexpress the lipid hydroperoxide-detoxifying enzyme glutathione peroxidase 4. Finally, we propose that cytosolic phospholipase A2 may be a potential source of these hydroperoxides.
Bhattacharya
Arunabh
A
Department of Cellular and Structural Biology and the Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900 and the South Texas Veterans Health Care System, San Antonio, Texas 78284-7762; Department of Cellular and Structural Biology and the Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900 and the South Texas Veterans Health Care System, San Antonio, Texas 78284-7762.
Muller
Florian L
FL
Department of Cellular and Structural Biology and the Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900 and the South Texas Veterans Health Care System, San Antonio, Texas 78284-7762.
Liu
Yuhong
Y
Department of Cellular and Structural Biology and the Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900 and the South Texas Veterans Health Care System, San Antonio, Texas 78284-7762; Department of Cellular and Structural Biology and the Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900 and the South Texas Veterans Health Care System, San Antonio, Texas 78284-7762.
Sabia
Marian
M
Department of Cellular and Structural Biology and the Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900 and the South Texas Veterans Health Care System, San Antonio, Texas 78284-7762.
Liang
Hanyu
H
Department of Cellular and Structural Biology and the Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900 and the South Texas Veterans Health Care System, San Antonio, Texas 78284-7762; Department of Cellular and Structural Biology and the Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900 and the South Texas Veterans Health Care System, San Antonio, Texas 78284-7762.
Song
Wook
W
Department of Cellular and Structural Biology and the Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900 and the South Texas Veterans Health Care System, San Antonio, Texas 78284-7762.
Jang
Youngmok C
YC
Department of Cellular and Structural Biology and the Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900 and the South Texas Veterans Health Care System, San Antonio, Texas 78284-7762.
Ran
Qitao
Q
Department of Cellular and Structural Biology and the Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900 and the South Texas Veterans Health Care System, San Antonio, Texas 78284-7762; Department of Cellular and Structural Biology and the Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900 and the South Texas Veterans Health Care System, San Antonio, Texas 78284-7762; Department of Cellular and Structural Biology and the Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900 and the South Texas Veterans Health Care System, San Antonio, Texas 78284-7762.
Van Remmen
Holly
H
Department of Cellular and Structural Biology and the Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900 and the South Texas Veterans Health Care System, San Antonio, Texas 78284-7762; Department of Cellular and Structural Biology and the Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900 and the South Texas Veterans Health Care System, San Antonio, Texas 78284-7762; Department of Cellular and Structural Biology and the Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900 and the South Texas Veterans Health Care System, San Antonio, Texas 78284-7762. Electronic address: vanremmen@uthscsa.edu.
D000818:Animals; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D008054:Lipid Peroxides / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051336:Mitochondrial Membranes / Q000378:metabolism*; D009121:Muscle Denervation; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000294:innervation / Q000473:pathology; D009133:Muscular Atrophy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D054510:Phospholipases A2, Cytosolic / Q000235:genetics / Q000378:metabolism*; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase
D008054:Lipid Peroxides; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; D054510:Phospholipases A2, Cytosolic