TY - JOUR
T1 - Denervation induces cytosolic phospholipase a 2-mediated fatty acid hydroperoxide generation by muscle mitochondria
AU - Bhattacharya, Arunabh
AU - Muller, Florian L.
AU - Liu, Yuhong
AU - Sabia, Marian
AU - Liang, Hanyu
AU - Song, Wook
AU - Jang, Youngmok C.
AU - Ran, Qitao
AU - Van Remmen, Holly
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2009/1/2
Y1 - 2009/1/2
N2 - Previously, we demonstrated that mitochondria from dener- vated 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 dener- vated 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 A 2 may be a potential source of these hydroperoxides.
AB - Previously, we demonstrated that mitochondria from dener- vated 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 dener- vated 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 A 2 may be a potential source of these hydroperoxides.
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U2 - 10.1074/jbc.M806311200
DO - 10.1074/jbc.M806311200
M3 - Article
C2 - 19001413
AN - SCOPUS:58649089163
SN - 0021-9258
VL - 284
SP - 46
EP - 55
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 1
ER -