Molecular insights into mitochondrial dysfunction in cancer-related muscle wasting
Molecular insights into mitochondrial dysfunction in cancer-related muscle wasting
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DOI：
10.1016/j.bbalip.2014.03.004
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发表时间：
2014-06-01
影响因子：
4.8
通讯作者：
Ferreira, Rita
中科院分区：
文献类型：
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作者：
Antunes, Diana;Padrao, Ana Isabel;Ferreira, Rita
之前曾提出癌症恶病质期间肌肉线粒体生物能的改变；然而，根本机制尚不清楚。因此，本研究的目的是评估癌症相关肌肉萎缩中的线粒体磷脂重塑及其对呼吸链活性和纤维细胞凋亡敏感性的影响。使用了暴露于 N-丁基-N-(4-羟丁基)-亚硝胺 (BBN) 诱导的尿路上皮癌动物模型，其特征是由于骨骼肌质量减少而导致体重显着减轻。肌肉萎缩的形态学证据与呼吸链活性降低和线粒体 UCP3 表达增加有关，这共同凸显了废弃肌肉产生 ATP 的能力较低。对分离线粒体的脂质组学分析显示，BBN 线粒体中磷脂酸、磷脂酰甘油和心磷脂显着减少，但被磷脂酰胆碱水平增加所抵消。除了对膜流动性的影响之外，这种磷脂重塑似乎至少部分证明了在废弃肌肉线粒体中观察到的较低氧化磷酸化活性及其对细胞凋亡的敏感性增加。奇怪的是，没有观察到脂质过氧化的证据，但来自 BBN 线粒体的蛋白质，特别是代谢蛋白质，似乎更容易发生羰基化，从而影响线粒体功能。总体而言，数据表明膀胱癌对骨骼肌活动产生负面影响，特别是通过影响线粒体磷脂动力学及其与蛋白质的相互作用，最终导致该细胞器的功能障碍。磷脂生物合成途径的调节可能被视为治疗癌症相关肌肉萎缩的潜在治疗靶点。 (C) 2014 Elsevier B.V. 保留所有权利。
Alterations in muscle mitochondrial bioenergetics during cancer cachexia were previously suggested; however, the underlying mechanisms are not known. So, the goal of this study was to evaluate mitochondrial phospholipid remodeling in cancer-related muscle wasting and its repercussions to respiratory chain activity and fiber susceptibility to apoptosis.An animal model of urothelial carcinoma induced by exposition to N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) and characterized by significant body weight loss due to skeletal muscle mass decrease was used. Morphological evidences of muscle atrophy were associated to decreased respiratory chain activity and increased expression of mitochondrial UCP3, which altogether highlight the lower ability of wasted muscle to produce ATP. Lipidomic analysis of isolated mitochondria revealed a significant decrease of phosphatidic acid, phosphatidylglycerol and cardiolipin in BBN mitochondria, counteracted by increased phosphatidylcholine levels. Besides the impact on membrane fluidity, this phospholipid remodeling seems to justify, at least in part, the lower oxidative phosphorylation activity observed in mitochondria from wasted muscle and their increased susceptibility to apoptosis. Curiously, no evidences of lipid peroxidation were observed but proteins from BBN mitochondria, particularly the metabolic ones, seem more prone to carbonylation with the consequent implications in mitochondria functionality. Overall, data suggest that bladder cancer negatively impacts skeletal muscle activity specifically by affecting mitochondrial phospholipid dynamics and its interaction with proteins, ultimately leading to the dysfunction of this organelle. The regulation of phospholipid biosynthetic pathways might be seen as potential therapeutic targets for the management of cancer-related muscle wasting. (C) 2014 Elsevier B.V. All rights reserved.