Tissue-Specific Loss of DARS2 Activates Stress Responses Independently of Respiratory Chain Deficiency in the Heart
Tissue-Specific Loss of DARS2 Activates Stress Responses Independently of Respiratory Chain Deficiency in the Heart
复制标题
DOI：
10.1016/j.cmet.2014.02.004
复制
发表时间：
2014-03-04
期刊：
影响因子：
29
通讯作者：
Trifunovic, Aleksandra
中科院分区：
文献类型：
--
作者：
Dogan, Sukru Anil;Pujol, Claire;Trifunovic, Aleksandra
线粒体功能障碍后激活的适应性应激反应被认为是为了抵消呼吸链缺陷而产生的。在这里，我们证明了DARS 2（线粒体氨酰-tRNA合成酶）的损失导致各种应激反应的激活，以组织特异性的方式独立于呼吸链缺乏。心脏和骨骼肌中的DARS 2缺失导致线粒体蛋白质合成的严重失调，随后在两种组织中均出现强烈的呼吸链缺陷，但适应性反应的激活主要在心肌细胞中观察到。我们发现，心脏线粒体蛋白质稳态的损伤激活了丝裂因子FGF 21的表达，FGF 21作为细胞自主和全身代谢变化的信号。相反，骨骼肌具有依赖于线粒体转录物的缓慢周转和较高的蛋白质稳定缓冲能力的内在机制。我们的研究结果表明，线粒体功能障碍的感觉独立的呼吸链缺陷，质疑目前的观点的压力反应在线粒体疾病中的作用。
Adaptive stress responses activated upon mitochondrial dysfunction are assumed to arise in order to counteract respiratory chain deficiency. Here, we demonstrate that loss of DARS2 (mitochondrial aspartyl-tRNA synthetase) leads to the activation of various stress responses in a tissue-specific manner independently of respiratory chain deficiency. DARS2 depletion in heart and skeletal muscle leads to the severe deregulation of mitochondrial protein synthesis followed by a strong respiratory chain deficit in both tissues, yet the activation of adaptive responses is observed predominantly in cardiomyocytes. We show that the impairment of mitochondrial proteostasis in the heart activates the expression of mitokine FGF21, which acts as a signal for cell-autonomous and systemic metabolic changes. Conversely, skeletal muscle has an intrinsic mechanism relying on the slow turnover of mitochondrial transcripts and higher proteostatic buffering capacity. Our results show that mitochondrial dysfunction is sensed independently of respiratory chain deficiency, questioning the current view on the role of stress responses in mitochondrial diseases.