PDF(Pubmed)
Abstract：
Mitochondria and lysosomes are two organelles that carry out both signaling and metabolic roles in cells. Recent evidence has shown that mitochondria and lysosomes are dependent on one another, as primary defects in one cause secondary defects in the other. Although there are functional impairments in both cases, the signaling consequences of primary mitochondrial dysfunction and lysosomal defects are dissimilar. Here, we used RNA sequencing to obtain transcriptomes from cells with primary mitochondrial or lysosomal defects to identify the global cellular consequences associated with mitochondrial or lysosomal dysfunction. We used these data to determine the pathways affected by defects in both organelles, which revealed a prominent role for the cholesterol synthesis pathway. We observed a transcriptional upregulation of this pathway in cellular and murine models of lysosomal defects, while it is transcriptionally downregulated in cellular and murine models of mitochondrial defects. We identified a role for the posttranscriptional regulation of transcription factor SREBF1, a master regulator of cholesterol and lipid biosynthesis, in models of mitochondrial respiratory chain deficiency. Furthermore, we found that retention of Ca2+ in lysosomes of cells with mitochondrial respiratory chain defects contributes to the differential regulation of the cholesterol synthesis pathway in the mitochondrial and lysosomal defects tested. Finally, we verified in vivo, using a model of mitochondria-associated disease in Caenorhabditis elegans that normalization of lysosomal Ca2+ levels results in partial rescue of the developmental delay induced by the respiratory chain deficiency.
摘要：
线粒体和溶酶体是两种细胞器，在细胞中同时发挥信号和代谢作用。最近的证据表明线粒体和溶酶体相互依赖，因为一个的主要缺陷会导致另一个的次要缺陷。虽然这两种情况都有功能障碍，原发性线粒体功能障碍和溶酶体缺陷的信号传导后果是不同的.这里,我们使用RNA测序从具有原发性线粒体或溶酶体缺陷的细胞获得转录组,以鉴定与线粒体或溶酶体功能障碍相关的整体细胞后果.我们使用这些数据来确定受两个细胞器缺陷影响的途径，这揭示了胆固醇合成途径的重要作用。我们在溶酶体缺陷的细胞和小鼠模型中观察到该途径的转录上调，而在线粒体缺陷的细胞和鼠模型中转录下调。我们确定了转录因子SREBF1的转录后调控作用，SREBF1是胆固醇和脂质生物合成的主要调节因子，在线粒体呼吸链缺陷模型中。此外，我们发现Ca2+在线粒体呼吸链缺陷细胞的溶酶体中的滞留有助于在所测试的线粒体和溶酶体缺陷中对胆固醇合成途径的差异调节.最后,我们在体内验证，使用秀丽隐杆线虫线粒体相关疾病的模型，溶酶体Ca2+水平的正常化导致部分挽救由呼吸链缺陷引起的发育延迟。
