PDF(Pubmed)
Abstract：
Genetic mutations causing primary mitochondrial disease (i.e those compromising oxidative phosphorylation [OxPhos]) resulting in reduced bioenergetic output display great variability in their clinical features, but the reason for this is unknown. We hypothesized that disruption of the communication between endoplasmic reticulum (ER) and mitochondria at mitochondria-associated ER membranes (MAM) might play a role in this variability. To test this, we assayed MAM function and ER-mitochondrial communication in OxPhos-deficient cells, including cybrids from patients with selected pathogenic mtDNA mutations. Our results show that each of the various mutations studied indeed altered MAM functions, but notably, each disorder presented with a different MAM \"signature\". We also found that mitochondrial membrane potential is a key driver of ER-mitochondrial connectivity. Moreover, our findings demonstrate that disruption in ER-mitochondrial communication has consequences for cell survivability that go well beyond that of reduced ATP output. The findings of a \"MAM-OxPhos\" axis, the role of mitochondrial membrane potential in controlling this process, and the contribution of MAM dysfunction to cell death, reveal a new relationship between mitochondria and the rest of the cell, as well as providing new insights into the diagnosis and treatment of these devastating disorders.
摘要：
导致原发性线粒体疾病的基因突变（i。e那些损害氧化磷酸化[OxPhos]）导致降低的生物能输出在其临床特征中显示出巨大的变异性，但原因不明。我们假设内质网（ER）与线粒体相关的内质网（MAM）之间的通讯中断可能在这种变异性中起作用。为了测试这个，我们测定了OxPhos缺陷细胞中的MAM功能和ER-线粒体通讯，包括具有选定致病性mtDNA突变的患者的杂种。我们的结果表明，所研究的各种突变中的每一个确实改变了MAM功能，但值得注意的是，每种疾病都有不同的MAM“签名”。我们还发现线粒体膜电位是ER-线粒体连接的关键驱动因素。此外，我们的研究结果表明,内质网-线粒体通讯中断对细胞生存能力的影响远远超过ATP输出减少的影响.“MAM-OxPhos”轴的发现，线粒体膜电位在控制这一过程中的作用，以及MAM功能障碍对细胞死亡的贡献，揭示线粒体和细胞其余部分之间的新关系，以及为这些毁灭性疾病的诊断和治疗提供新的见解。
