Department of BioSciences, Rice University, 6100 Main St, MS140, Houston, TX 77005, USA.
Genes (Basel). 2023 Apr 29;14(5):1009. doi: 10.3390/genes14051009.
Mitochondria are key organelles for cellular health and metabolism and the activation of programmed cell death processes. Although pathways for regulating and re-establishing mitochondrial homeostasis have been identified over the past twenty years, the consequences of disrupting genes that regulate other cellular processes, such as division and proliferation, on affecting mitochondrial function remain unclear. In this study, we leveraged insights about increased sensitivity to mitochondrial damage in certain cancers, or genes that are frequently mutated in multiple cancer types, to compile a list of candidates for study. RNAi was used to disrupt orthologous genes in the model organism , and a series of assays were used to evaluate these genes' importance for mitochondrial health. Iterative screening of ~1000 genes yielded a set of 139 genes predicted to play roles in mitochondrial maintenance or function. Bioinformatic analyses indicated that these genes are statistically interrelated. Functional validation of a sample of genes from this set indicated that disruption of each gene caused at least one phenotype consistent with mitochondrial dysfunction, including increased fragmentation of the mitochondrial network, abnormal steady-state levels of NADH or ROS, or altered oxygen consumption. Interestingly, RNAi-mediated knockdown of these genes often also exacerbated α-synuclein aggregation in a model of Parkinson's disease. Additionally, human orthologs of the gene set showed enrichment for roles in human disorders. This gene set provides a foundation for identifying new mechanisms that support mitochondrial and cellular homeostasis.
线粒体是细胞健康和代谢以及程序性细胞死亡过程激活的关键细胞器。尽管在过去的二十年中已经确定了调节和重建线粒体动态平衡的途径，但调节其他细胞过程（如分裂和增殖）的基因的破坏对影响线粒体功能的后果仍不清楚。在这项研究中，我们利用了某些癌症中对线粒体损伤的敏感性增加或在多种癌症类型中经常发生突变的基因的见解，来编制候选基因的研究清单。RNAi 用于破坏模型生物中的同源基因，并使用一系列测定来评估这些基因对线粒体健康的重要性。对约 1000 个基因进行反复筛选，产生了一组 139 个被预测在维持或功能线粒体中发挥作用的候选基因。生物信息学分析表明这些基因在统计学上是相互关联的。对该基因集中的一组基因进行功能验证表明，每个基因的破坏至少引起一种与线粒体功能障碍一致的表型，包括线粒体网络的碎片化增加、NADH 或 ROS 的稳态水平异常或耗氧量改变。有趣的是，这些基因的 RNAi 介导的敲低也常常加剧了帕金森病模型中α-突触核蛋白的聚集。此外，该基因集的人类同源物富集了在人类疾病中发挥作用的角色。该基因集为鉴定支持线粒体和细胞动态平衡的新机制提供了基础。
