Mitonuclear coordination of gene expression across complex cellular states using mitoribosome profiling

项目总结/摘要 细胞内跨细胞核和线粒体基因组的基因表达的协调对于细胞的生长至关重要。 正确组装氧化磷酸化（OXPHOS）复合物，组成电子传递链 并使有氧生活成为可能。这种线粒体平衡必须由分子参与者紧密地协调， 细胞区室和关键必须适应一个动态的细胞环境。平衡基因表达 当我们考虑复杂的细胞状态时，这些基因组构成了一个独特的挑战，例如老化的细胞 它必须处理其他损伤中的蛋白质组下降或长寿，形态复杂的细胞， 神经元的协调会迅速崩溃。未能保持适当的二尖瓣平衡， 由此产生的线粒体功能障碍与无数的人类疾病有关，包括 神经退行性疾病和癌症，以及衰老过程本身。 我们的实验室先前已经证明线粒体和核基因组调节协调基因， 双源OXPHOS基因需要在翻译而非转录水平上的表达程序 在线粒体生物合成过程中建立呼吸复合体。这些研究使用了同时的细胞溶质 和线粒体核糖体分析技术，但迄今为止仅在健康的中期进行 相酵母。我们的长期目标是了解线粒体基因组是如何被调控的 在不同的细胞状态和生物环境中。我们提出这项建议的具体目标将有助于我们实现 这些目标是双重的：（1）确定在细胞的生长过程中细胞环境恶化的影响， 寿命对线粒体基因表达和线粒体协调的影响，以及（2） 确定有丝分裂后的神经元在索马中必须有不同的线粒体需求， 能够维持线粒体的正常协调，并适当调节线粒体基因 在这种长寿的形态复杂的细胞的生命周期中表达。综上所述， 这项研究将促进我们对细胞中线粒体基因调控和线粒体生物学的认识。 与人类疾病和衰老有关的状态。

PROJECT SUMMARY / ABSTRACT Coordination of gene expression across nuclear and mitochondrial genomes within a cell is crucial for the correct assembly of oxidative phosphorylation (OXPHOS) complexes that make up the electron transport chain and enable aerobic life. This mitonuclear balance must be tightly orchestrated by molecular players across cellular compartments and critically must adapt to a dynamic cellular milieu. Balanced gene expression across these genomes poses a unique challenge when we consider complex cellular states, for example aged cells that must deal with declining proteomes among other insults or long-lived, morphologically complex cells like neurons where this coordination could rapidly breakdown. Failure to maintain proper mitonuclear balance and the resulting mitochondrial dysfunction is implicated in a myriad of human diseases, including neurodegenerative diseases and cancer, as well as the aging process itself. Our lab has previously demonstrated that mitochondrial and nuclear genomes regulate coordinated gene expression programs on the translational but not transcriptional level for dual-origin OXPHOS genes required to build respiratory complexes during mitochondrial biogenesis. These studies utilized simultaneous cytosolic and mitochondrial ribosome profiling techniques, but to date have only been performed in healthy mid-log phase yeast. Our long-term objectives are now to understand how mitochondrial genomes are regulated across diverse cellular states and biological contexts. Our specific aims for this proposal that will help us attain these objectives are twofold: (1) to determine the effects of a deteriorating cellular environment during a cell’s lifespan on mitochondrial gene expression and mitonuclear coordination using replicatively-aged yeast and (2) determine how post-mitotic neurons which must have different mitochondrial demands in the soma compared to distal neurites can maintain proper mitonuclear coordination and appropriately regulate mitochondrial gene expression over the lifespan of this long-lived and morphologically complex cell. In summary this proposed research will advance our knowledge of mitochondrial gene regulation and mitochondrial biology in cellular states with relevance to human disease and aging.