Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, China.
Department of Physics, Toronto Metropolitan University, Toronto, ON, M5B 2K3, Canada.
Nat Commun. 2024 Sep 27;15(1):8274. doi: 10.1038/s41467-024-52183-y.
A decline in mitochondrial function is a hallmark of aging and neurodegenerative diseases. It has been proposed that changes in mitochondrial morphology, including fragmentation of the tubular mitochondrial network, can lead to mitochondrial dysfunction, yet the mechanism of this loss of function is unclear. Most proteins contained within mitochondria are nuclear-encoded and must be properly targeted to the mitochondria. Here, we report that sustained mRNA localization and co-translational protein delivery leads to a heterogeneous protein distribution across fragmented mitochondria. We find that age-induced mitochondrial fragmentation drives a substantial increase in protein expression noise across fragments. Using a translational kinetic and molecular diffusion model, we find that protein expression noise is explained by the nature of stochastic compartmentalization and that co-translational protein delivery is the main contributor to increased heterogeneity. We observed that cells primarily reduce the variability in protein distribution by utilizing mitochondrial fission-fusion processes rather than relying on the mitophagy pathway. Furthermore, we are able to reduce the heterogeneity of the protein distribution by inhibiting co-translational protein targeting. This research lays the framework for a better understanding of the detrimental impact of mitochondrial fragmentation on the physiology of cells in aging and disease.
线粒体功能下降是衰老和神经退行性疾病的一个标志。有人提出，线粒体形态的变化，包括管状线粒体网络的碎片化，可能导致线粒体功能障碍，但这种功能丧失的机制尚不清楚。大多数存在于线粒体中的蛋白质是核编码的，必须正确靶向到线粒体。在这里，我们报告说，持续的 mRNA 定位和共翻译蛋白转运导致碎片化线粒体中存在异质的蛋白分布。我们发现，年龄诱导的线粒体碎片化导致碎片中蛋白质表达噪声显著增加。通过翻译动力学和分子扩散模型，我们发现蛋白质表达噪声可以用随机隔室化的性质来解释，并且共翻译蛋白转运是增加异质性的主要原因。我们观察到，细胞主要通过利用线粒体分裂融合过程来减少蛋白质分布的变异性，而不是依赖于线粒体自噬途径。此外，我们可以通过抑制共翻译蛋白靶向来降低蛋白质分布的异质性。这项研究为更好地理解线粒体碎片化对衰老和疾病细胞生理学的有害影响奠定了基础。
