Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada, V6T 1Z3.
Nat Commun. 2021 Jan 20;12(1):479. doi: 10.1038/s41467-020-20784-y.
As organisms develop, individual cells generate mitochondria to fulfill physiological requirements. However, it remains unknown how mitochondrial network expansion is scaled to cell growth. The mitochondrial unfolded protein response (UPR) is a signaling pathway mediated by the transcription factor ATFS-1 which harbors a mitochondrial targeting sequence (MTS). Here, using the model organism Caenorhabditis elegans we demonstrate that ATFS-1 mediates an adaptable mitochondrial network expansion program that is active throughout normal development. Mitochondrial network expansion requires the relatively inefficient MTS in ATFS-1, which allows the transcription factor to be responsive to parameters that impact protein import capacity of the mitochondrial network. Increasing the strength of the ATFS-1 MTS impairs UPR activity by increasing accumulation within mitochondria. Manipulations of TORC1 activity increase or decrease ATFS-1 activity in a manner that correlates with protein synthesis. Lastly, expression of mitochondrial-targeted GFP is sufficient to expand the muscle cell mitochondrial network in an ATFS-1-dependent manner. We propose that mitochondrial network expansion during development is an emergent property of the synthesis of highly expressed mitochondrial proteins that exclude ATFS-1 from mitochondrial import, causing UPR activation.
随着生物体的发育，个体细胞会产生线粒体以满足生理需求。然而，线粒体网络的扩展如何与细胞生长相适应仍不清楚。线粒体未折叠蛋白反应（UPR）是一种由转录因子 ATFS-1 介导的信号通路，该转录因子具有一个线粒体靶向序列（MTS）。在这里，我们使用模式生物秀丽隐杆线虫证明，ATFS-1 介导了一种适应性的线粒体网络扩展程序，该程序在正常发育过程中始终保持活跃。线粒体网络的扩展需要 ATFS-1 中相对低效的 MTS，这使得转录因子能够对影响线粒体网络蛋白导入能力的参数做出反应。增加 ATFS-1 MTS 的强度会通过增加其在线粒体中的积累来损害 UPR 活性。TORC1 活性的操纵以与蛋白质合成相关的方式增加或减少 ATFS-1 的活性。最后，线粒体靶向 GFP 的表达足以以依赖于 ATFS-1 的方式扩展肌肉细胞的线粒体网络。我们提出，发育过程中线粒体网络的扩展是高度表达的线粒体蛋白合成的一个突现属性，这些蛋白将 ATFS-1 排除在线粒体导入之外，导致 UPR 的激活。
