Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Cell Rep. 2022 Dec 27;41(13):111875. doi: 10.1016/j.celrep.2022.111875.
Nutrient availability regulates the C. elegans life cycle as well as mitochondrial physiology. Food deprivation significantly reduces mitochondrial genome (mtDNA) numbers and leads to aging-related phenotypes. Here we show that the bZIP (basic leucine zipper) protein ATFS-1, a mediator of the mitochondrial unfolded protein response (UPR), is required to promote growth and establish a functional germline after prolonged starvation. We find that recovery of mtDNA copy numbers and development after starvation requires mitochondrion-localized ATFS-1 but not its nuclear transcription activity. We also find that the insulin-like receptor DAF-2 functions upstream of ATFS-1 to modulate mtDNA content. We show that reducing DAF-2 activity represses ATFS-1 nuclear function while causing an increase in mtDNA content, partly mediated by mitochondrion-localized ATFS-1. Our data indicate the importance of the UPR in recovering mitochondrial mass and suggest that atfs-1-dependent mtDNA replication precedes mitochondrial network expansion after starvation.
营养物质的可利用性调节着线虫的生命周期和线粒体生理状态。食物匮乏会显著降低线粒体基因组（mtDNA）数量，并导致与衰老相关的表型。本研究表明，作为线粒体未折叠蛋白反应（UPR）的中介体的 bZIP（碱性亮氨酸拉链）蛋白 ATFS-1，是在长时间饥饿后促进生长和建立功能性生殖系所必需的。研究发现，mtDNA 拷贝数的恢复和饥饿后的发育需要定位于线粒体的 ATFS-1，但不需要其核转录活性。研究还发现胰岛素样受体 DAF-2 在前馈调节 ATFS-1 以调节 mtDNA 含量方面发挥作用。研究表明，降低 DAF-2 活性会抑制 ATFS-1 的核功能，同时导致 mtDNA 含量增加，这部分是由定位于线粒体的 ATFS-1 介导的。本研究数据表明 UPR 在恢复线粒体质量方面的重要性，并表明 atfs-1 依赖性 mtDNA 复制先于饥饿后线粒体网络的扩张。
