Department of Biology, University of Texas Arlington, Arlington, Texas, United States of America.
PLoS Genet. 2020 Dec 18;16(12):e1009234. doi: 10.1371/journal.pgen.1009234. eCollection 2020 Dec.
Cells use a variety of mechanisms to maintain optimal mitochondrial function including the mitochondrial unfolded protein response (UPRmt). The UPRmt mitigates mitochondrial dysfunction by differentially regulating mitoprotective gene expression through the transcription factor ATFS-1. Since UPRmt activation is commensurate with organismal benefits such as extended lifespan and host protection during infection, we sought to identify pathways that promote its stimulation. Using unbiased forward genetics screening, we isolated novel mutant alleles that could activate the UPRmt. Interestingly, we identified one reduction of function mutant allele (osa3) in the mitochondrial ribosomal gene mrpl-2 that activated the UPRmt in a diet-dependent manner. We find that mrpl-2(osa3) mutants lived longer and survived better during pathogen infection depending on the diet they were fed. A diet containing low levels of vitamin B12 could activate the UPRmt in mrpl-2(osa3) animals. Also, we find that the vitamin B12-dependent enzyme methionine synthase intersects with mrpl-2(osa3) to activate the UPRmt and confer animal lifespan extension at the level of ATFS-1. Thus, we present a novel gene-diet pairing that promotes animal longevity that is mediated by the UPRmt.
细胞使用多种机制来维持最佳的线粒体功能，包括线粒体未折叠蛋白反应 (UPRmt)。UPRmt 通过转录因子 ATFS-1 差异调节线粒体保护基因的表达来减轻线粒体功能障碍。由于 UPRmt 的激活与生物体的益处相称，例如延长寿命和在感染期间宿主保护，我们试图确定促进其刺激的途径。我们使用无偏见的正向遗传学筛选，分离出能够激活 UPRmt 的新型突变等位基因。有趣的是，我们在线粒体核糖体基因 mrpl-2 中鉴定出一个功能降低的突变等位基因 (osa3)，该基因以饮食依赖的方式激活 UPRmt。我们发现，mrpl-2(osa3)突变体在依赖饮食的情况下活得更长，在病原体感染时存活得更好。含有低水平维生素 B12 的饮食可以在 mrpl-2(osa3)动物中激活 UPRmt。此外，我们发现维生素 B12 依赖性酶蛋氨酸合酶与 mrpl-2(osa3)相交，以激活 UPRmt 并在 ATFS-1 水平上赋予动物寿命延长。因此，我们提出了一种新的基因-饮食配对，通过 UPRmt 促进动物长寿。
