Deficiency of the RNA-binding protein Cth2 extends yeast replicative lifespan by alleviating its repressive effects on mitochondrial function

Iron dyshomeostasis contributes to aging, but little information is available about the molecular mechanisms. Here, we provide evidence that, in Saccharomyces cerevisiae, aging is associated with altered expression of genes involved in iron homeostasis. We further demonstrate that defects in the conserved mRNA-binding protein Cth2, which controls stability and translation of mRNAs encoding iron-containing proteins, increase lifespan by alleviating its repressive effects on mitochondrial function. Mutation of the conserved cysteine residue in Cth2 that inhibits its RNA-binding activity is sufficient to confer longevity, whereas Cth2 gain-of-function shortens replicative lifespan. Consistent with its function in RNA degradation, we demonstrate that Cth2 deficiency relieves Cth2-mediated post-transcriptional repression of nuclear-encoded components of the electron transport chain. Our findings uncover a major role of the RNA-binding protein Cth2 in the regulation of lifespan and suggest that modulation of iron starvation signaling can serve as a target for potential aging interventions.铁稳态失衡可促进衰老，但目前关于其背后的分子机制仍知之甚少。本研究以酿酒酵母（Saccharomyces cerevisiae）为研究对象，证实衰老与铁稳态相关基因的表达异常密切相关。我们进一步发现，保守型mRNA结合蛋白（mRNA-binding protein）Cth2可调控含铁蛋白编码mRNA的稳定性与翻译过程；该蛋白的功能缺陷可通过缓解其对线粒体功能的抑制作用，延长酵母寿命。若对Cth2中抑制其RNA结合活性的保守半胱氨酸残基进行突变，即可赋予酵母长寿表型；而Cth2的功能获得性突变则会缩短酵母的复制寿命。与其在RNA降解过程中的功能相符，本研究证实Cth2缺失可解除Cth2介导的、对细胞核编码电子传递链组分的转录后抑制作用。本研究结果揭示了RNA结合蛋白Cth2在寿命调控中的核心作用，并提示调控铁饥饿信号通路可作为潜在的衰老干预靶点。