Mitochondrial function degenerates with ageing and in ageing-related neuromuscular degenerative diseases, causing physiological decline of the cell. Factors that can delay the degenerative process are actively sought after. Here, we show that reduced cytosolic protein synthesis is a robust cellular strategy that suppresses ageing-related mitochondrial degeneration. We modelled autosomal dominant progressive external ophthalmoplegia (adPEO), an adult- or later-onset degenerative disease, by introducing the A128P mutation into the adenine nucleotide translocase Aac2p of Saccharomyces cerevisiae. The aac2(A128P) allele dominantly induces ageing-dependent mitochondrial degeneration and phenotypically tractable degenerative cell death, independently of its ADP/ATP exchange activity. Mitochondrial degeneration was suppressed by lifespan-extending nutritional interventions and by eight longevity mutations, which are all known to reduce cytosolic protein synthesis. These longevity interventions also independently suppressed ageing-related mitochondrial degeneration in the pro-ageing prohibitin mutants. The aac2(A128P) mutant has reduced mitochondrial membrane potential (delta psi(m)) and is synthetically lethal to low delta psi(m) conditions, including the loss of prohibitin. Mitochondrial degeneration was accelerated by defects in protein turnover on the inner membrane and was suppressed by cycloheximide, a specific inhibitor of cytosolic ribosomes. Reduced cytosolic protein synthesis suppressed membrane depolarization and defects in mitochondrial gene expression in aac(A128P) cells. Our finding thus establishes a link between protein homeostasis (proteostasis), cellular bioenergetics and mitochondrial maintenance during ageing.

中文翻译：

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减少的细胞质蛋白合成抑制线粒体变性。

线粒体功能随着衰老和衰老相关的神经肌肉退行性疾病而退化，导致细胞生理衰退。积极寻找可以延缓退化过程的因素。在这里，我们表明减少的细胞质蛋白合成是一种强大的细胞策略，可以抑制与衰老相关的线粒体变性。我们通过将 A128P 突变引入酿酒酵母的腺嘌呤核苷酸转位酶 Aac2p 来模拟常染色体显性进行性外眼肌麻痹 (adPEO)，这是一种成人或晚发性退行性疾病。aac2(A128P) 等位基因主要诱导衰老依赖性线粒体变性和表型易处理的退行性细胞死亡，与其 ADP/ATP 交换活性无关。延长寿命的营养干预和八种长寿突变抑制了线粒体变性，众所周知，这些突变都会减少细胞质蛋白的合成。这些长寿干预措施还独立地抑制了促衰老抑制素突变体中与衰老相关的线粒体变性。aac2(A128P) 突变体降低了线粒体膜电位 (delta psi(m))，并且在低 delta psi(m) 条件下合成致死，包括抑制素的丢失。线粒体变性因内膜蛋白质周转缺陷而加速，并被放线菌酮（一种胞质核糖体的特异性抑制剂）抑制。减少的细胞质蛋白合成抑制膜去极化和 aac(A128P) 细胞中线粒体基因表达的缺陷。