Reduced cytosolic protein synthesis suppresses mitochondrial degeneration.
Reduced cytosolic protein synthesis suppresses mitochondrial degeneration.
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DOI：
10.1038/ncb1769
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发表时间：
2008-09
影响因子：
21.3
通讯作者：
Chen, Xin Jie
中科院分区：
文献类型：
--
作者：
Wang, Xiaowen;Zuo, Xiaoming;Kucejova, Blanka;Chen, Xin Jie
Mitochondrial function degenerates during aging and in aging-related neuromuscular degenerative diseases, which leads to the 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 aging-related mitochondrial degeneration. We modelled the adult-or later-onset degenerative disease, autosomal dominant Progressive External Ophthalmoplegia (adPEO), by introducing the A128P mutation into the yeast adenine nucleotide translocase, Aac2p. The aac2A128P allele dominantly induces aging-dependent mitochondrial degeneration and phenotypically tractable degenerative cell death independent of its ADP/ATP exchange activity. Mitochondrial degeneration is suppressed by lifespan-extending nutritional interventions and by 8 longevity mutations, which are all known to reduce cytosolic protein synthesis. These longevity interventions also independently suppress aging-related mitochondrial degeneration in the pro-aging prohibitin mutants. The aac2A128P mutant has reduced mitochondrial membrane potential (Δψm) and is synthetically lethal to low Δψm conditions, including the loss of prohibitin. Mitochondrial degeneration is accelerated by defects in protein turnover on the inner membrane and is suppressed by cycloheximide, a specific inhibitor of cytosolic ribosomes. Reduced cytosolic protein synthesis suppresses membrane depolarization and defects in mitochondrial gene expression in aac2A128P cells. Our finding thus provides a link between protein homeostasis (proteostasis), cellular bioenergetics and mitochondrial maintenance during aging.
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