Letter abstract
Nature Cell Biology 10, 1090 - 1097 (1000)
Published online: 10 August 2008 | doi:10.1038/ncb1769
Reduced cytosolic protein synthesis suppresses mitochondrial degeneration
Xiaowen Wang1,2, Xiaoming Zuo2, Blanka Kucejova2 & Xin Jie Chen1,2
Mitochondrial function degenerates with ageing and in ageing-related neuromuscular degenerative diseases, causing physiological decline of the cell1. 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 aac2A128P 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 aac2A128P mutant has reduced mitochondrial membrane potential (
m) and is synthetically lethal to low 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 aac2A128P cells. Our finding thus establishes a link between protein homeostasis (proteostasis), cellular bioenergetics and mitochondrial maintenance during ageing.
- Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, New York 13210, USA.
- Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9148, USA.
Correspondence to: Xin Jie Chen1,2 e-mail: chenx@upstate.edu
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