Reference: Wang X, et al. (2008) Reduced cytosolic protein synthesis suppresses mitochondrial degeneration. Nat Cell Biol 10(9):1090-7

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Abstract


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.

Reference Type
Journal Article | Research Support, Non-U.S. Gov't | Research Support, N.I.H., Extramural
Authors
Wang X, Zuo X, Kucejova B, Chen XJ
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