期刊
EMBO JOURNAL
卷 40, 期 16, 页码 -出版社
WILEY
DOI: 10.15252/embj.2021107913
关键词
huntingtin; Mia40; mitochondria; protein aggregation; protein translocation
资金
- Deutsche Forschungsgemeinschaft (DIP MitoBalance) [SPP1710, IRTG1830, HE2803/10-1, CRC1218/B02, WE2174/7-1, WI/2111-6, WI/2111/8]
- Landesschwerpunkt BioComp
- Joachim Herz Stiftung
- Elitenetzwerk Bayern (Biological Physics program)
- Deutsche Forschungsgemeinschaft
- State Government of North Rhine-Westphalia [INST 213/840-1 FUGG]
- Projekt DEAL
The study investigates the regulation of aggregation-prone polyQ protein behavior by mitochondrial processes, revealing that Mia40 plays a rate-limiting role in the import of mitochondrial precursor proteins and can be exploited to stabilize cytosolic proteostasis.
The formation of protein aggregates is a hallmark of neurodegenerative diseases. Observations on patient samples and model systems demonstrated links between aggregate formation and declining mitochondrial functionality, but causalities remain unclear. We used Saccharomyces cerevisiae to analyze how mitochondrial processes regulate the behavior of aggregation-prone polyQ protein derived from human huntingtin. Expression of Q97-GFP rapidly led to insoluble cytosolic aggregates and cell death. Although aggregation impaired mitochondrial respiration only slightly, it considerably interfered with the import of mitochondrial precursor proteins. Mutants in the import component Mia40 were hypersensitive to Q97-GFP, whereas Mia40 overexpression strongly suppressed the formation of toxic Q97-GFP aggregates both in yeast and in human cells. Based on these observations, we propose that the post-translational import of mitochondrial precursor proteins into mitochondria competes with aggregation-prone cytosolic proteins for chaperones and proteasome capacity. Mia40 regulates this competition as it has a rate-limiting role in mitochondrial protein import. Therefore, Mia40 is a dynamic regulator in mitochondrial biogenesis that can be exploited to stabilize cytosolic proteostasis.
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