FUS Interacts with HSP60 to Promote Mitochondrial Damage

Jianwen Deng, Mengxue Yang, Yanbo Chen, Xiaoping Chen, Jianghong Liu, Shufeng Sun, Haipeng Cheng, Yang Li, Eileen H. Bigio, Marsel Mesulam, Qi Xu, Sidan Du, Kazuo Fushimi, Li Zhu*, Jane Y. Wu

*Corresponding author for this work

Research output: Contribution to journalArticle

61 Scopus citations


FUS-proteinopathies, a group of heterogeneous disorders including ALS-FUS and FTLD-FUS, are characterized by the formation of inclusion bodies containing the nuclear protein FUS in the affected patients. However, the underlying molecular and cellular defects remain unclear. Here we provide evidence for mitochondrial localization of FUS and its induction of mitochondrial damage. Remarkably, FTLD-FUS brain samples show increased FUS expression and mitochondrial defects. Biochemical and genetic data demonstrate that FUS interacts with a mitochondrial chaperonin, HSP60, and that FUS translocation to mitochondria is, at least in part, mediated by HSP60. Down-regulating HSP60 reduces mitochondrially localized FUS and partially rescues mitochondrial defects and neurodegenerative phenotypes caused by FUS expression in transgenic flies. This is the first report of direct mitochondrial targeting by a nuclear protein associated with neurodegeneration, suggesting that mitochondrial impairment may represent a critical event in different forms of FUS-proteinopathies and a common pathological feature for both ALS-FUS and FTLD-FUS. Our study offers a potential explanation for the highly heterogeneous nature and complex genetic presentation of different forms of FUS-proteinopathies. Our data also suggest that mitochondrial damage may be a target in future development of diagnostic and therapeutic tools for FUS-proteinopathies, a group of devastating neurodegenerative diseases.

Original languageEnglish (US)
Article numbere1005357
JournalPLoS genetics
Issue number9
StatePublished - 2015

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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    Deng, J., Yang, M., Chen, Y., Chen, X., Liu, J., Sun, S., Cheng, H., Li, Y., Bigio, E. H., Mesulam, M., Xu, Q., Du, S., Fushimi, K., Zhu, L., & Wu, J. Y. (2015). FUS Interacts with HSP60 to Promote Mitochondrial Damage. PLoS genetics, 11(9), [e1005357]. https://doi.org/10.1371/journal.pgen.1005357