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  • The EMBO Journal: 38 (3)

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A mitochondrial FUNDC1/HSC70 interaction organizes the proteostatic stress response at the risk of cell morbidity

Yanjun Li, Yanhong Xue, Xiaojun Xu, Guopeng Wang, Yiqun Liu, Hao Wu, Wenhui Li, Yueying Wang, Ziheng Chen, Weilin Zhang, View ORCID ProfileYushan Zhu, Wei Ji, View ORCID ProfileTao Xu, Lei Liu, View ORCID ProfileQuan Chen
DOI 10.15252/embj.201798786 | Published online 27.12.2018
The EMBO Journal (2019) 38, e98786
Yanjun Li
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
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Yanhong Xue
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
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Xiaojun Xu
College of Life Science and Technology, HuaZhong University of Science and Technology, Wuhan, Hubei, China
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Guopeng Wang
School of Life Sciences, Peking University, Beijing, China
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Yiqun Liu
School of Life Sciences, Peking University, Beijing, China
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Hao Wu
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
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Wenhui Li
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
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Yueying Wang
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
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Ziheng Chen
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
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Weilin Zhang
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
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Yushan Zhu
College of Life Sciences, Nankai University, Tianjin, China
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Wei Ji
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
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Tao Xu
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, ChinaCollege of Life Science and Technology, HuaZhong University of Science and Technology, Wuhan, Hubei, China
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Lei Liu
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
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Quan Chen
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, ChinaCollege of Life Sciences, Nankai University, Tianjin, ChinaUniversity of Chinese Academy of Sciences, Beijing, China
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Author Affiliations

  1. Yanjun Li1,
  2. Yanhong Xue2,
  3. Xiaojun Xu3,
  4. Guopeng Wang4,
  5. Yiqun Liu4,
  6. Hao Wu1,
  7. Wenhui Li1,
  8. Yueying Wang1,
  9. Ziheng Chen1,
  10. Weilin Zhang1,
  11. Yushan Zhu5,
  12. Wei Ji2,
  13. Tao Xu2,3,
  14. Lei Liu (liulei{at}ioz.ac.cn)*,1 and
  15. Quan Chen (chenq{at}ioz.ac.cn)*,1,5,6
  1. 1State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
  2. 2National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
  3. 3College of Life Science and Technology, HuaZhong University of Science and Technology, Wuhan, Hubei, China
  4. 4School of Life Sciences, Peking University, Beijing, China
  5. 5College of Life Sciences, Nankai University, Tianjin, China
  6. 6University of Chinese Academy of Sciences, Beijing, China
  1. ↵* Corresponding author. Tel: +86 10 64807329; E‐mail: liulei{at}ioz.ac.cn
    Corresponding author. Tel: +86 10 64807321; E‐mail: chenq{at}ioz.ac.cn
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Abstract

Both protein quality and mitochondrial quality are vital for the cellular activity, and impaired proteostasis and mitochondrial dysfunction are common etiologies of aging and age‐related disorders. Here, we report that the mitochondrial outer membrane protein FUNDC1 interacts with the chaperone HSC70 to promote the mitochondrial translocation of unfolded cytosolic proteins for degradation by LONP1 or for formation of non‐aggresomal mitochondrion‐associated protein aggregates (MAPAs) upon proteasome inhibition in cultured human cells. Integrative approaches including csCLEM, Apex, and biochemical analysis reveal that MAPAs contain ubiquitinated cytosolic proteins, autophagy receptor p62, and mitochondrial proteins. MAPAs are segregated from mitochondria in a FIS1‐dependent manner and can subsequently be degraded via autophagy. Although the FUNDC1/HSC70 pathway promotes the degradation of unfolded cytosolic proteins, excessive accumulation of unfolded proteins on the mitochondria prior to MAPA formation impairs mitochondrial integrity and activates AMPK, leading to cellular senescence. We suggest that human mitochondria organize cellular proteostatic response at the risk of their own malfunction and cell lethality.

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An interaction between mitochondrial outer membrane protein FUNDC1 and chaperone HSC70 promotes degradation or aggregation of unfolded cytosolic proteins on the mitochondria, thereby maintaining cellular proteostasis but reducing mitochondrial fitness.

  • Upon proteostatic stress, FUNDC1 interacts with HSC70 to promote the mitochondrial translocation of proteasomal clients, which are subsequently degraded by LONP1.

  • Mitochondrial translocation of proteasomal clients promotes the formation of mitochondrion‐associated protein aggregates (MAPAs).

  • MAPAs are distinct from aggresomes and contain ubiquitinated proteins, P62 and mitochondrial proteins.

  • FUNDC1 mediates the autophagic degradation of MAPAs, linking mitophagy and aggrephagy.

  • FUNDC1/HSC70‐mediated mitochondrial translocation of proteasomal clients prior to MAPA formation contributes to cell senescence.

  • cellular senescence
  • mitochondria
  • mitochondrial quality control
  • mitophagy
  • proteostatic stress

The EMBO Journal (2019) 38: e98786

  • Received December 7, 2017.
  • Revision received August 25, 2018.
  • Accepted October 4, 2018.
  • © 2018 The Authors
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Volume 38, Issue 3
01 February 2019
The EMBO Journal: 38 (3)
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