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USP19 promotes hypoxia-induced mitochondrial division via FUNDC1 at ER-mitochondria contact sites

Peiyuan Chai1, Yiru Cheng1, Chuyi Hou1

  • 1Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education and State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing, China.

The Journal of Cell Biology
|May 12, 2021
PubMed

Insights

USP19, an endoplasmic reticulum protein, promotes mitochondrial division during hypoxia by deubiquitinating FUNDC1, a key protein at ER-mitochondria contact sites. This mechanism regulates mitochondrial dynamics under stress.

Area of Science:

  • Cell Biology
  • Mitochondrial Dynamics
  • Hypoxia Response

Background:

  • The endoplasmic reticulum (ER) interacts with mitochondria, influencing mitochondrial function.
  • Mitochondrial fission is crucial for adapting to hypoxic stress, but ER-mediated regulation is unclear.
  • FUNDC1 at ER-mitochondria contact sites is known to recruit Drp1 for fission.

Purpose of the Study:

  • To elucidate the mechanisms by which the ER regulates hypoxia-induced mitochondrial fission.
  • To identify novel ER proteins involved in managing mitochondrial dynamics under hypoxic conditions.

Main Methods:

  • Investigated the role of USP19, an ER-resident deubiquitinase, in hypoxia-induced mitochondrial fission.
  • Examined the interaction between USP19, FUNDC1, and Drp1 at ER-mitochondria contact sites.
  • Assessed the impact of USP19 on Drp1 activity and mitochondrial division.

Main Results:

  • USP19 accumulates at ER-mitochondria contact sites during hypoxia.
  • USP19 deubiquitinates FUNDC1, enhancing Drp1 oligomerization and GTPase activity.
  • USP19 promotes hypoxia-induced mitochondrial division by modulating the FUNDC1-Drp1 axis.

Conclusions:

  • USP19 is a critical ER-resident protein that regulates mitochondrial fission under hypoxia.
  • USP19 acts via deubiquitinating FUNDC1, thereby controlling Drp1-mediated mitochondrial division.
  • This study reveals a novel ER-mediated pathway governing mitochondrial dynamics during cellular stress.

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