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DJ-1 regulates the integrity and function of ER-mitochondria association through interaction with IP3R3-Grp75-VDAC1

Yi Liu1,2, Xiaopin Ma2, Hisashi Fujioka3

  • 1Department of Neurology and Collaborative Innovation Center for Brain Science, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200020 Shanghai, People's Republic of China.

Proceedings of the National Academy of Sciences of the United States of America
|November 27, 2019
PubMed

Insights

Loss of DJ-1 protein disrupts crucial connections between the endoplasmic reticulum and mitochondria, impacting calcium signaling and contributing to Parkinson's disease pathogenesis. Restoring DJ-1 function rescues these deficits.

Area of Science:

  • Cell Biology
  • Neuroscience
  • Molecular Biology

Background:

  • Loss-of-function mutations in DJ-1 are linked to early-onset Parkinson's disease (PD), but the precise pathogenic mechanisms are not fully understood.
  • The role of DJ-1 in cellular organelles and its interaction with key protein complexes involved in intracellular communication requires further elucidation.

Purpose of the Study:

  • To investigate the localization and function of DJ-1 at the mitochondria-associated membrane (MAM).
  • To determine how DJ-1 loss affects the integrity of the endoplasmic reticulum (ER)-mitochondria connection and calcium homeostasis.
  • To explore the implications of DJ-1 dysfunction in the context of Parkinson's disease pathogenesis.

Main Methods:

  • In vitro and in vivo studies using cell lines and DJ-1 knockout mice.
  • Co-immunoprecipitation to assess protein-protein interactions (DJ-1, IP3R3, Grp75, VDAC1).
  • Confocal microscopy to evaluate ER-mitochondria association and organelle function.
  • Analysis of DJ-1 levels and protein complex integrity in post-mortem brain tissue from PD patients.

Main Results:

  • DJ-1 was found to localize to the MAM and is an integral part of the IP3R3-Grp75-VDAC1 complex.
  • Loss of DJ-1 disrupted this complex, leading to reduced ER-mitochondria association, impaired MAM function, and altered calcium handling.
  • DJ-1 deficiency caused accumulation of IP3R3 at the MAM and reduced its degradation.
  • Similar molecular deficits were observed in DJ-1 knockout mice and in the substantia nigra of sporadic PD patients, correlating with reduced DJ-1 levels and impaired ER-mitochondria communication.

Conclusions:

  • DJ-1 plays a critical role in maintaining the structural and functional integrity of the MAM by regulating the IP3R3-Grp75-VDAC1 complex.
  • Impaired ER-mitochondria association and calcium cross-talk due to DJ-1 dysfunction contribute to the cellular pathology observed in Parkinson's disease.
  • These findings highlight a novel mechanism linking DJ-1 to PD pathogenesis and suggest potential therapeutic targets related to ER-mitochondria communication.
Keywords:
DJ-1ER-mitochondria associationIP3R3Parkinson’s diseasemitochondrial dysfunction

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