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Mitochondria-associated membrane collapse impairs TBK1-mediated proteostatic stress response in ALS

Seiji Watanabe1, Yuri Murata1, Yasuyoshi Oka2

  • 1Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.

Proceedings of the National Academy of Sciences of the United States of America
|November 15, 2023
PubMed

Insights

The mitochondria-associated membrane (MAM) is vital for TANK-binding kinase 1 (TBK1) activation during cellular stress. MAM disruption worsens proteostatic stress in amyotrophic lateral sclerosis (ALS) by inactivating TBK1.

Area of Science:

  • Cell Biology
  • Neuroscience
  • Molecular Biology

Background:

  • The mitochondria-associated membrane (MAM) is a critical cellular microdomain involved in homeostasis.
  • MAM disruption is a known pathological feature in amyotrophic lateral sclerosis (ALS).

Purpose of the Study:

  • To elucidate the precise role of the MAM in ALS pathogenesis.
  • To investigate the MAM's function in TANK-binding kinase 1 (TBK1) activation under proteostatic stress.

Main Methods:

  • Investigated the role of MAM-specific E3 ubiquitin ligase, autocrine motility factor receptor, in protein ubiquitination and TBK1 activation.
  • Assessed cellular vulnerability in vitro and motor function in vivo following MAM or TBK1 deficiency under proteostatic stress.

Main Results:

  • The MAM is essential for activating TBK1 during proteostatic stress.
  • A MAM-specific E3 ubiquitin ligase activates TBK1, leading to ribosomal protein degradation.
  • MAM or TBK1 deficiency increases cellular vulnerability and causes motor impairment.

Conclusions:

  • MAM disruption exacerbates proteostatic stress in ALS through TBK1 inactivation.
  • The MAM-TBK1 axis mediates a crucial proteostatic mechanism.
  • Organelle contact sites, like the MAM, are physiologically important for cellular health.
Keywords:
TANK-binding kinase 1amyotrophic lateral sclerosismitochondria-associated membranesigma-1 receptorstress granules

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