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Genome-wide kinase-MAM interactome screening reveals the role of CK2A1 in MAM Ca2+ dynamics linked to DEE66

Truong Thi My Nhung1, Nguyen Phuoc Long2, Tran Diem Nghi1

  • 1Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Republic of Korea.

Proceedings of the National Academy of Sciences of the United States of America
|July 31, 2023
PubMed

Insights

Mitochondria-associated ER membranes (MAMs) regulate calcium (Ca2+) homeostasis. Pathological PACS2 mutations disrupt MAMs, impairing Ca2+ uptake and increasing cytosolic Ca2+, which affects neurotransmitter release in neurons.

Area of Science:

  • Cell Biology
  • Neuroscience
  • Molecular Biology

Background:

  • Mitochondria-associated ER membranes (MAMs) are crucial for cellular calcium (Ca2+) homeostasis.
  • Disruption of MAMs leads to widespread effects in the nervous system.

Purpose of the Study:

  • To identify kinases regulating MAM composition and Ca2+ transport.
  • To elucidate the role of casein kinase 2 alpha 1 (CK2A1) and PACS2 in MAM function and neuronal Ca2+ signaling.

Main Methods:

  • Genome-wide kinase-MAM interactome screening.
  • Analysis of PACS2 phosphorylation and its impact on MAM localization.
  • Investigation of Ca2+ homeostasis and neurotransmitter release in response to PACS2 mutations.

Main Results:

  • CK2A1 was identified as a regulator of MAMs.
  • CK2A1 phosphorylates PACS2, facilitating the CK2A1-PACS2-PKD2 complex at MAMs and regulating mitochondrial Ca2+ influx.
  • Mutations in PACS2 associated with developmental and epileptic encephalopathy-66 (DEE66) impair MAM integrity, reduce mitochondrial Ca2+ uptake, and increase cytosolic Ca2+ levels.

Conclusions:

  • Pathological PACS2 mutations disrupt MAMs, leading to altered Ca2+ signaling.
  • These MAM alterations modulate Ca2+-dependent neurotransmitter release at glutamatergic synapses.
  • Findings reveal a molecular mechanism linking MAM dysfunction to neurological disorders.
Keywords:
calciumcasein kinase 2developmental and epileptic encephalopathy-66mitochondria-associated ER membranes

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