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BOK controls apoptosis by Ca2+ transfer through ER-mitochondrial contact sites.

Abstract
Calcium transfer from the endoplasmic reticulum (ER) to mitochondria is a critical contributor to apoptosis. B cell lymphoma 2 (BCL-2) ovarian killer (BOK) localizes to the ER and binds the inositol 1,4,5-trisphosophate receptor (IP3R). Here, we show that BOK is necessary for baseline mitochondrial calcium levels and stimulus-induced calcium transfer from the ER to the mitochondria. Murine embryonic fibroblasts deficient for BOK have decreased proximity of the ER to the mitochondria and altered protein composition of mitochondria-associated membranes (MAMs), which form essential calcium microdomains. Rescue of the ER-mitochondrial juxtaposition with drug-inducible interorganelle linkers reveals a kinetic disruption, which when overcome in Bok-/- cells is still insufficient to rescue thapsigargin-induced calcium transfer and apoptosis. Likewise, a BOK mutant unable to interact with IP3R restores ER-mitochondrial proximity, but not ER-mitochondrial calcium transfer, MAM protein composition, or apoptosis. This work identifies the dynamic coordination of ER-mitochondrial contact by BOK as an important control point for apoptosis.
AuthorsMarcos A Carpio, Robert E Means, Allison L Brill, Alva Sainz, Barbara E Ehrlich, Samuel G Katz
JournalCell reports (Cell Rep) Vol. 34 Issue 10 Pg. 108827 (03 09 2021) ISSN: 2211-1247 [Electronic] United States
PMID33691099 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Bok protein, mouse
  • Inositol 1,4,5-Trisphosphate Receptors
  • Proto-Oncogene Proteins c-bcl-2
  • Thapsigargin
  • Calcium
Topics
  • Animals
  • Apoptosis (drug effects)
  • Calcium (metabolism)
  • Cells, Cultured
  • Endoplasmic Reticulum (metabolism)
  • Fibroblasts (cytology, metabolism)
  • Inositol 1,4,5-Trisphosphate Receptors (metabolism)
  • Ion Transport (drug effects)
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Fluorescence
  • Mitochondrial Membranes (metabolism)
  • Proto-Oncogene Proteins c-bcl-2 (deficiency, genetics, metabolism)
  • Thapsigargin (pharmacology)

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