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.
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Authors | Marcos A Carpio, Robert E Means, Allison L Brill, Alva Sainz, Barbara E Ehrlich, Samuel G Katz |
Journal | Cell reports
(Cell Rep)
Vol. 34
Issue 10
Pg. 108827
(03 09 2021)
ISSN: 2211-1247 [Electronic] United States |
PMID | 33691099
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 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
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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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