DRP1 levels determine the apoptotic threshold during embryonic differentiation through a mitophagy-dependent mechanism.
apoptosis
early development
embryonic stem cell differentiation
mitochondrial dynamics
mitophagy
pluripotency
Journal
Developmental cell
ISSN: 1878-1551
Titre abrégé: Dev Cell
Pays: United States
ID NLM: 101120028
Informations de publication
Date de publication:
06 06 2022
06 06 2022
Historique:
received:
03
04
2020
revised:
20
09
2021
accepted:
28
04
2022
pubmed:
22
5
2022
medline:
10
6
2022
entrez:
21
5
2022
Statut:
ppublish
Résumé
The changes that drive differentiation facilitate the emergence of abnormal cells that need to be removed before they contribute to further development or the germline. Consequently, in mice in the lead-up to gastrulation, ∼35% of embryonic cells are eliminated. This elimination is caused by hypersensitivity to apoptosis, but how it is regulated is poorly understood. Here, we show that upon exit of naive pluripotency, mouse embryonic stem cells lower their mitochondrial apoptotic threshold, and this increases their sensitivity to cell death. We demonstrate that this enhanced apoptotic response is induced by a decrease in mitochondrial fission due to a reduction in the activity of dynamin-related protein 1 (DRP1). Furthermore, we show that in naive pluripotent cells, DRP1 prevents apoptosis by promoting mitophagy. In contrast, during differentiation, reduced mitophagy levels facilitate apoptosis. Together, these results indicate that during early mammalian development, DRP1 regulation of mitophagy determines the apoptotic response.
Identifiants
pubmed: 35597240
pii: S1534-5807(22)00306-9
doi: 10.1016/j.devcel.2022.04.020
pmc: PMC9297746
mid: NIHMS1810445
pii:
doi:
Substances chimiques
Dnm1l protein, mouse
EC 3.6.5.5
Dynamins
EC 3.6.5.5
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1316-1330.e7Subventions
Organisme : Wellcome Trust
ID : WT098424AIA
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/T028637/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S025618/1
Pays : United Kingdom
Organisme : British Heart Foundation
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N00275X/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R010676/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L020149/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R022259/1
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : R35 GM144103
Pays : United States
Organisme : Medical Research Council
ID : MR/J0003042/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L02036X/1
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 212625/Z/18/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N009371/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/S008284/1
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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