DRP1 levels determine the apoptotic threshold during embryonic differentiation through a mitophagy-dependent mechanism.
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Date
2022-06-06ICR Author
Author
Pernaute, B
Pérez-Montero, S
Sánchez Nieto, JM
Di Gregorio, A
Lima, A
Lawlor, K
Bowling, S
Liccardi, G
Tomás, A
Meier, P
Sesaki, H
Rutter, GA
Barbaric, I
Rodríguez, TA
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
apoptosis
early development
embryonic stem cell differentiation
mitochondrial dynamics
mitophagy
pluripotency
Animals
Apoptosis
Dynamins
Mammals
Mice
Mitochondria
Mitochondrial Dynamics
Mitophagy
Research team
Cell Death and Immunity
Language
eng
Date accepted
2022-04-28
License start date
2022-06-06
Citation
Developmental Cell, 2022, 57 (11), pp. 1316 - 1330.e7
Publisher
CELL PRESS