DRP1 levels determine the apoptotic threshold during embryonic differentiation through a mitophagy-dependent mechanism.
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Embargo End Date
ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2022-06-06
Date Accepted
2022-04-28
Abstract
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.
Citation
Developmental Cell, 2022, 57 (11), pp. 1316 - 1330.e7
Source Title
Developmental Cell
Publisher
CELL PRESS
ISSN
1534-5807
eISSN
1878-1551
1878-1551
1878-1551
Collections
Research Team
Cell Death and Immunity