Pernaute, B., Pérez-Montero, S., Sánchez Nieto, J.M. et al. (11 more authors) (2022) DRP1 levels determine the apoptotic threshold during embryonic differentiation through a mitophagy-dependent mechanism. Developmental Cell, 57 (11). pp. 1316-1330. ISSN 1878-1551
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
Keywords: | apoptosis; early development; embryonic stem cell differentiation; mitochondrial dynamics; mitophagy; pluripotency |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) |
Funding Information: | Funder Grant number MEDICAL RESEARCH COUNCIL MR/N009371/1 MEDICAL RESEARCH COUNCIL MR/R015724/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 31 May 2022 10:14 |
Last Modified: | 10 Feb 2023 14:13 |
Status: | Published |
Publisher: | Elsevier |
Refereed: | Yes |
Identification Number: | 10.1016/j.devcel.2022.04.020 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:187449 |