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DRP1 levels determine the apoptotic threshold during embryonic differentiation through a mitophagy-dependent

Barbara Pernaute1, Salvador Pérez-Montero1, Juan Miguel Sánchez Nieto1

  • 1National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.

Developmental Cell
|May 21, 2022
PubMed

Insights

During early development, mouse embryonic stem cells undergo apoptosis due to reduced mitochondrial fission. Dynamin-related protein 1 (DRP1) regulates this process by controlling mitophagy, impacting cell elimination.

Area of Science:

  • Cell Biology
  • Developmental Biology
  • Mitochondrial Dynamics

Background:

  • Embryonic development involves significant cell elimination to remove abnormal cells.
  • Apoptosis, or programmed cell death, is crucial for normal development.
  • The precise regulation of apoptosis during early mammalian development, particularly concerning mitochondrial function, remains incompletely understood.

Purpose of the Study:

  • To investigate the molecular mechanisms regulating the hypersensitivity to apoptosis in mouse embryonic stem cells exiting naive pluripotency.
  • To elucidate the role of mitochondrial dynamics, specifically fission, in controlling apoptosis during early development.
  • To determine the function of dynamin-related protein 1 (DRP1) in regulating mitophagy and its impact on cell survival.

Main Methods:

  • Analysis of mitochondrial fission and fusion dynamics in mouse embryonic stem cells.
  • Assessment of apoptotic sensitivity and cell death pathways.
  • Investigation of dynamin-related protein 1 (DRP1) activity and its effects on mitochondrial fission.
  • Evaluation of mitophagy levels and their correlation with DRP1 activity and apoptosis.

Main Results:

  • Mouse embryonic stem cells exhibit a lower mitochondrial apoptotic threshold upon exiting naive pluripotency, increasing cell death sensitivity.
  • Reduced mitochondrial fission, mediated by decreased dynamin-related protein 1 (DRP1) activity, induces this enhanced apoptotic response.
  • Dynamin-related protein 1 (DRP1) promotes mitophagy in naive pluripotent cells, preventing apoptosis.
  • During differentiation, decreased mitophagy facilitates apoptosis, highlighting a shift in cell death regulation.

Conclusions:

  • Dynamin-related protein 1 (DRP1) plays a critical role in regulating apoptosis during early mammalian development.
  • DRP1-mediated regulation of mitophagy is a key determinant of the apoptotic response in differentiating embryonic cells.
  • Understanding these mechanisms provides insight into the precise control of cell elimination essential for normal development.
Keywords:
apoptosisearly developmentembryonic stem cell differentiationmitochondrial dynamicsmitophagypluripotency

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