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Updated: Aug 23, 2025

Detection of Mitochondria Membrane Potential to Study CLIC4 Knockdown-induced HN4 Cell Apoptosis In Vitro
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MARCH5 regulates mitotic apoptosis through MCL1-dependent and independent mechanisms

Yang Wang1, Randy Y C Poon2,3

  • 1Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.

Cell Death and Differentiation
|November 4, 2022
PubMed

Insights

Mitochondrial ligase MARCH5 regulates apoptosis during cell division. While MARCH5 stabilizes anti-apoptotic MCL1, its absence paradoxically enhances mitotic apoptosis via mitochondrial pathways, not MCL1 levels.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Apoptosis Regulation

Background:

  • The anti-apoptotic protein MCL1 is crucial for preventing programmed cell death during mitosis.
  • MCL1 levels decrease progressively during mitotic arrest, diminishing its protective function.
  • Understanding the regulation of MCL1 and its role in mitotic apoptosis is vital.

Purpose of the Study:

  • To investigate the role of ubiquitin ligases, including MARCH5, in the mitotic degradation of MCL1.
  • To elucidate the mechanisms by which MARCH5 influences mitotic apoptosis.
  • To determine if MARCH5-mediated regulation of mitotic apoptosis is dependent on MCL1 levels.

Main Methods:

  • Utilized knockout strategies for ubiquitin ligase components (APC/C, SCF, MARCH5).
  • Assessed MCL1 levels and degradation dynamics during mitotic arrest.
  • Investigated apoptosis induction using BAK-dependent assays and analyzed mitochondrial fission factor DRP1 disruption.

Main Results:

  • Knockout of APC/C, SCF, or MARCH5 did not prevent MCL1's mitotic degradation.
  • MARCH5 influenced the initial MCL1-NOXA network levels but its absence paradoxically increased BAK-dependent mitotic apoptosis.
  • Disrupting MARCH5 accelerated mitotic apoptosis independently of MCL1 levels; DRP1 inhibition reduced this effect.

Conclusions:

  • MARCH5 regulates mitotic apoptosis through MCL1-independent pathways, notably involving mitochondrial maintenance.
  • The stabilization of MCL1 upon MARCH5 ablation does not prevent, but rather enhances, mitotic cell death.
  • Mitochondrial dynamics, regulated by factors like DRP1, play a significant role in MARCH5-mediated apoptosis control.

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