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Endolysosomal Targeting of Mitochondria Is Integral to BAX-Mediated Mitochondrial Permeabilization during Apoptosis

Tim Sen Wang1, Isabelle Coppens2, Anna Saorin2

  • 1W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA; Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Developmental Cell
|June 7, 2020
PubMed

Insights

Endolysosomes dynamically target mitochondria during apoptosis, controlling BAX clustering and cytochrome c release. This inter-organelle communication is crucial for mitochondrial outer membrane permeabilization (MOMP) execution.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Mitochondrial outer membrane permeabilization (MOMP) is a critical step in apoptosis.
  • The precise mechanisms governing BAX and BAK pore formation during MOMP are not fully elucidated.

Purpose of the Study:

  • To investigate the role of endolysosomes (ELs) in the process of MOMP.
  • To understand how EL-mitochondria interactions regulate BAX and BAK activation during apoptosis.

Main Methods:

  • Observation of EL-mitochondria dynamics during MOMP induction.
  • Genetic manipulation (knockdown) of key proteins involved in EL trafficking (Rab5A, Rab5C, USP15, Rabex-5).
  • Assessment of BAX clustering and cytochrome c release as indicators of MOMP execution.

Main Results:

  • Endolysosomes (ELs) dynamically target and accumulate within mitochondria during MOMP.
  • EL-mitochondrial interactions are essential for BAX recruitment and pore formation.
  • Disruption of EL targeting pathways (e.g., Rab5A, Rab5C, USP15 knockdown) uncouples BAX clustering from cytochrome c release.
  • Impairment of Rabex-5 function affects both BAX clustering and cytochrome c release.

Conclusions:

  • Endolysosome-mitochondria inter-organelle communication is a critical regulatory mechanism for MOMP.
  • EL targeting is integral to the coordinated execution of apoptosis signaling pathways.
Keywords:
ApoptosisBCL-2-associated X protein (BAX)Rab5Rabex-5/RabGEF1USP15endolysosomesendosomesmitochondriamitochondrial outer membrane permeabilization (MOMP)regulated cell death

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