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Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis

Joel S Riley1,2, Giovanni Quarato3, Catherine Cloix1,2

  • 1Cancer Research UK Beatson Institute, Glasgow, UK.

The EMBO Journal
|July 28, 2018
PubMed

Insights

Mitochondrial inner membrane permeabilisation (MIMP) releases mitochondrial DNA (mtDNA) during cell death, activating inflammatory pathways. This process explains how mtDNA triggers immune responses in caspase-independent cell death following BAX/BAK-mediated mitochondrial outer membrane permeabilisation (MOMP).

Area of Science:

  • Cell Biology
  • Immunology
  • Molecular Biology

Background:

  • Apoptosis involves BAX/BAK activation, mitochondrial outer membrane permeabilisation (MOMP), and caspase activation leading to cell death.
  • Caspase-independent cell death also follows MOMP and triggers inflammation via mitochondrial DNA (mtDNA) activating cGAS-STING signaling.
  • The mechanism of matrix mtDNA release into the cytosol, despite the intact inner mitochondrial membrane, remained unclear.

Purpose of the Study:

  • To investigate how mitochondrial matrix mtDNA is released to activate cytosolic cGAS-STING signaling during caspase-independent cell death.
  • To elucidate the role of the mitochondrial inner membrane in mtDNA release following MOMP.

Main Methods:

  • Super-resolution imaging to visualize mtDNA release.
  • Temporal analysis of BAX/BAK-mediated pore dynamics.
  • Assessment of mitochondrial inner membrane permeabilisation (MIMP) during cell death.

Main Results:

  • Mitochondrial DNA (mtDNA) is efficiently released from mitochondria after MOMP.
  • BAX/BAK-mediated outer membrane pores gradually widen, allowing inner membrane extrusion into the cytosol.
  • The extruded inner membrane subsequently permeabilises, leading to mtDNA release into the cytosol.

Conclusions:

  • Mitochondrial inner membrane permeabilisation (MIMP) occurs during BAX/BAK-dependent cell death.
  • MIMP is crucial for the release of mtDNA into the cytosol.
  • This mtDNA release underpins the inflammatory and immunogenic effects of caspase-independent cell death.
Keywords:
BAX/BAKapoptosiscGAS‐STINGmitochondriamtDNA

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