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VDAC oligomer pores: A mechanism in disease triggered by mtDNA release

Jialong Yan1, Wei Liu2, Fen Feng3

  • 1Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology, University of South China, Hengyang, Hunan, China.

Cell Biology International
|July 28, 2020
PubMed

Insights

Voltage-dependent anion channel (VDAC) oligomer pores release mitochondrial DNA (mtDNA) into the cytosol, activating immune responses and potentially causing systemic lupus erythematosus. This challenges previous understandings of mtDNA release mechanisms.

Area of Science:

  • Cell Biology
  • Immunology
  • Molecular Biology

Background:

  • Mitochondrial outer membrane permeabilization (MOMP) is traditionally associated with apoptosis via BAX/BAK.
  • Cytosolic mitochondrial DNA (mtDNA) is a known trigger for innate immune responses.
  • The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway is a key mediator of type I interferon (IFN) production.

Purpose of the Study:

  • To investigate the role of voltage-dependent anion channel (VDAC) oligomer pores in mitochondrial outer membrane permeabilization and mtDNA release.
  • To explore the implications of VDAC-mediated mtDNA release in triggering innate immune responses.
  • To challenge the established view of mtDNA release occurring exclusively through BAX/BAK macropores.

Main Methods:

  • Live-cell imaging to observe VDAC oligomer pore formation and mtDNA release.
  • Biochemical assays to analyze the interaction between mtDNA and VDAC1.
  • Immune response assays to detect type I IFN activation.

Main Results:

  • VDAC oligomer pores were found to promote MOMP and facilitate mtDNA release into the cytosol in live cells.
  • mtDNA release via VDAC pores was observed independently of BAX/BAK.
  • Cytosolic mtDNA activated the cGAS-STING pathway, leading to type I IFN production.
  • Specific residues (Lys12, Arg15, Lys20) on VDAC1 were identified as crucial for mtDNA interaction and VDAC oligomerization.

Conclusions:

  • VDAC oligomer pores represent a novel mechanism for mtDNA release, distinct from BAX/BAK pathways.
  • V DAC-mediated mtDNA release contributes to type I IFN responses and may be implicated in autoimmune diseases like systemic lupus erythematosus.
  • Targeting VDAC oligomerization could offer new therapeutic strategies for mtDNA release-related disorders.
Keywords:
biochemistrydiseasesintercellular communicationmitochondria

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