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Prohibitin 1 regulates mtDNA release and downstream inflammatory responses

Hao Liu1,2,3, Hualin Fan2,4, Pengcheng He5,6,7,8

  • 1Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, China.

The EMBO Journal
|October 17, 2022
PubMed

Insights

Mitochondrial DNA (mtDNA) release into the cytosol triggers inflammation. Prohibitin 1 (PHB1) regulates this release by controlling inner mitochondrial membrane permeability, impacting immune responses.

Area of Science:

  • Immunology
  • Cell Biology
  • Mitochondrial Biology

Background:

  • Cytosolic exposure of mitochondrial DNA (mtDNA) activates innate immunity.
  • Mechanisms of mtDNA translocation across the inner mitochondrial membrane remain unclear.

Purpose of the Study:

  • To elucidate the role of prohibitin 1 (PHB1) in regulating mitochondrial inner membrane permeability and mtDNA release.
  • To investigate the link between PHB1, mitochondrial integrity, and inflammatory responses.

Main Methods:

  • Investigated PHB1 function in macrophages and knockout mouse models (Phb1MyeKO).
  • Analyzed interleukin-1β (IL-1β) levels in serum and cells.
  • Assessed inflammatory responses and mtDNA release in PHB1-deficient cells.
  • Utilized pharmacological inhibitors of mitochondrial permeability transition pore (mPTP) and VDAC oligomerization.

Main Results:

  • Loss of PHB1 disrupts mitochondrial integrity and function, leading to increased mtDNA release.
  • PHB1 deficiency in macrophages and mice correlates with elevated IL-1β levels and heightened inflammatory responses.
  • Inflammatory stresses downregulate PHB1 expression, promoting mtDNA release.
  • PHB1 normally restrains mPTP opening by interacting with AFG3L2 and SPG7; PHB1 loss enhances this interaction, causing mPTP opening and mtDNA release.

Conclusions:

  • PHB1 is a critical regulator of inner mitochondrial membrane permeability, controlling mtDNA release and subsequent inflammatory signaling.
  • Dysregulation of PHB1 contributes to inflammatory conditions, as observed in sepsis models.
  • Targeting PHB1 or mPTP could offer therapeutic strategies for inflammatory diseases driven by mtDNA release.
Keywords:
AFG3L2MIMPPHBSPG7mtDNA

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