Prohibitin 1 regulates mtDNA release and downstream inflammatory 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.