BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis

Area of Science:

• Cell biology
• Immunology
• Molecular biology

Background:

• Mitochondrial outer membrane permeabilization (MOMP) by BAK and BAX proteins initiates apoptosis.
• Dying cells lacking active caspases can activate the cGAS/STING innate immune pathway via mitochondrial DNA (mtDNA).
• The mechanism by which mtDNA accesses cytosolic sensors like cGAS is not fully understood.

Purpose of the Study:

• To investigate how mitochondrial DNA (mtDNA) gains access to the cytosol during apoptosis.
• To elucidate the role of BAK/BAX pores in mtDNA release and innate immune activation.

Main Methods:

• Live-cell lattice light-sheet microscopy was employed to visualize the mitochondrial network dynamics in mouse embryonic fibroblasts.
• The study focused on cells undergoing BAK/BAX-mediated apoptosis with cytochrome c loss.

Main Results:

• Activation of BAK/BAX led to mitochondrial network breakdown and the formation of large pores in the outer mitochondrial membrane.
• These BAK/BAX macropores facilitated the herniation of the inner mitochondrial membrane into the cytosol.
• Herniation delivered mitochondrial matrix contents, including mtDNA, into the cytosol, enabling cGAS/STING pathway activation.
• Active caspases were observed to dismantle the cell, potentially suppressing mtDNA-induced immune signaling.

Conclusions:

• BAK/BAX-mediated macropores are crucial for inner mitochondrial membrane herniation and cytosolic release of mtDNA during apoptosis.
• This herniation mechanism explains how mtDNA accesses cytosolic innate immune sensors.
• Cellular dismantling by caspases may serve to limit self-DNA-triggered inflammation.