Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis

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.