Mitochondrial ROS promotes susceptibility to infection via gasdermin D-mediated necroptosis

Area of Science:

• Immunology
• Cell Biology
• Mitochondrial Biology

Background:

• Mutations in mitochondrial genes are linked to inflammation and infection susceptibility.
• Mechanisms connecting mitochondrial dysfunction to immune responses are not fully understood.

Purpose of the Study:

• To investigate how the Lrrk2 G2019S mutation impacts mitochondrial homeostasis and cell death pathways in macrophages.
• To elucidate the role of gasdermin D (GSDMD) in mediating cell death and immune responses in the context of Lrrk2 mutations.

Main Methods:

• Utilized macrophages expressing the Lrrk2 G2019S gain-of-function allele.
• Analyzed inflammasome activation, mitochondrial reactive oxygen species (mtROS) production, and cell death pathways (necroptosis).
• Infected Lrrk2 G2019S mice with Mycobacterium tuberculosis to assess in vivo immune pathology.

Main Results:

• The Lrrk2 G2019S mutation perturbs mitochondrial homeostasis and reprograms cell death.
• Elevated mtROS in Lrrk2 G2019S macrophages directs GSDMD to mitochondrial membranes, promoting necroptosis.
• Lrrk2 G2019S mice exhibit hyperinflammation and severe immunopathology upon Mycobacterium tuberculosis infection due to enhanced necroptosis.

Conclusions:

• Mitochondrial dysfunction can dictate immune outcomes by switching cell death modalities.
• GSDMD acts as a key executor of multiple cell death pathways, including necroptosis.
• Targeting GSDMD-dependent necroptosis may mitigate LRRK2 mutation-associated immunopathology.