An OMA1 redox site controls mitochondrial homeostasis, sarcoma growth, and immunogenicity

Area of Science:

• Mitochondrial dynamics and cancer biology
• Immunology and tumor microenvironment

Background:

• Aggressive tumors often exhibit mitochondrial dysfunction.
• Mitochondrial fission, regulated by OMA1 and OPA1, is crucial during oxidative stress.
• A redox-sensing mechanism in yeast OMA1 suggests a similar role in mammalian cells, potentially involving cysteine 403.

Purpose of the Study:

• To investigate the role of OMA1 cysteine 403 in mitochondrial stress response and tumor development.
• To determine if OMA1 inactivation impacts anti-tumor immunity and sarcoma progression.

Main Methods:

• Development of a mouse sarcoma cell line using prime editing to mutate OMA1 cysteine 403 to alanine.
• Analysis of mitochondrial function, apoptosis resistance, and mitochondrial DNA release in mutant cells.
• In vivo tumor development studies in immunocompetent and immunodeficient mouse models (nude, cDC1-deficient).
• Assessment of CD8+ T cell infiltration and tumor control.
• Correlation analysis of OMA1 and OPA1 transcript levels with clinical data in soft tissue sarcoma patients.

Main Results:

• Mutant cells displayed impaired ATP production, reduced mitochondrial fission, increased apoptosis resistance, and enhanced mitochondrial DNA release.
• OMA1 mutation prevented tumor development in immunocompetent mice, but not in nude or cDC1-deficient mice.
• Mutant tumors showed increased CD8+ T cell accumulation, and their depletion delayed tumor control, indicating enhanced anti-tumor immunity.
• High OPA1 expression correlated with shorter metastasis-free survival, while low OPA1 expression was linked to anti-tumor immune signatures in sarcoma patients.

Conclusions:

• Inactivation of OMA1 at cysteine 403 enhances anti-tumor immunity and inhibits sarcoma development.
• Targeting OMA1 activity represents a potential strategy to improve sarcoma immunogenicity and therapeutic outcomes.