Antigen receptor stimulation induces purifying selection against pathogenic mitochondrial tRNA mutations

Area of Science:

• Immunology
• Mitochondrial Biology
• Genetics

Background:

• Mitochondrial (mt) tRNA gene mutations cause oxidative phosphorylation (OXPHOS) defects and multisyndromic conditions.
• Mitochondrial diseases are linked to immune system abnormalities, but the molecular mechanisms involving heteroplasmic mtDNA mutations remain unclear.

Purpose of the Study:

• To investigate how heteroplasmic mtDNA mutations affect the immune system at a molecular level.
• To explore the impact of pathogenic mtDNA mutations on T and B cell populations and their function.

Main Methods:

• Analysis of pathogenic mtDNA mutation burdens in T cells, B cells, and myeloid cells from mice and MELAS patients.
• Assessment of mutation dilution in T and B cell cultures under proliferation and metabolic stress.
• Evaluation of CD8+ T cell metabolic remodeling and Interferon-gamma (IFN-γ) production post-activation.

Main Results:

• Memory T and B cells exhibited lower pathogenic mtDNA mutation loads compared to naive cells, even after vaccination.
• Pathogenic mutation dilution was less significant in myeloid cells than lymphoid cells.
• Antigen receptor-triggered proliferation and metabolic stress accelerated C5024T mutation dilution in T and B cell cultures.
• The C5024T mutation dysregulated CD8+ T cell metabolic reprogramming and IFN-γ production.

Conclusions:

• Lymphocyte generation influences the mitochondrial DNA (mtDNA) landscape.
• Pathogenic mtDNA variants can dysregulate immune responses, particularly in memory lymphocytes.
• Understanding these mechanisms is crucial for managing mitochondrial diseases with immune components.