Mitochondrial DNA as a regulator of the immune function

Mitochondrial DNA as a regulator of the immune function

Abstract: Mitochondrial DNA (mtDNA) variants are associated with a diverse range of diseases, yet the precise mechanisms underlying their impact remain elusive. Leveraging our unique mitochondrial mouse models, characterized by identical nuclear DNA (nDNA) but divergent mtDNA haplotypes (mtDNAB6, mtDNA129, and mtDNANZB), we have uncovered profound effects on immune function. Our investigations revealed that mtDNA variants can: 1) Enhance anti-tumor immunity: mtDNANZB mice exhibit heightened anti-tumor responses against malignancies such as melanoma and leukemia; 2) Dysregulation of T-cell subsets: T cells from mtDNANZB mice display diminished T regulatory (Treg) function and independently also increased T effector (Teff) cell activity compared to mtDNAB6-derived T cells; and 3) Enhance antigen presenting cell (APC) potency: APCs derived from mtDNANZB mice elicit robust T cell proliferation relative to mtDNA129-derived APCs. These findings collectively suggest a predisposition of immune cells from mtDNANZB mice towards a pro-inflammatory state, fostering an enhanced anti-tumor immune milieu. We postulate that mitochondrial metabolites, impacted by different mtDNA variants, mediate the different effects on the immune system, thereby shaping disease susceptibility. Our ongoing investigations aim to validate this hypothesis using our mitochondrial mouse models, variable T cells sources and subsets, models of several malignancies and cutting-edge instruments. For example: our preliminary data indicate that activation of mtDNANZB  T cells upregulates genes enriched in neurodegeneration pathways, contrasting with the enrichment of cancer-related pathways upon activation of mtDNAB6 T cells. Through this elucidation of the interplay between mtDNA variants and immune function, we strive to unravel novel insights into disease mechanisms and therapeutics.