Antigen receptor stimulation drives selection against pathogenic mtDNA variants that dysregulate lymphocyte responses

Zhang, J.; Koolmeister, C.; Han, J.; Filograna, R.; Hanke, L.; Adori, M.; Sheward, D. J.; Teifel, S.; Liu, Y.; Harris, R. A.; Murrell, B.; Mcinerney, G.; Aoun, M.; Backdahl, L.; Holmdahl, R.; Pekalski, M.; Wedell, A.; Engvall, M.; Wredenberg, A.; Karlsson Hedestam, G. B.; Castro Dopico, X.; Rorbach, J.

Pathogenic mitochondrial (mt)DNA molecules can exhibit heteroplasmy in single cells and tissues and cause a range of clinical phenotypes, although their contribution to immunity is poorly understood. Here, in mice carrying heteroplasmic C5024T in mt-tRNA Ala - that impairs oxidative phosphorylation - we found a reduced mutation burden in peripheral T and B memory lymphocyte subsets, compared to their naive counterparts. Furthermore, selection diluting the mutation was induced in vitro by triggering T and B cell antigen receptors. While C5024T dysregulated naive CD8+ T cell respiration and metabolic remodeling post-activation, these phenotypes were partially ameliorated by selection. Analogous to mice, peripheral blood memory T and B lymphocyte subsets from human MELAS (Mitochondrial Encephelomyopathy with Lactic Acidoses and Stroke-like episodes) patients - carrying heteroplasmic A3243G in mt-tRNA Leu - displayed a reduced mutation burden, compared to naive cells. In both humans and mice, mtDNA selection was observed in IgG+ antigen-specific B cells after SARS-CoV-2 Spike vaccination, illustrating an ongoing process in vivo. Taken together, these data illustrate purifying selection of pathogenic mtDNA variants during the oxidative phosphorylation checkpoints of the naive-memory lymphocyte transition.