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


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.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

The work was funded by Max Planck Institute, Karolinska Institutet (WAF2017, awarded to JR), the Knut & Alice Wallenberg Foundation (KAW 2018.0080, awarded to JR; 2015.0063 awarded to RHo), and the Swedish Research Council (VR2016-02179, awarded to AWr; VR2015-02662, awarded to RHo).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.


The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethical approval for the use of peripheral blood samples and clinical information from human MELAS patients was granted by Swedish Ethical Review Authority (registration number 2018/1498-31/3). Ethical approval for investigation of C5024T mice, including vaccination challenge, was granted by the Swedish Board of Agriculture (permit numbers 10513-2020, 2001-2018 and 20513-2020).

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