A genetic bottleneck of mitochondrial DNA during human lymphocyte development

Abstract

Mitochondria are essential organelles in eukaryotic cells that provide critical support for energetic and metabolic homeostasis. Mutations that accumulate in mitochondrial DNA (mtDNA) in somatic cells have been implicated in cancer, degenerative diseases, and the aging process. However, the mechanisms used by somatic cells to maintain proper functions despite their mtDNA mutation load are poorly understood. Here, we analyzed somatic mtDNA mutations in more than 30,000 human single peripheral and bone marrow mononuclear cells and observed a significant overrepresentation of homoplastic mtDNA mutations in B, T and NK lymphocytes despite their lower mutational burden than other hematopoietic cells. The characteristic mutational landscape of mtDNA in lymphocytes were validated with data from multiple platforms and individuals. Single-cell RNA-seq and computational modeling demonstrated a stringent mitochondrial bottleneck during lymphocyte development likely caused by lagging mtDNA replication relative to cell proliferation. These results illuminate a potential mechanism used by highly metabolically active immune cells for quality control of their mitochondrial genomes.

T cell differentiation drives the negative selection of pathogenic mtDNA variants

“…Previous modelling results are consistent with a decline initiating in haemopoietic stem cells, with a mechanism involving the random segregation of mtDNA molecules at mitosis followed by the elimination of cells that have reached a biochemical threshold due to the accumulation of high levels of variant mtDNA (10). More recently, an enhanced decline of m.3243A>G within T cells has been demonstrated (12); this is consistent with a proposed mtDNA bottleneck within lymphoid cell development (13).…”