Mitochondrial DNA segregation in hematopoietic lineages does not depend on MHC presentation of mitochondrially encoded peptides

Abstract

Mutations in mitochondrial DNA (mtDNA) are associated with a broad spectrum of clinical disorders. The segregation pattern of pathogenic mtDNAs is an important determinant of both the onset and the severity of the disease phenotype, but the mechanisms controlling mtDNA segregation remain poorly understood. To investigate this, we previously generated heteroplasmic mice containing two different mtDNA haplotypes and showed that BALB/c mtDNA was invariably selected over NZB mtDNA in blood and spleen. Here, we have characterized this process in hematopoietic tissues and tested whether it involves the presentation of mtDNA-encoded peptides by MHC class Ib molecules. Selection against NZB mtDNA was widespread across different hematopoietic cell lineages and proportional to heteroplasmy levels. Backcrossing heteroplasmic mice with CAST/Ei, a strain in which the MHC class Ib molecule H2-M3 is silent, completely abolished selection against NZB mtDNA in the spleen. To test whether this effect depended on an intact immune system, we generated heteroplasmic mice missing functional copies of Tap1, beta2m or Rag1 to impair presentation or recognition of mtDNA-encoded peptides. The kinetics of selection against NZB mtDNA were unaltered in these mice compared with their wild-type littermates. We conclude that mtDNA selection in hematopoietic tissues is not based on an immune mechanism, but likely involves metabolic signaling.

Assessing human germ‐cell mutagenesis in the Postgenome Era: A celebration of the legacy of William Lawson (Bill) Russell

“…Shoubridge used a mouse model to analyze the segregation of mtDNA variants during oocyte development and early embryogenesis [Battersby et al, 2005]. His findings suggest that mtDNA rapidly segregates by a stochastic process that does not ensure equal distribution of variant mtDNA genomes.…”

Quantitative Changes in Gimap3 and Gimap5 Expression Modify Mitochondrial DNA Segregation in Mice

“…On the nuclear background of M. m. domesticus in several different mouse strains (BALB/c, C3H, C57BL/6J, DBA, NZB, and 129Sv) there are no differences in these tissue-specific mtDNA segregation phenotypes (Battersby et al 2003(Battersby et al , 2005). In contrast, crosses onto a M. m. castaneus nuclear background have a significant effect on these mtDNA segregation phenotypes (Battersby et al 2003(Battersby et al , 2005. This allowed us to identify three nuclear loci that affect mtDNA segregation in a tissue-specific manner (Battersby et al 2003).…”

“…Germline or somatic-cell mtDNA mutations lead to the co-occurrence of two or more sequence variants in a cell, a state known as heteroplasmy. In the absence of selection, the segregation of mtDNA sequence variants is neutral and can be modeled as a random walk (Chinnery and Samuels 1999); however, in some cases there is preferential selection for a mtDNA sequence variant that is dependent upon the nucleotide sequence, tissue, and nuclear background (Battersby and Shoubridge 2001;Battersby et al 2003Battersby et al , 2005Jokinen and Battersby 2013;Burgstaller et al 2014). The majority of pathogenic mtDNA mutations are heteroplasmic and some mutations display skewed segregation patterns in somatic tissues.…”

“…However, postnatally there is age-dependent selection of one haplotype over the other in three tissue types (liver, kidney, and hematopoietic tissues), while all other tissues in these mice are neutral with respect to mtDNA segregation (Jenuth et al 1997). In the liver and kidney there is selection for the NZB haplotype to fixation (Jenuth et al 1997;Battersby and Shoubridge 2001;Battersby et al 2003Battersby et al , 2005. In contrast, the hematopoietic tissues (bone marrow, blood, thymus, and spleen) select against the NZB mtDNA haplotype, which can be modeled as an exponential decay (Battersby et al 2005).…”

“…In the liver and kidney there is selection for the NZB haplotype to fixation (Jenuth et al 1997;Battersby and Shoubridge 2001;Battersby et al 2003Battersby et al , 2005. In contrast, the hematopoietic tissues (bone marrow, blood, thymus, and spleen) select against the NZB mtDNA haplotype, which can be modeled as an exponential decay (Battersby et al 2005). This tissue-specific mtDNA segregation is best treated as a quantitative genetic phenotype and one that cannot be explained by detectable functional differences in the mitochondrial respiratory chain or by differential rates in mtDNA replication (Battersby and Shoubridge 2001).…”