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Mitochondria are dynamic organelles that divide and fuse by remodeling an outer and inner membrane in response to developmental, physiological and stress stimuli. These events are coordinated by conserved dynamin-related GTPases. The dynamics of mitochondrial morphology require coordination with mitochondrial DNA (mtDNA) to ensure faithful genome transmission, however, this process remains poorly understood. Mitochondrial division is linked to the segregation of mtDNA but how it affects cases of mtDNA heteroplasmy, where two or more mtDNA variants/mutations co-exist in a cell, is unknown. Segregation of heteroplasmic human pathogenic mtDNA mutations is a critical factor in the onset and severity of human mitochondrial diseases. Here, we investigated the coupling of mitochondrial morphology to the transmission and segregation of mtDNA in mammals by taking advantage of two genetically modified mouse models: one with a dominant-negative mutation in the dynamin-related protein 1 (Drp1 or Dnm1l) that impairs mitochondrial fission and the other, heteroplasmic mice segregating two neutral mtDNA haplotypes (BALB and NZB). We show a tissue-specific response to mtDNA segregation from a defect in mitochondrial fission. Only mtDNA segregation in the hematopoietic compartment is modulated from impaired Dnm1l function. In contrast, no effect was observed in other tissues arising from the three germ layers during development and in mtDNA transmission through the female germline. Our data suggest a robust organization of a heteroplasmic mtDNA segregating unit across mammalian cell types that can overcome impaired mitochondrial division to ensure faithful transmission of the mitochondrial genome., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Mammalian mitochondrial DNA (mtDNA) is a high-copy maternally inherited genome essential for aerobic energy metabolism. Mutations in mtDNA can lead to heteroplasmy, the co-occurence of two different mtDNA variants in the same cell, which can segregate in a tissue-specific manner affecting the onset and severity of mitochondrial dysfunction. To investigate mechanisms regulating mtDNA segregation we use a heteroplasmic mouse model with two polymorphic neutral mtDNA haplotypes (NZB and BALB) that displays tissue-specific and age-dependent selection for mtDNA haplotypes. In the hematopoietic compartment there is selection for the BALB mtDNA haplotype, a phenotype that can be modified by allelic variants of Gimap3. Gimap3 is a tail-anchored member of the GTPase of the immunity-associated protein (Gimap) family of protein scaffolds important for leukocyte development and survival. Here we show how the expression of two murine Gimap3 alleles from Mus musculus domesticus and M. m. castaneus differentially affect mtDNA segregation. The castaneus allele has incorporated a uORF (upstream open reading frame) in-frame with the Gimap3 mRNA that impairs translation and imparts a negative effect on the steady-state protein abundance. We found that quantitative changes in the expression of Gimap3 and the paralogue Gimap5, which encodes a lysosomal protein, affect mtDNA segregation in the mouse hematopoietic tissues. We also show that Gimap3 localizes to the endoplasmic reticulum and not mitochondria as previously reported. Collectively these data show that the abundance of protein scaffolds on the endoplasmic reticulum and lysosomes are important to the segregation of the mitochondrial genome in the mouse hematopoietic compartment., (Copyright © 2015 by the Genetics Society of America.)

Mitochondrial DNA (mtDNA) is essential for aerobic energy production in eukaryotic cells, and mutations in this genome can lead to mitochondrial dysfunction. Human mtDNA mutations are typically heteroplasmic, a mix of mutant and wild-type genomes, which can present as a heterogeneous group of disorders ranging in severity from mild to fatal, and commonly affecting highly aerobic tissues such as heart, skeletal muscle, and neurons. During the 1990s, many research groups started to notice that mtDNA mutations could segregate depending upon the mutation and tissue. This segregation pattern can have a direct effect on the onset and severity of these mutations. However, these segregation patterns could not be easily explained by respiratory chain function, implying that there is regulation of mtDNA independent of its bioenergetic role. A lot of research on this topic has been largely descriptive, but over the last several years advances in mitochondrial biology have provided some mechanistic insight into the regulation of the organelle and its genome. This review addresses these advances with respect to somatic segregation of mtDNA in mammals.

Mitochondrial DNA (mtDNA) sequence variants segregate in mutation and tissue-specific manners, but the mechanisms remain unknown. The segregation pattern of pathogenic mtDNA mutations is a major determinant of the onset and severity of disease. Using a heteroplasmic mouse model, we demonstrate that Gimap3, an outer mitochondrial membrane GTPase, is a critical regulator of this process in leukocytes. Gimap3 is important for T cell development and survival, suggesting that leukocyte survival may be a key factor in the genetic regulation of mtDNA sequence variants and in modulating human mitochondrial diseases., Competing Interests: The authors have declared that no competing interests exist.