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Title: Gimap3 Regulates Tissue-Specific Mitochondrial DNA Segregation}
Article:
Abstract:
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.
Introduction:
Mammalian mitochondrial DNA( mtDNA) is a maternally inherited high copy genome. Copy number ranges from 102 to 105 depending upon the cell type, and typically, there is a single haplotype or sequence variant in a cell( homoplasmy)[1]–[3]. Germline or somatic cell mutations in mtDNA 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 can be modeled as a random walk using two parameters: copy number and rate of turnover[4]. However, in some cases there is preferential selection for one mtDNA sequence variant over another, which depends upon the variant, tissue, and nuclear background. Most human pathogenic mtDNA mutations are heteroplasmic, and typically oxidative phosphorylation function is impaired when the proportion of mutant mtDNA exceeds a critical threshold in the cell[5],[6], leading to a wide spectrum of clinical disorders, generally affecting tissues with a high aerobic demand[1]. Transmission of most mutations through the female germline is stochastic[7]; however, in somatic tissues, mtDNA mutations can have skewed segregation patterns depending upon the mutation, tissue, and pedigree[6]–[14]. For instance, there is negative selection for the A3243G mutation in tRNAleu usually associated with MELAS( Mitochondrial Encephalomyopathy, Lactic Acidosis, Stroke-like episodes) in peripheral blood, but not in other tissues[15],[16]. However, this segregation pattern is not observed for other mitochondrial tRNA mutations, such as A8344G associated with MERRF( Myoclonic Epilepsy with Ragged-red fibers)[13],[17]. Thus, while both tRNA mutations impair mitochondrial translation, genetically these mutations are treated differently in the same cell types. To investigate the molecular basis for tissue-specific mtDNA segregation, we have used a heteroplasmic mouse model segregating two neutral mtDNA haplotypes derived from two old inbred mouse strains, BALB and NZB[18]. Transmission of these haplotypes through the female germline is neutral[18]; however, in post-natal life, the BALB mtDNA haplotype accumulates in hematopoietic tissues, while in the kidney and liver there is selection for the NZB haplotype[19]. In every other tissue investigated there is no preference for either mtDNA haplotype. The mechanisms for this mtDNA selection between tissues are apparently completely different[20],[21]. Previously, we demonstrated that nuclear-encoded genes regulate this selection process and mapped the quantitative trait loci( QTL) involved[22]. Further, we showed that selection for the BALB mtDNA haplotype in hematopoietic tissues can be completely eliminated in certain nuclear backgrounds[21]. In this study, we show that Gimap3 is a critical gene for regulating mtDNA segregation hematopoietic tissues in this model.
Discussion:
In this study, we identify the first nuclear-encoded gene that influences mtDNA segregation in mammals. Gimap3 is an outer mitochondrial membrane GTPase, which we show genetically can regulate the rate of mtDNA segregation in hematopoietic tissues. We also demonstrate that segregation of mtDNA haplotypes in mouse hematopoietic tissues is a complex genetic trait regulated with age but independent of mtDNA copy number. Variation in Gimap3 alone does not account for the entire segregation phenotype for the following reasons. At three months of age, some mice homozygous for the CAST allele still exhibit mtDNA selection, the phenotype is age-dependent, and in our transgenic mice, overexpression of the CAST Gimap3 had a quantitative effect on the rate of mtDNA segregation. These observations suggest other genes, such as the two suggestive loci detected on chromosome 11 and 13 in the linkage analysis are involved in the regulation of mtDNA segregation. MtDNA selection in hematopoietic tissues of both humans and mice can be modeled as an exponential function, however, the rates are significantly different, up to 70 times faster in our mouse model than in humans[17]. In humans carrying the A3243G MELAS mutation, there is depletion of mtDNA independent of heteroplasmy level and age, which might be a secondary effect of the mutation and a driver for selection of wild type mtDNA[16]. However, the mechanism that leads to a decreased copy number and drives selection for the wild type mtDNA remains unknown. Rajasimha et al.[17] have postulated that selection against the A3243G MELAS mutation likely occurs in the stem cell population of rapidly dividing cells. Data from our mouse model do not support this mechanism of segregation, even though in our BALB/c heteroplasmic mouse model, selection for mtDNA occurs in leukocytes from both lymphoid and myeloid lineages[21]. In rapidly dividing colonic crypts there is no selection for mtDNA haplotypes[18], and, in our F2( BALB/c X CAST/Ei) cross the frequency of mice that have lost mtDNA selection changes with age. Gimap3 is a member of the conserved Gimap( GTPase of immunity-associated protein) gene cluster found only in vertebrates, with an orthologue in angiosperm plants[25]–[28]. Both Gimap3 and Gimap5( a paralogue of Gimap3) contain a G1 to G5 switch GTPase, two coiled-coil motifs, and a hydrophobic conserved box[25]. In humans, only GIMAP5 is a functional gene producing two splice variants with predicted molecular masses of 34. 8 and 39. 5 kDa, while GIMAP3 appears to be a pseudogene[25]. Very little is known about protein function, and in particular the role of the GTPase domain and the conserved box remain an enigma. These two proteins are critical for T cell development and cell survival, and shown to interact with anti-apoptotic Bcl-2 family members, but the mechanisms are not understood[27]. Gimap5 was originally identified as the factor responsible for the severe T cell lymphopenia in the diabetes prone BioBreeding rat[29], although in mice loss of Gimap5 function produces a broader and more severe phenotype, which includes a leukocyte developmental defect, liver dysfunction, and lethality( median age of death around 14–15 weeks)[30]. The CAST/Ei variant of Gimap3 only differs at the N-terminus, leaving intact all of the known functional domains of the protein, including the C-terminus required for membrane insertion and localization. How these extra 58 amino acids in the CAST/Ei Gimap3 variant affect protein function requires further characterization of Gimap3 in leukocytes. How can an outer mitochondrial membrane protein regulate mtDNA segregation in hematopoietic tissues? Selection for mtDNA haplotypes can only be directed at two levels, either at the DNA sequence itself or at the proteins encoded within it. Analysis of Gimap3 protein sequence does not support a direct physical interaction with mtDNA, because the protein does not appear to span both mitochondrial membranes into the matrix space in order to facilitate such an interaction. One possibility is that Gimap3 acts as a node or switch on the outer membrane for a retrograde signaling cascade involving mitochondrial peptide export, a process that occurs across eukaryotes[31]–[34]. Bacteria use peptide export-import as a control circuit to regulate processes, such as nutrient uptake and sporulation[35]. Further work on Gimap3 will establish its function within mtDNA segregation and whether peptide export or cell survival are involved.
Mitochondria are essential cellular organelles , which contain their own small circular genome in mammals . The mitochondrial genome is maternally inherited and encodes proteins critical for aerobic energy production . Mutations in mitochondrial DNA can lead to disruptions in aerobic energy production , which manifest as a wide spectrum of human clinical disorders . These mutations can segregate in mitotic and post-mitotic tissues , so that the proportion of the mutant genome can change with age , thereby affecting the clinical onset and severity of disease . The mechanisms regulating mtDNA segregation in mammals are not understood . We have used a mouse model of mtDNA segregation to elucidate the molecular basis of this process . Here , we demonstrate that the gene , Gimap3 , can regulate mtDNA segregation in mouse white blood cells . This is the first gene identified to regulate mtDNA segregation in mammals , which is also an important factor in cell survival . Future work on this protein will provide critical insight into the pathways that regulate mitochondrial DNA in white blood cells , an important factor in the pathogenesis of human mitochondrial DNA mutations .