Gimap3 Regulates Tissue-Specific Mitochondrial DNA Segregation

Jokinen, Riikka; Marttinen, Paula; Sandell, H Katarin; Manninen, Tuula; Teerenhovi, Heli; Wai, Timothy; Teoli, Daniella; Loredo-Osti, J. Concepción; Shoubridge, Eric A.; Battersby, Brendan J.

doi:10.1371/journal.pgen.1001161

Cited by 58 publications

(66 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Previously we identified M. musculus allelic variants of Gimap3 that affect mtDNA segregation in hematopoietic tissues (Jokinen et al 2010). In the common lab mouse strains with a M. m. domesticus background, such as BALB/c, Gimap3 contains five exons and transcription produces an mRNA with two AUG codons as potential start codons for translation initiation ( Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

“…Surprisingly, the uORF has a greater Kozak consensus sequence around the AUG than that seen for the downstream reading frame of Gimap3 ( Figure 1B). Unless indicated otherwise, hereafter Gimap3 refers to the allele found among the common lab strains with a M. m. domesticus background that encodes the 301-aminoacid protein (Jokinen et al 2010). In contrast, the subspecies M. m. castaneus has a mutation in the splice acceptor site of exon 4 causing a splicing defect leading to the absence of exon 4 from the CAST Gimap3 mRNA ( Figure 1A) (Jokinen et al 2010).…”

Section: Resultsmentioning

confidence: 99%

“…Unless indicated otherwise, hereafter Gimap3 refers to the allele found among the common lab strains with a M. m. domesticus background that encodes the 301-aminoacid protein (Jokinen et al 2010). In contrast, the subspecies M. m. castaneus has a mutation in the splice acceptor site of exon 4 causing a splicing defect leading to the absence of exon 4 from the CAST Gimap3 mRNA ( Figure 1A) (Jokinen et al 2010). In this CAST allele the AUG of the uORF is used for translation initiation producing a 359 amino acid protein ( Figure 1A and Figure S1).…”

Section: Resultsmentioning

confidence: 99%

“…This allowed us to identify three nuclear loci that affect mtDNA segregation in a tissue-specific manner (Battersby et al 2003). At one of these loci we have successfully cloned Gimap3 (Jokinen et al 2010), which can modulate the segregation of mtDNA in leukocytes.…”

mentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2015

Self Cite

View full text Add to dashboard Cite

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. KEYWORDS mitochondria; mitochondrial DNA; mice; segregation; Gimap M AMMALIAN mitochondrial DNA (mtDNA) is a maternally inherited small circular multicopy genome that encodes 13 proteins that are essential subunits of four of the five complexes required for mitochondrial oxidative phosphorylation. 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. (Larsson et al. 1990;Boulet et al. 1992;Kawakami et al. 1994;Dunbar et al. 1995;Fu et al. 1996;Chinnery et al. 1997Weber et al. 1997), which can affect the onset and severity of mitochondrial dysfunction. Currently, the molecular basis for this regulation of the mitochondrial genome is largely un...

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…These two different normal mtDNA were found to be actively segregated for during the animal lifespan, in a non-random fashion as one genotype was favored in kidney and liver while the other one was favored in blood and spleen [35]. Using linkage analysis and crosses with distantly related mouse species, Battersby et al found three potential loci controlling the tissular segregation [36] and, more recently, identified GIMAP3 as a gene controlling active mtDNA segregation in blood [37]. How this gene can influence the fate of a normal mtDNA still remains an open question.…”

Section: Lessons From Animal Modelsmentioning

confidence: 99%

Unsolved issues related to human mitochondrial diseases

et al. 2014

View full text Add to dashboard Cite

Human mitochondrial diseases, defined as the diseases due to a mitochondrial oxidative phosphorylation defect, represent a large group of very diverse diseases with respect to phenotype and genetic causes. They present with many unsolved issues, the comprehensive analysis of which is beyond the scope of this review. We here essentially focus on the mechanisms underlying the diversity of targeted tissues, which is an important component of the large panel of these diseases phenotypic expression. The reproducibility of genotype/phenotype expression, the presence of modifying factors, and the potential causes for the restricted pattern of tissular expression are reviewed.Special emphasis is made on heteroplasmy, a specific feature of mitochondrial diseases, defined as the coexistence within the cell of mutant and wild type mitochondrial DNA molecules. Its existence permits unequal segregation during mitoses of the mitochondrial DNA populations and consequently heterogeneous tissue distribution of the mutation load. The observed tissue distributions of recurrent human mitochondrial DNA deleterious mutations are diverse but reproducible for a given mutation demonstrating that the segregation is not a random process. Its extent and mechanisms remain essentially unknown despite recent advances obtained in animal models.

show abstract

Near-Identical Segregation of mtDNA Heteroplasmy in Blood, Muscle, Urinary Epithelium, and Hair Follicles in Twins With Optic Atrophy, Ptosis, and Intractable Epilepsy

et al. 2013

View full text Add to dashboard Cite

Structured Abstract Importance Mitochondrial DNA (mtDNA) disorders have emerged as major cause of inherited neurological disease. Despite being well recognized for over two decades, the clinical presentation continues to broaden. The phenotypic heterogeneity is partly due to different percentage levels of mutant mtDNA heteroplasmy in different tissues, but the factors influencing this are poorly understood. Observations A case report describing monozygotic male twins with ptosis, optic atrophy, and recent onset intractable myoclonic epilepsy. The assessment of respiratory chain enzyme activities in muscle from one twin revealed a severe and isolated defect involving mitochondrial complex I. MtDNA sequencing revealed a pathogenic m.14487T>C MTND6 mutation, which was present at very high levels of heteroplasmy (84%) in muscle, and lower levels in blood (15%), urinary epithelium (75%), and buccal mucosa (58%). Of particular interest, his identical twin was found to harbor very similar levels of the m.14487T>C mutation in his blood, urine, buccal mucosa and hair follicle DNA samples, whilst the presence of low levels in the mother’s tissues confirmed maternal transmission. Conclusions and relevance m14487T>C can also cause the unusual combination of optic atrophy, ptosis, and encephalomyopathy leading to intractable seizures. Near-identical heteroplasmy levels in different tissues in both siblings supports a nuclear genetic mechanism controlling the tissue segregation of mtDNA mutations.

show abstract

Gimap3 Regulates Tissue-Specific Mitochondrial DNA Segregation

Cited by 58 publications

References 33 publications

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

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

Unsolved issues related to human mitochondrial diseases

Near-Identical Segregation of mtDNA Heteroplasmy in Blood, Muscle, Urinary Epithelium, and Hair Follicles in Twins With Optic Atrophy, Ptosis, and Intractable Epilepsy

Contact Info

Product

Resources

About