title: Quantitative changes in Gimap3 and Gimap5 expression modify mitochondrial DNA segregation in mice.
abstract: 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.
authors: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, 00290 Helsinki, Finland.
authors: Riikka
authors: R
authors: Jokinen
authors: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, 00290 Helsinki, Finland.
authors: Taina
authors: T
authors: Lahtinen
authors: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, 00290 Helsinki, Finland.
authors: Paula
authors: P
authors: Marttinen
authors: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, 00290 Helsinki, Finland.
authors: Maarit
authors: M
authors: Myöhänen
authors: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, 00290 Helsinki, Finland.
authors: Pilvi
authors: P
authors: Ruotsalainen
authors: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, 00290 Helsinki, Finland.
authors: Nicolas
authors: N
authors: Yeung
authors: Department of Biochemistry and Biocenter Oulu, University of Oulu, 90014 Oulu, Finland.
authors: Antonina
authors: A
authors: Shvetsova
authors: Department of Biochemistry and Biocenter Oulu, University of Oulu, 90014 Oulu, Finland.
authors: Alexander J
authors: AJ
authors: Kastaniotis
authors: Department of Biochemistry and Biocenter Oulu, University of Oulu, 90014 Oulu, Finland.
authors: J Kalervo
authors: JK
authors: Hiltunen
authors: Institute of Biotechnology, University of Helsinki, 00290 Helsinki, Finland.
authors: Tiina
authors: T
authors: Öhman
authors: Institute of Biotechnology, University of Helsinki, 00290 Helsinki, Finland.
authors: Tuula A
authors: TA
authors: Nyman
authors: Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin 53266.
authors: Hartmut
authors: H
authors: Weiler
authors: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, 00290 Helsinki, Finland brendan.battersby@helsinki.fi.
authors: Brendan J
authors: BJ
authors: Battersby
mesh_terms: D016475:3T3 Cells; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004272:DNA, Mitochondrial / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D006239:Haplotypes; D008214:Lymphocytes / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D021381:Protein Transport
chemical_list: D004272:DNA, Mitochondrial; C534135:Gimap5 protein, mouse; C425002:Ian4 protein, mouse; D008565:Membrane Proteins; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins
keywords: Gimap; mice; mitochondria; mitochondrial DNA; segregation