RESUMO
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.
Assuntos
DNA Mitocondrial/genética , GTP Fosfo-Hidrolases/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Haplótipos/genética , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Embrião de Mamíferos/citologia , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , GTP Fosfo-Hidrolases/genética , Proteínas de Ligação ao GTP/genética , Sistema Hematopoético/metabolismo , Humanos , Rim/metabolismo , Leucócitos/citologia , Leucócitos/metabolismo , Fígado/metabolismo , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Proteínas Mitocondriais/genética , Dados de Sequência Molecular , Homologia de Sequência de Aminoácidos , Homologia de Sequência do Ácido Nucleico , Baço/metabolismoRESUMO
In mammals, mitochondrial DNA (mtDNA) sequence variants are observed to segregate rapidly between generations despite the high mtDNA copy number in the oocyte. This has led to the concept of a genetic bottleneck for the transmission of mtDNA, but the mechanism remains contentious. Several studies have suggested that the bottleneck occurs during embryonic development, as a result of a marked reduction in germline mtDNA copy number. Mitotic segregation of mtDNAs during preimplantation, or during the expansion of primordial germ cells (PGCs) before they colonize the gonad, is thought to account for the increase in genotypic variance observed among mature oocytes from heteroplasmic mothers. This view has, however, been challenged by studies suggesting that the bottleneck occurs without a reduction in germline mtDNA content. To resolve this controversy, we measured mtDNA heteroplasmy and copy number in single germ cells isolated from heteroplasmic mice. By directly tracking the evolution of mtDNA genotypic variance during oogenesis, we show that the genetic bottleneck occurs during postnatal folliculogenesis and not during embryonic oogenesis.