title: Neurological phenotype and reduced lifespan in heterozygous Tim23 knockout mice, the first mouse model of defective mitochondrial import.
abstract: The Tim23 protein is the key component of the mitochondrial import machinery. It locates to the inner mitochondrial membrane and its own import is dependent on the DDP1/TIM13 complex. Mutations in human DDP1 cause the Mohr-Tranebjaerg syndrome (MTS/DFN-1; OMIM #304700), which is one of the two known human diseases of the mitochondrial protein import machinery. We created a Tim23 knockout mouse from a gene trap embryonic stem cell clone. Homozygous Tim23 mice were not viable. Heterozygous F1 mutants showed a 50% reduction of Tim23 protein in Western blot, a neurological phenotype and a markedly reduced life span. Haploinsufficiency of the Tim23 mutation underlines the critical role of the mitochondrial import machinery for maintaining mitochondrial function.
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Ahting
authors.forename: Thomas
authors.initials: T
authors.lastname: Floss
authors.forename: Nikolas
authors.initials: N
authors.lastname: Uez
authors.forename: Ilka
authors.initials: I
authors.lastname: Schneider-Lohmar
authors.forename: Lore
authors.initials: L
authors.lastname: Becker
authors.forename: Eva
authors.initials: E
authors.lastname: Kling
authors.forename: Arcangela
authors.initials: A
authors.lastname: Iuso
authors.forename: Andreas
authors.initials: A
authors.lastname: Bender
authors.forename: Martin Hrabé
authors.initials: MH
authors.lastname: de Angelis
authors.forename: Valérie
authors.initials: V
authors.lastname: Gailus-Durner
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000502:physiology; D005552:Forelimb / Q000502:physiology; D005838:Genotype; D018737:Hand Strength; D006801:Humans; D008017:Life Expectancy; D008565:Membrane Proteins / Q000172:deficiency*; D026901:Membrane Transport Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics*; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics; D009154:Mutation; D009958:Orofaciodigital Syndromes / Q000235:genetics; D010641:Phenotype; D021381:Protein Transport / Q000235:genetics; D045442:Rotarod Performance Test
chemical_list: D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins; C118122:TIMM8A protein, human; C433865:Timm23 protein, mouse