Neurological phenotype and reduced lifespan in heterozygous Tim23 knockout mice, the first mouse model of defective mitochondrial import.
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.
Ahting
Uwe
U
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
Floss
Thomas
T
Uez
Nikolas
N
Schneider-Lohmar
Ilka
I
Becker
Lore
L
Kling
Eva
E
Iuso
Arcangela
A
Bender
Andreas
A
de Angelis
Martin Hrabé
MH
Gailus-Durner
Valérie
V
Fuchs
Helmut
H
Meitinger
Thomas
T
Wurst
Wolfgang
W
Prokisch
Holger
H
Klopstock
Thomas
T
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
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