Mitochondria are intracellular organelles of eukayotic cells. One of their main tasks is the generation of the cell's supply of chemical energy for metabolic processes. In addition to supplying cellular energy, mitochondria are involved in a range of other essential metabolic processes of cells. Within all organelles mitochondria are special: a mitochondrion has its own independent genome. Nevertheless, the vast majority of mitochondrially located proteins is encoded by nuclear genes and then imported into the organelle by a complex import machinery. The Tim23 protein is the key component of this process, in mice as well as in humans. The Mohr-Tranebjaerg syndrome is one of two known human diseases described that are caused by defects of the mitochondrial protein import machinery. It is characterized by progressive sensorineural hearing loss and deafness, dystonia, mental deficiency, and visual disability. Although the mutated gene in this disease is not TIM23 but TIM8A, it shows the importance of the mitochondrial import process for cells and the organism.
To better understand the function of Tim23, Uwe Ahting and colleagues analysed mice where the Tim23-gene was knocked out. Homozygous animals were not viable. With one intact copy of the gene the mice on a mixed background were alive. However, they show significantly reduced lifespan. While they were analysed in the German Mouse Clinic they showed further abnormalities. Female mice had less forelimb grip strength compared to wildtypes. On the rotarod, where mice are put onto a turning wheel, males showed a significantly reduced dwell time on the rotating drum at higher speed compared to wildtype mice. This indicates that the ability of motor coordination and balance was reduced.
The Tim23 mouse mutant is the first mouse model of defective mitochondrial import. Until now, there is no known human disease with Tim23 mutations, maybe because the loss of Tim23 does not necessarily lead to a severe condition. The mouse model indicates however, that heterozygosity for this gene defect is compatible with life and may manifest as a premature aging phenotype.
Neurological phenotype and reduced lifespan in heterozygous Tim23 knockout mice, the first mouse model of defective mitochondrial import “, Ahting et al., Biochimica et Biophysica Acta 1787 (2009) 371–376