The majority of Amyotrophic Lateral Sklerosis (ALS) cases as well as many patients suffering from Frontotemporal Lobar Dementia (FTLD) with ubiquitinated inclusion bodies show TDP-43 pathology, the protein encoded by the TAR-DNA binding protein (Tardbp) gene. We used recombinase-mediated cassette exchange (RMCE) to introduce an ALS patient cDNA into the mouse Tdp-43 locus. Expression levels of human A315T TDP-43 protein were 300% elevated in heterozygotes while the endogenous mouse Tdp-43 was decreased to 20% of wildtype levels as a result of disturbed feedback regulation. Heterozygous TDP-43A315TKi mutants lost 10% of their body weight and developed insoluble TDP-43 protein starting as early as 3 months after birth, a pathology that was exacerbated with age. We analyzed the splicing patterns of known Tdp-43 target genes, as well as genome-wide gene expression levels in different tissues that indicated mitochondrial dysfunction. In heterozygous mutant animals we observed a relative decrease in expression of Parkin (Park2) and the fatty acid transporter CD36 along with an increase in fatty acids, HDL cholesterol and glucose in the blood. As seen in Transmission Electron Microscopy, neuronal cells in motor cortices of TDP-43A315TKi animals had abnormal neuronal mitochondrial cristae formation. Motor neurons were reduced to 90% but only slight motoric impairment was detected. The observed phenotype was interpreted as a pre-disease model which might be valuable for the identification of further environmental or genetic triggers of neurodegeneration.