Expression of functional mitochondrial creatine kinase in liver of transgenic mice

The mitochondrial isoform of creatine kinase (MiCK) is localized to the mitochondrial intermembrane space, and its precise role in vivo is still actively being investigated. Here, we report a transgenic mouse model in which MiCK is expressed in liver, a tissue that does not normally express significant levels of CK. Expression of the genomic clone for human, ubiquitous MiCK was controlled by the promoter/enhancer region of the transthyretin gene. Three of seven founder mice were chosen to establish lines and had MiCK activity values ranging from 13 to 269 micromol x min(-1) x g wet wt(-1). Differential centrifugation and histochemical staining demonstrated that >90% of the CK activity is localized to the mitochondrial intermembrane space. An unusual mitochondrial morphology characterized by an angular nature to the membranes was detected using electron microscopy in the transgenic line expressing the highest levels of MiCK. Increasing hepatic total creatine levels led to a return to normal mitochondrial morphology. 31P-nuclear magnetic resonance spectroscopy demonstrated that the expressed MiCK is capable of producing and utilizing phosphocreatine. These mice will be useful for investigating gain of function effects of MiCK in cellular energetics.