(38) MITOCHONDRIAL CREATINE KINASE SUBSTRATES MODULATE MITOCHONDRIAL PERMEABILITY TRANSITION AND NEURONAL CELL DEATH

Rima Kaddurah-Daouk (1), Robert J. Ferrante (2), Russell T. Matthews (3), Peter Klivenyi (3), Lichuan Yang (3), Autumn M. Klein (2), Gerald Mueller (3) and M. Flint Beal (3)
(1) Avicena Group Inc., Cambridge, MA
(2) Department of Neurology, Pathology and Psychiatry, Boston University School of Medicine, Boston, MA
(3) Neurochemistry Laboratory, Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston, MA

Creatine kinases (CK) are a group of isoenzymes involved in ATP homeostasis in cells with high and fluctuating energy demands such as the brain [1]. The enzymes catalyze reversibly the transfer of a phosphoryl group from phosphocreatine to ADP. The mitochondrial creatine kinase (Mi-CK) is located in the mitochondrial intermembrane space where it is believed to occur predominantly as an octamer forming a cube like structure with a channel extending along a four fold axis [2]. Structural and functional interactions between Mi-CK and the adenine nucleotide translocator (ANT) has been strongly suggested and recently Mi-CK has been implicated in the regulation of mitochondrial permeability transition [3]. The substrate creatine and a synthetic analog were shown to inhibit permeability transition in the liver of transgenic mice expressing mitochondrial CK suggesting that such compounds could potentially regulate apoptosis. We present data to support the neuroprotective effect of creatine and some of its analogs both in vitro and in vivo. In vitro we demonstrate protection against glutamate neurotoxicity. In vivo we demonstrate neuroprotection in animal models of Huntington's, Parkinson's and ALS diseases. In the Huntington's disease models we demonstrate protection against malonate lesions and 3-NP induced neurotoxicity. Also in this model we show protection against 3-NP induced depletions of phosphocreatine and ATP, protection against increases in striatal lactate concentrations and protection against increases in biochemical markers of oxidative injury. In the MPTP model of Parkinson's disease and in transgenic mice with the G93A Cu,Zn superoxide dismutase (SOD1) mutation linked to ALS disease creatine was also shown to be an effective neuroprotective agent. Structure function analysis studies are under way to evaluate effects of creatine compounds on mitochondrial transition pore function, Mi-CK activity and neuronal cell apoptosis. Such studies could potentially result in the development of a new class of compounds with therapeutic benefit for the treatment of several neurodegenerative diseases.

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[2] Fritz-Wolf K, Schnyder T, Wallimann T, Kabsch W (1996) Nature 381:341-345.
[3] O'Gorman D, Beutner G, Dolder M, Koretsky A, Brdiczka D, Wallimann T (1997) FEBS Letters 414:253-257.