Role of Creatine Kinase – Hexokinase Complex in the Migration of Adenine Nucleotides in Mitochondrial Dysfunction

Creatine phosphokinase (CK) (ATP: creatine phosphotransferase, ЕС 2.7.3.2.) is found in a variety of cells with high and fluctuating energy requirements. It catalyses the reversible transfer of the high-energy-N-phosphoryl group from phosphocreatine to ADP. Creatine kinase connects sites of energy production with sites of energy consumption (Dolder et. al., 2001; Focant et al., 1970; Grossmann et al., 1985; Lipskaya et al., 1989; Walzel et al., 2002; Wyss, 2000). There are know to be three cytosolic and two mitochondrial isoforms of CK. The more basic mitochondrial creatine kinase MiCKb is accumulated in mitochondria of cardiac muscle and skeletal muscle. The more acidic mitochondrial creatine kinase MiCKa was found in the brain (Eppenberger-Eberhardt et al., 1991; Fridman, Roberts, 1994). Creatine kinase can exist in two interconvertible forms: dimer and octamer (Eriksson et al., 1998; Shen et al., 2002). Creatine kinase binds to the outer leaflet of the entire inner mitochondrial membrane and is specifically enriched in the so-called contact sites where inner and outer membranes are in close proximity (Boero et al., 2003; Chen et al, 1994; Lin et al., al., 1996; Wang et al., 2005). A change in the octamer/dimer ratio may influence on the association behavior of mitochondrial creatine kinase in general and thus modulate mitochondrial energy flux (Brdiczka, 2003; Dolder et al., 2001; Schnyder et al., 1995). Mitochondrial creatine kinase forms the functional microcompartment together with the mitochondrial porin (voltage-dependent anion channel) in the outer membrane and as well as the transmembrane protein adenine nucleotide translocase in the inner membrane (FritzWolf et al., 1996; Kaldis, Wallimann, 1994; Schnyder et al., 1988). Hexokinase (HK) (ATP:D-hexokinase-6-phosphotransferase, EC 2.7.11) is the enzyme with variable cellular localization (Mulichak et al., 1998; Xie & Wilson, 1990). The type I isoenzyme of mammalian hexokinase is ubiquitously expressed in mammalian tissues but is found particularly at high levels in the brain where it plays an important role in regulating the rate of cerebral glucose metabolism (Schwab & Wilson, 1989; Wilson, 1985). The major portion of the hexokinase activity in the brain is associated with mitochondria. About 85% of hexokinase is bound to the outer mitochondrial membrane, forming the specific complex with porin (Magnani et al., 1982; Redker et al., 1972; Wilson, 1995). This