Altered brain phosphocreatine and ATP regulation when mitochondrial creatine kinase is absent

In cerebral gray matter, ATP concentration is closely maintained despite ra pid, large increases in turnover and low substrate reserves. As seen in viv o by P-31 nuclear magnetic resonance (NMR) spectroscopy, brain ATP is stabl e early in seizures, a state of high energy demand, and in mild hypoxia, a state of substrate deficiency. Like other tissues with high and variable AT P turnover, cerebral gray matter has high phosphocreatine (PCr) concentrati on and both cytosolic and mitochondrial creatine kinase (UbMi-CK) isoenzyme s. To understand the physiology of brain creatine kinases, we used P-31 NMR to study PCr and ATP regulation during seizures and hypoxia in mice with t argeted deletion of the UbMi-CK gene. The baseline CK reaction rate constan t (k) was higher in mutants than wild-types. During seizures, PCr and ATP d ecreased in mutants but not in wild-types. The k-value for the CK catalyzed reaction rate increased in wild-types but not in the mutants. Hypoxic muta nts and wild-types showed similar PCr losses and stable ATP. During recover y from hypoxia, brain PCr and ATP concentrations returned to baseline in wi ld-types but were 20% higher than baseline in the mutants. We propose that UbMi-CK couples ATP turnover to the CK catalyzed reaction rate and regulate s ATP concentration when synthesis is increased. (C) 2001 Wiley-Liss, Inc.