COMPROMISED MITOCHONDRIAL-FUNCTION RESULTS IN DEPHOSPHORYLATION OF TAU THROUGH A CALCIUM-DEPENDENT PROCESS IN RAT-BRAIN CEREBRAL CORTICAL SLICES

Mitochondria play an important role in modulating intracellular levels of calcium, and therefore compromised mitochondrial function often le ads to disruptions in calcium homeostasis. In this study, the effects of two uncouplers of oxidative phosphorylation, carbonyl cyanide-3-chl orophenylhydrazone (CCCP) and p-trifluoromethoxyphenylhydrazone (FCCP) ,on calcium-mediated modifications of the microtubule-associated prote in, tau, in rat brain slices were examined. Incubation of slices with CCCP or FCCP resulted in an increase in electrophoretic mobility of se veral of the tau isoforms, with no apparent loss of intact tan or the appearance of degradation products. These data indicated that disrupti ng mitochondrial function by dissipating the transmembrane potential r esulted in the dephosphorylation of tau. This finding was confirmed by using a front phosphorylation assay to demonstrate a CCCP-induced dec rease in the phosphorylation state of tau. The dephosphorylation of ta u induced by the proton-ionophores appeared to be calcium-dependent si nce the effect was blocked by EGTA. In addition, the CCCP-induced deph osphorylation of tau was blocked by cyclosporin A, a selective inhibit or of the calcium-dependent phosphatase, calcineurin. These data stron gly indicate that tau is a substrate for calcineurin in vivo. Finally, the levels of ATP were depleted to a similar extent in brain slices i ncubated in the presence of CCCP or CCCP and EGTA. These results demon strated depletion of ATP alone was not sufficient to stimulate the dep hosphorylation of tau in this experimental paradigm.