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Compromised mitochondrial function results in dephosphorylation of tau through a calcium-dependent process in rat brain cerebral cortical slices

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Abstract

Mitochondria play an important role in modulating intracellular levels of calcium, and therefore compromised mitochondrial function often leads to disruptions in calcium homeostasis. In this study, the effects of two uncouplers of oxidative phosphorylation, carbonyl cyanide-3-chlorophenylhydrazone (CCCP) and p-trifluoromethoxyphenylhydrazone (FCCP), on calcium-mediated modifications of the microtubule-associated protein, tau, in rat brain slices were examined. Incubation of slices with CCCP or FCCP resulted in an increase in electrophoretic mobility of several of the tau isoforms, with no apparent loss of intact tau or the appearance of degradation products. These data indicated that disrupting mitochondrial function by dissipating the transmembrane potential resulted in the dephosphorylation of tau. This finding was confirmed by using a front phosphorylation assay to demonstrate a CCCP-induced decrease in the phosphorylation state of tau. The dephosphorylation of tau induced by the proton-ionophores appeared to be calcium-dependent since the effect was blocked by EGTA. In addition, the CCCP-induced dephosphorylation of tau was blocked by cyclosporin A, a selective inhibitor of the calcium-dependent phosphatase, calcineurin. These data strongly indicate that tau is a substrate for calcineurin in vivo. Finally, the levels of ATP were depleted to a similar extent in brain slices incubated in the presence of CCCP or CCCP and EGTA. These results demonstrated depletion of ATP alone was not sufficient to stimulate the dephosphorylation of tau in this experimental paradigm.

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  1. Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, 35294-0017, Birmingham, Alabama

    Sandra G. P. Norman & Gail V. W. Johnson

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  1. Sandra G. P. Norman
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  2. Gail V. W. Johnson
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Norman, S.G.P., Johnson, G.V.W. Compromised mitochondrial function results in dephosphorylation of tau through a calcium-dependent process in rat brain cerebral cortical slices. Neurochem Res 19, 1151–1158 (1994). https://doi.org/10.1007/BF00965149

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