Axon degeneration is a hallmark of many neurological disorders, including Alzheimer's disease, motor neuron disease, and nerve trauma. Multiple factors trigger axon degeneration, and glutamate excitotoxicity is one of them. We have recently found that stabilization of microtubules and components of the dynein-dynactin complex modulate the process of excitotoxicity-induced axon degeneration. However, the molecular mechanisms involving these microtubule-based functions remain poorly understood. Here, we used hippocampal cultures and find that inhibition of p53 transactivation and microtubule stabilization function cooperatively to suppress excitotoxicity-induced mitochondrial dysfunction. Inhibition of p53 association with mitochondria has no effect on excitotoxicity-induced mitochondria] dysfunction, however, induces axon degeneration in normal condition. Association of p150Glued with mitochondria is significantly increased by simultaneously inhibiting p53 transactivation and microtubule stabilization under excitotoxic condition. Importantly, we find that inhibition of p53 transactivation and microtubule stabilization function cooperatively to suppress excitotoxicity-induced axon degeneration. Overexpression of p150Glued does not improve the effect by inhibition of p53 transactivation on axon degeneration suggesting that p150Glued and p53 function in a linear pathway in the process of axon degeneration. (C) 2012 Elsevier Inc. All rights reserved.