Axonal degeneration occurs in multiple neurodegenerative disorders of the central and peripheral nervous system. Although the underlying molecular pathways leading to axonal degeneration are incompletely understood, accumulating evidence suggests contributions of impaired mitochondrial function, disrupted axonal transport, and/or dysfunctional intracellular Ca2+-homeostasis in the injurious cascade associated with axonal degeneration. Utilizing an in vitro model of axonal degeneration, we studied a subset of mouse peripheral sensory neurons in which neurites were exposed selectively to conditions associated with the pathogenesis of axonal neuropathies in vivo . Rotenone-induced mitochondrial dysfunction resulted in neurite degeneration accompanied by reduced ATP levels and increased ROS levels in neurites. Blockade of voltage-gated sodium channels with TTX and reverse (Ca2+-importing) mode of the sodium-calcium exchanger (NCX) with KB-R7943 partially protected rotenone-treated neurites from degeneration, s...