Wld ^S prevents axon degeneration through increased mitochondrial flux and enhanced mitochondrial Ca ²⁺ buffering

Wld ^S (slow Wallerian degeneration) is a remarkable protein that can suppress Wallerian degeneration of axons and synapses [1], but how it exerts this effect remains unclear [2]. Here, using Drosophila and mouse models, we identify mitochondria as a key site of action for Wld ^S neuroprotective function. Targeting the NAD ⁺ biosynthetic enzyme Nmnat to mitochondria was sufficient to fully phenocopy Wld ^S, and Wld ^S was specifically localized to mitochondria in synaptic preparations from mouse brain. Axotomy of live wild-type axons induced a dramatic spike in axoplasmic Ca ²⁺ and termination of mitochondrial movement - Wld ^S potently suppressed both of these events. Surprisingly, Wld ^S also promoted increased basal mitochondrial motility in axons before injury, and genetically suppressing mitochondrial motility in vivo dramatically reduced the protective effect of Wld ^S. Intriguingly, purified mitochondria from Wld ^S mice exhibited enhanced Ca ²⁺ buffering capacity. We propose that the enhanced Ca ²⁺ buffering capacity of Wld ^S+ mitochondria leads to increased mitochondrial motility, suppression of axotomy-induced Ca ²⁺ elevation in axons, and thereby suppression of Wallerian degeneration.