Wld S (slow Wallerian degeneration) is a remarkable protein that can suppress Wallerian degeneration of axons and synapses , but how it exerts this effect remains unclear . 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.
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Agricultural and Biological Sciences(all)