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.
|Number of pages||5|
|State||Published - Apr 10 2012|
Bibliographical noteFunding Information:
All animal procedures were carried out in accordance with National Institutes of Health (NIH) guidelines and the Institutional Animal Care and Use Committee regulations of the University of Kentucky and the University of Edinburgh. This work was supported by NIH grant NS062993 (J.W.G. and P.G.S.), the Wellcome Trust (T.H.G. and M.R.F.), and NIH grant NS059991 (to M.R.F.). M.R.F. is an Early Career Scientist with the Howard Hughes Medical Institute. T.M.R. was supported by a grant from the Department of Defense (BC093796). We thank Vimala Bondada and Dingyuan Lou for preliminary work on the mitochondrial Ca 2+ dynamics and all members of the laboratories for helpful discussions.
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology (all)
- Agricultural and Biological Sciences (all)