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

Michelle A. Avery, Timothy M. Rooney, Jignesh D. Pandya, Thomas M. Wishart, Thomas H. Gillingwater, James W. Geddes, Patrick G. Sullivan, Marc Freeman

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)596-600
Number of pages5
JournalCurrent Biology
Volume22
Issue number7
DOIs
StatePublished - Apr 10 2012
Externally publishedYes

Fingerprint

Mitochondria
axons
Axons
Wallerian Degeneration
mitochondria
Fluxes
Axotomy
buffering capacity
mice
synapse
NAD
Synapses
Drosophila
protective effect
Brain
animal models
brain
Wounds and Injuries
Enzymes
enzymes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Wld S prevents axon degeneration through increased mitochondrial flux and enhanced mitochondrial Ca 2+ buffering. / Avery, Michelle A.; Rooney, Timothy M.; Pandya, Jignesh D.; Wishart, Thomas M.; Gillingwater, Thomas H.; Geddes, James W.; Sullivan, Patrick G.; Freeman, Marc.

In: Current Biology, Vol. 22, No. 7, 10.04.2012, p. 596-600.

Research output: Contribution to journalArticle

Avery, MA, Rooney, TM, Pandya, JD, Wishart, TM, Gillingwater, TH, Geddes, JW, Sullivan, PG & Freeman, M 2012, 'Wld S prevents axon degeneration through increased mitochondrial flux and enhanced mitochondrial Ca 2+ buffering', Current Biology, vol. 22, no. 7, pp. 596-600. https://doi.org/10.1016/j.cub.2012.02.043
Avery, Michelle A. ; Rooney, Timothy M. ; Pandya, Jignesh D. ; Wishart, Thomas M. ; Gillingwater, Thomas H. ; Geddes, James W. ; Sullivan, Patrick G. ; Freeman, Marc. / Wld S prevents axon degeneration through increased mitochondrial flux and enhanced mitochondrial Ca 2+ buffering. In: Current Biology. 2012 ; Vol. 22, No. 7. pp. 596-600.
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