Anthranilate Fluorescence Marks a Calcium-Propagated Necrotic Wave That Promotes Organismal Death in C. elegans

Cassandra Coburn, Erik Allman, Parag Mahanti, Alexandre Benedetto, Filipe Cabreiro, Zachary Pincus, Filip Matthijssens, Caroline Araiz, Abraham Mandel, Manolis Vlachos, Sally Anne Edwards, Grahame Fischer, Alexander Davidson, Rosina E. Pryor, Ailsa Stevens, Frank J. Slack, Nektarios Tavernarakis, Bart P. Braeckman, Frank C. Schroeder, Keith NehrkeDavid Gems

Research output: Contribution to journalArticlepeer-review

83 Scopus citations

Abstract

For cells the passage from life to death can involve a regulated, programmed transition. In contrast to cell death, the mechanisms of systemic collapse underlying organismal death remain poorly understood. Here we present evidence of a cascade of cell death involving the calpain-cathepsin necrosis pathway that can drive organismal death in Caenorhabditis elegans. We report that organismal death is accompanied by a burst of intense blue fluorescence, generated within intestinal cells by the necrotic cell death pathway. Such death fluorescence marks an anterior to posterior wave of intestinal cell death that is accompanied by cytosolic acidosis. This wave is propagated via the innexin INX-16, likely by calcium influx. Notably, inhibition of systemic necrosis can delay stress-induced death. We also identify the source of the blue fluorescence, initially present in intestinal lysosome-related organelles (gut granules), as anthranilic acid glucosyl esters-not, as previously surmised, the damage product lipofuscin. Anthranilic acid is derived from tryptophan by action of the kynurenine pathway. These findings reveal a central mechanism of organismal death in C. elegans that is related to necrotic propagation in mammals-e.g., in excitotoxicity and ischemia-induced neurodegeneration. Endogenous anthranilate fluorescence renders visible the spatio-temporal dynamics of C. elegans organismal death.

Original languageEnglish
Article numbere1001613
JournalPLoS biology
Volume11
Issue number7
DOIs
StatePublished - Jul 2013

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