Journal
PLOS BIOLOGY
Volume 11, Issue 7, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pbio.1001613
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Funding
- BBSRC
- EU [FP7-259679 IDEAL, FP6-036894, FP6-518230]
- Wellcome Trust [098565/Z/12/Z]
- Jane Coffin Child postdoctoral fellowship
- NIH [R01 AG033921, AG033839, GM088290]
- NSF [IOS 0919848]
- Ruth L. Kirschstein National Research Service Institutional Training Grant [T32 GM068411]
- University of Ghent
- Direct For Biological Sciences
- Division Of Integrative Organismal Systems [919848] Funding Source: National Science Foundation
- Medical Research Council [G0700729B] Funding Source: researchfish
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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.
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