Final published version
Licence: CC BY: Creative Commons Attribution 4.0 International License
Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
}
TY - JOUR
T1 - Anthranilate fluorescence marks a calcium-propagated necrotic wave that promotes organismal death in C. elegans
AU - Coburn, Cassandra
AU - Allman, Erik
AU - Mahanti, Parag
AU - Benedetto, Alexandre
AU - Cabreiro, Filipe
AU - Pincus, Zachary
AU - Matthijssens, Filip
AU - Araiz, Caroline
AU - Mandel, Abraham
AU - Vlachos, Manolis
AU - Edwards, Sally-Anne
AU - Fischer, Grahame
AU - Davidson, Alexander
AU - Pryor, Rosina E
AU - Stevens, Ailsa
AU - Slack, Frank J
AU - Tavernarakis, Nektarios
AU - Braeckman, Bart P
AU - Schroeder, Frank C
AU - Nehrke, Keith
AU - Gems, David
PY - 2013/7/23
Y1 - 2013/7/23
N2 - 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.
AB - 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.
KW - Animals
KW - Caenorhabditis elegans
KW - Esters
KW - Fluorescence
KW - Oxidative Stress
KW - ortho-Aminobenzoates
KW - Journal Article
KW - Research Support, N.I.H., Extramural
KW - Research Support, Non-U.S. Gov't
KW - Research Support, U.S. Gov't, Non-P.H.S.
U2 - 10.1371/journal.pbio.1001613
DO - 10.1371/journal.pbio.1001613
M3 - Journal article
C2 - 23935448
VL - 11
JO - Plos Biology
JF - Plos Biology
SN - 1544-9173
IS - 7
M1 - e1001613
ER -