Anthranilate fluorescence marks a calcium-propagated necrotic wave that promotes organismal death in C. elegans.
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.
Institute of Healthy Ageing, and Research Department of Genetics, Evolution and Environment, University College London, London, United Kingdom.
Cassandra
C
Coburn
Erik
E
Allman
Parag
P
Mahanti
Alexandre
A
Benedetto
Filipe
F
Cabreiro
Zachary
Z
Pincus
Filip
F
Matthijssens
Caroline
C
Araiz
Abraham
A
Mandel
Manolis
M
Vlachos
Sally-Anne
SA
Edwards
Grahame
G
Fischer
Alexander
A
Davidson
Rosina E
RE
Pryor
Ailsa
A
Stevens
Frank J
FJ
Slack
Nektarios
N
Tavernarakis
Bart P
BP
Braeckman
Frank C
FC
Schroeder
Keith
K
Nehrke
David
D
Gems
D000818:Animals; D017173:Caenorhabditis elegans / Q000737:chemistry*; D004952:Esters / Q000737:chemistry; D005453:Fluorescence; D018384:Oxidative Stress; D062367:ortho-Aminobenzoates / Q000737:chemistry*
D004952:Esters; D062367:ortho-Aminobenzoates; C031385:anthranilic acid