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

被引:101
作者
Coburn, Cassandra [1 ]
Allman, Erik [2 ]
Mahanti, Parag [3 ,4 ]
Benedetto, Alexandre [1 ]
Cabreiro, Filipe [1 ,6 ]
Pincus, Zachary [5 ]
Matthijssens, Filip
Araiz, Caroline [1 ]
Mandel, Abraham [1 ]
Vlachos, Manolis [7 ]
Edwards, Sally-Anne [1 ]
Fischer, Grahame [1 ]
Davidson, Alexander [1 ]
Pryor, Rosina E. [1 ]
Stevens, Ailsa [1 ]
Slack, Frank J. [5 ]
Tavernarakis, Nektarios [7 ]
Braeckman, Bart P. [6 ]
Schroeder, Frank C. [3 ,4 ]
Nehrke, Keith [2 ,8 ]
Gems, David [1 ]
机构
[1] UCL, Inst Hlth Ageing, London, England
[2] Univ Rochester, Med Ctr, Dept Physiol & Pharmacol, Rochester, NY 14642 USA
[3] Cornell Univ, Boyce Thompson Inst, Ithaca, NY USA
[4] Cornell Univ, Dept Chem & Chem Biol, Ithaca, NY USA
[5] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT USA
[6] Univ Ghent, Dept Biol, B-9000 Ghent, Belgium
[7] Univ Crete, Inst Mol Biol & Biotechnol, Iraklion, Crete, Greece
[8] Univ Rochester, Med Ctr, Dept Med, Rochester, NY 14642 USA
基金
英国生物技术与生命科学研究理事会; 英国惠康基金; 美国国家科学基金会;
关键词
CELL-DEATH; CAENORHABDITIS-ELEGANS; OXIDATIVE STRESS; RHYTHMIC BEHAVIOR; GENETIC-ANALYSIS; NEURONAL DEATH; GAP-JUNCTIONS; NECROSIS; ACID; LIPOFUSCIN;
D O I
10.1371/journal.pbio.1001613
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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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页数:17
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