Abstract
Author SummaryIn the nematode Caenorhabditis elegans, intestinal lysosome-related organelles (or “gut granules”) contain a bright blue fluorescent substance of unknown identity. This has similar spectral properties to lipofuscin, a product of oxidative damage known to accumulate with age in postmitotic mammalian cells. Blue fluorescence seems to increase in aging worm populations, and lipofuscin has been proposed to be the source. To analyze this further, we measure fluorescence levels after exposure to oxidative stress and during aging in individually tracked worms. Surprisingly, neither of these conditions increases fluorescence levels; instead blue fluorescence increases in a striking and rapid burst at death. Such death fluorescence (DF) also appears in young worms when killed, irrespective of age or cause of death. We chemically identify DF as anthranilic acid glucosyl esters derived from tryptophan, and not lipofuscin. In addition, we show that DF generation in the intestine is dependent upon the necrotic cell death cascade, previously characterized as a driver of neurodegeneration. We find that necrosis spreads in a rapid wave along the intestine by calcium influx via innexin ion channels, accompanied by cytosolic acidosis. Inhibition of necrosis pathway components can delay stress-induced death, supporting its role as a driver of organismal death. This necrotic cascade provides a model system to study neurodegeneration and organismal death.
Highlights
While mechanisms of cell death such as apoptosis are well characterized [1], less is known about the mechanisms of organismal death, in invertebrate model organisms
We chemically identify death fluorescence (DF) as anthranilic acid glucosyl esters derived from tryptophan, and not lipofuscin
We show that DF generation in the intestine is dependent upon the necrotic cell death cascade, previously characterized as a driver of neurodegeneration
Summary
While mechanisms of cell death such as apoptosis are well characterized [1], less is known about the mechanisms of organismal death, in invertebrate model organisms. We investigate organismal death in the nematode C. elegans, using a newly discovered, endogenous fluorescent marker of death. One possibility is that organismal death results from a cascade of cell death. As first defined by Kerr et al in 1972 [1], cell death has been viewed as taking two forms: controlled (apoptotic) or uncontrolled (necrotic). More recent elucidation of the mechanisms underlying necrotic cell death reveals that it too can be a regulated process [2,3,4,5]. Biochemical hallmarks of necrosis include calcium-mediated initiation, lysosomal membrane permeabilization (LMP), and activation of noncaspase proteases (calpains and cathepsins) [5,6,7]
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