Life span and stress resistance of Caenorhabditis elegans are differentially affected by glutathione transferases metabolizing 4-hydroxynon-2-enal.
The lipid peroxidation product 4-hydroxynon-2-enal (4-HNE) forms as a consequence of oxidative stress, and acts as a signaling molecule or, at superphysiological levels, as a toxicant. The steady-state concentration of the compound reflects the balance between its generation and its metabolism, primarily through glutathione conjugation. Using an RNAi-based screen, we identified in Caenorhabditis elegans five glutathione transferases (GSTs) capable of catalyzing 4-HNE conjugation. RNAi knock-down of these GSTs (products of the gst-5, gst-6, gst-8, gst-10, and gst-24 genes) sensitized the nematode to electrophilic stress elicited by exposure to 4-HNE. However, interference with the expression of only two of these genes (gst-5 and gst-10) significantly shortened the life span of the organism. RNAi knock-down of the other GSTs resulted in at least as much 4-HNE adducts, suggesting tissue specificity of effects on longevity. Our results are consistent with the oxidative stress theory of organismal aging, broadened by considering electrophilic stress as a contributing factor. According to this extended hypothesis, peroxidation of lipids leads to the formation of 4-HNE in a chain reaction which amplifies the original damage. 4-HNE then acts as an "aging effector" via the formation of 4-HNE-protein adducts, and a resulting change in protein function.
Ayyadevara
Srinivas
S
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Dandapat
Abhijit
A
Singh
Sharda P
SP
Siegel
Eric R
ER
Shmookler Reis
Robert J
RJ
Zimniak
Ludwika
L
Zimniak
Piotr
P
D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D017173:Caenorhabditis elegans / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D008136:Longevity / Q000502:physiology*; D034622:RNA Interference; D013315:Stress, Psychological
D000447:Aldehydes; D029742:Caenorhabditis elegans Proteins; D005982:Glutathione Transferase; C027576:4-hydroxy-2-nonenal