Abstract
Sirtuins are NAD⁺-dependent deacetylases, lipoamidases, and ADP-ribosyltransferases that link cellular metabolism to multiple intracellular pathways that influence processes as diverse as cell survival, longevity, and cancer growth. Sirtuins influence the extent of neuronal death in stroke. However, different sirtuins appear to have opposite roles in neuronal protection. In Caenorhabditis elegans, we found that knock-out of mitochondrial sirtuin sir-2.3, homologous to mammalian SIRT4, is protective in both chemical ischemia and hyperactive channel induced necrosis. Furthermore, the protective effect of sir-2.3 knock-out is enhanced by block of glycolysis and eliminated by a null mutation in daf-16/FOXO transcription factor, supporting the involvement of the insulin/IGF pathway. However, data in Caenorhabditis elegans cell culture suggest that the effects of sir-2.3 knock-out act downstream of the DAF-2/IGF-1 receptor. Analysis of ROS in sir-2.3 knock-out reveals that ROS become elevated in this mutant under ischemic conditions in dietary deprivation (DD), but to a lesser extent than in wild type, suggesting more robust activation of a ROS scavenging system in this mutant in the absence of food. This work suggests a deleterious role of SIRT4 during ischemic processes in mammals that must be further investigated and reveals a novel pathway that can be targeted for the design of therapies aimed at protecting neurons from death in ischemic conditions.
Highlights
Sirtuins function as NAD+-dependent deacetylases, lipoamidases, and or ADP-ribosyltransferases that control the acetylation, lipoylation, and ADP-ribosylation levels of several substrates in the cell, effectively linking nutrient availability to cellular processes [1,2]
In this manuscript we report that knock-out of Caenorhabditis elegans mitochondrial sirtuin 2.3, homolog of mammalian SIRT4, spares neurons from ischemic neuronal death and that this protective effect is enhanced by block of glycolysis
Knock-out of a mitochondrial sirtuin is protective against chemicallyinduced ischemic neuronal death
Summary
Sirtuins function as NAD+-dependent deacetylases, lipoamidases, and or ADP-ribosyltransferases that control the acetylation, lipoylation, and ADP-ribosylation levels of several substrates in the cell, effectively linking nutrient availability to cellular processes [1,2]. Sirtuin-mediated modification of substrates results in the regulation of many different intracellular pathways that control various processes such as degeneration, ageing, and cancer growth [3,4,5,6,7,8]. Knock-out of sir-2.1 abolishes life-extension mediated by caloric restriction [17]. Though this effect seems dependent on the conditions [18,19,20,21,22]. Inhibition of SIRT2 protects against degeneration induced by αsynuclein toxicity [23] and treatment with sirtuin inhibitor sirtinol protects cultured cortical neurons against cell death in a model of excitotoxicity [24]. It was shown that resveratrol is neuroprotective or neurotoxic depending on the concentrations used [11,24]
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