Knock-out of a mitochondrial sirtuin protects neurons from degeneration in < i > Caenorhabditis elegans < /i >

by Rachele Sangaletti, Massimo D ’Amico, Jeff Grant, David Della-Morte, Laura Bianchi 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. Howe ver, different sirtuins appear to have opposite roles in neuronal protection. InCaenorhabditis elegans, we found that knock-out of mitochondrial sirtuinsir-2.3, homologous to mammalian SIRT4, is protective in both chemical ischemia and hyperactive channel induced necrosis. Furthermore, the protective effect ofsir-2.3 knock-out is enhanced by block of glycolysis and eliminated by a null mutation indaf-16/FOXO transcription factor, supporting the involvement of the insulin/IGF pathway. However, data inCaenorhabditis elegans cell culture suggest that the effects ofsir-2.3 knock-out act downstream of the DAF-2/IGF-1 receptor. Analysis of ROS insir-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 ...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research