SIN3 is critical for stress resistance and modulates adult lifespan

Abstract

Coordinate control of gene activity is critical for fitness and longevity of an organism. The SIN3 histone deacetylase (HDAC) complex functions as a transcriptional repressor of many genes. SIN3-regulated genes include those that encode proteins affecting multiple aspects of mitochondrial function, such as energy production and stress responsiveness, important for health maintenance. Here we used Drosophila melanogaster as a model organism to examine the role of SIN3 in the regulation of fitness and longevity. Adult flies with RNA interference (RNAi) induced knockdown expression of Sin3A have reduced climbing ability; an activity that likely requires fully functional mitochondria. Additionally, compared to wild type, adult Sin3A knockdown flies were more sensitive to oxidative stress. Interestingly, media supplementation with the antioxidant glutathione largely restored fly tolerance to oxidative stress. Although Sin3A knockdown flies exhibited decreased longevity compared to wild type, no significant changes in expression of many well-categorized aging genes were observed. We found, however, that Sin3A knockdown corresponded to a significant reduction in expression of genes encoding proteins involved in the de novo synthesis of glutathione. Taken together, the data support a model whereby SIN3 regulates a gene expression program required for proper mitochondrial function and effective stress response during adulthood.

The conserved histone chaperone LIN‐53 is required for normal lifespan and maintenance of muscle integrity in Caenorhabditis elegans

“…While we do not see premature aging upon depletion of specific NuRD subunits such as LIN‐40, LIN‐61, or LET‐418 in C. elegans, we identified the Sin3 complex to be relevant for the aging phenotype upon loss of LIN‐53. We speculate that the Sin3 complex might also play a role during aging regulation in other species as it has also been shown by a previous study in Drosophila that knockdown of the Sin3A gene causes a shortened lifespan (Barnes et al, ).…”

Energy Homeostasis Control in Drosophila Adipokinetic Hormone Mutants

“…In Drosophila, foodborne paraquat exposure is the standard assay for testing oxidative stress resistance (Rzezniczak et al 2011;Sun et al 2013) and many fly studies successfully used this single agent (e.g., Alic et al 2011;Barnes et al 2014;Lin et al 2014). Following this protocol, we observed increased paraquat resistance in all tested mutants deficient in AKH signaling.…”

“…However, the AKH titer positively correlated with oxidative stress induced by bacterial toxin in Leptinotarsa decemlineata , and by paraquat in P. apterus (Večeřa et al 2007) and L. decemlineata ). Moreover, co-injection of AKH alleviated the effect of paraquat by enhancing the antioxidative capacity in the firebug (Večeřa et al 2007), suggesting a protective role of AKH during oxidative stress response.In Drosophila, foodborne paraquat exposure is the standard assay for testing oxidative stress resistance (Rzezniczak et al 2011;Sun et al 2013) and many fly studies successfully used this single agent (e.g., Alic et al 2011;Barnes et al 2014;Lin et al 2014). Following this protocol, we observed increased paraquat resistance in all tested mutants deficient in AKH signaling.…”

Selective Inhibition of FOXO1 Activator/Repressor Balance Modulates Hepatic Glucose Handling

“…Interestingly, cholesterol content is also decreased in iL -Sin3a/b mice. This can reflect GCK- or/and FOXO1-independent functions of SIN3A in liver metabolism, for example through its role to regulate mitochondrial activity (Barnes et al, 2014; Pile et al, 2003), or cholesterol biosynthesis (Solaimani et al, 2013). There are likely to be additional functions to hepatic SIN3A, in particular in the development of bile ducts, that account for the abnormal liver function tests, histopathologic abnormalities, and splenomegaly (likely secondary to portal hypertension) seen in mice with constitutive liver deletion.…”