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Mitochondrial sirtuins and their relationships with metabolic disease and cancer.

ABSTRACT: Maintenance of metabolic homeostasis is critical for cellular and organismal health. Proper regulation of mitochondrial functions represents a crucial element of overall metabolic homeostasis. Mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5) play pivotal roles in promoting this homeostasis by regulating numerous aspects of mitochondrial metabolism in response to environmental stressors.New work has illuminated multiple links between mitochondrial sirtuins and cancer. SIRT5 has been shown to regulate the recently described post-translational modifications succinyl-lysine, malonyl-lysine, and glutaryl-lysine. An understanding of these modifications is still in its infancy. Enumeration of SIRT3 and SIRT5 targets via advanced proteomic techniques promises to dramatically enhance insight into functions of these proteins.In this review, we highlight the roles of mitochondrial sirtuins and their targets in cellular and organismal metabolic homeostasis. Furthermore, we discuss emerging roles for mitochondrial sirtuins in suppressing and/or promoting tumorigenesis, depending on the cellular and molecular context.Currently, hundreds of potential SIRT3 and SIRT5 molecular targets have been identified in proteomic experiments. Future studies will need to validate the major targets of these enzymes, and elucidate how acetylation and/or acylation modulate their functionality. A great deal of interest exists in targeting sirtuins pharmacologically; this endeavor will require development of sirtuin-specific modulators (activators and inhibitors) as potential treatments for cancer and metabolic disease.

SUBMITTER: Kumar S

PROVIDER: S-EPMC4389911 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Mitochondrial sirtuins and their relationships with metabolic disease and cancer.

Kumar Surinder S Lombard David B DB

Antioxidants & redox signaling 20150210 12

<h4>Significance</h4>Maintenance of metabolic homeostasis is critical for cellular and organismal health. Proper regulation of mitochondrial functions represents a crucial element of overall metabolic homeostasis. Mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5) play pivotal roles in promoting this homeostasis by regulating numerous aspects of mitochondrial metabolism in response to environmental stressors.<h4>Recent advances</h4>New work has illuminated multiple links between mitochondrial sirt ...[more]

PMID: 25545135

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Project description:Sirtuins are NAD+ dependent deacetylases, which regulate mitochondrial energy metabolism as well as cellular response to stress. The NAD/NADH-system plays a crucial role in oxidative phosphorylation linking sirtuins and the mitochondrial respiratory chain. Furthermore, sirtuins are able to directly deacetylate and activate different complexes of the respiratory chain. This prompted us to analyse sirtuin levels in skin fibroblasts from patients with cytochrome c-oxidase (COX) deficiency and to test the impact of different pharmaceutical activators of sirtuins (SRT1720, paeonol) to modulate sirtuins and possibly respiratory chain enzymes in patient cells in vitro.We assayed intracellular levels of sirtuin 1 and the mitochondrial sirtuins SIRT3 and SIRT4 in human fibroblasts from patients with COX- deficiency. Furthermore, sirtuins were measured after inhibiting complex IV in healthy control fibroblasts by cyanide and after incubation with activators SRT1720 and paeonol. To determine the effect of sirtuin inhibition at the cellular level we measured total cellular acetylation (control and patient cells, with and without treatment) by Western blot.We observed a significant decrease in cellular levels of all three sirtuins at the activity, protein and transcriptional level (by 15% to 50%) in COX-deficient cells. Additionally, the intracellular concentration of NAD+ was reduced in patient cells. We mimicked the biochemical phenotype of COX- deficiency by incubating healthy fibroblasts with cyanide and observed reduced sirtuin levels. A pharmacological activation of sirtuins resulted in normalized sirtuin levels in patient cells. Hyper acetylation was also reversible after treatment with sirtuin activators. Pharmacological modulation of sirtuins resulted in altered respiratory chain complex activities.We found inhibition of situins 1, 3 and 4 at activity, protein and transcriptional levels in fibroblasts from patient with COX-deficiency. Pharmacological activators were able to restore reduced sirtuin levels and thereby modulate respiratory chain activities.

Project description:Sirtuins are NAD+-dependent deacetylase enzymes that have gained considerable interest in mammals for their recognized importance in gene silencing and expression and in cell metabolism. Conversely, knowledge about plant sirtuins remains limited, although a sirtuin-mediated regulation of mitochondrial energy metabolism has been recently reported in Arabidopsis. However, so far, no information is available about direct measurement of intracellular plant sirtuin activity, i.e., in cell extracts and/or subcellular organelles. In this study, a novel approach was proposed for reliable evaluation of native sirtuin activity in plant samples, based on (i) an adequate combinatory application of enzymatic assays very different for chemical basis and rationale and (ii) a comparative measurement of activity of a recombinant sirtuin isoform. In particular, two sirtuin assays were applied, based on bioluminescence emission and Homogeneous Time-Resolved Fluorescence (HTRF®) technology, and the human SIRT1 isoform (hSIRT1) was used for comparison. For the first time in plants, this new approach allowed measuring directly a high and nicotinamide-sensitive sirtuin activity in highly purified mitochondrial fraction obtained from durum wheat (WM). WM-sirtuin activity was 268 ± 10 mU?mg-1 protein, as measured by HTRF® assay, and 166 ± 12 ng hSIRT1 eq.?mg-1 protein, as evaluated by the bioluminescent assay and calculated on the basis of the hSIRT1 calibration curve. Moreover, effects of resveratrol and quercetin, reported as potent hSIRT1 activators, but whose activation mechanism is still debated, were also studied. No effect of resveratrol was found on both WM-sirtuin and hSIRT1 activities, while only a slight increase, up to about 20%, of hSIRT1 activity by quercetin was observed. In the whole, results of this study indicate that WM may represent a good system for studying native plant sirtuins. In fact, the high yield of purified WM and their high sirtuin activity, together with use of microplate readers, allow performing a large number of measurements from the same preparation, so qualifying the approach for application to large-scale high-throughput screening. Moreover, WM may also represent an excellent tool to investigate physiological role and modulation of plant sirtuins under experimental conditions more physiologically relevant with respect to recombinant purified enzymes.

Dataset Information

Mitochondrial sirtuins and their relationships with metabolic disease and cancer.

Publications

Mitochondrial sirtuins and their relationships with metabolic disease and cancer.

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