Sirt4 is a mitochondrial regulator of metabolism and lifespan in
            <i>Drosophila melanogaster</i>

Wood, Jason G.; Schwer, Bjoern; Wickremesinghe, Priyan; Hartnett, Davis A.; Burhenn, Lucas; Garcia, Meyrolin; Li, Michael; Verdin, Eric; Helfand, Stephen L.

doi:10.1073/pnas.1720673115

Cited by 73 publications

(33 citation statements)

References 35 publications

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“…Last, it has been shown that overexpression of sirt-4 in the fat body increases D . melanogaster lifespan [ 118 ], a trait also affected by Wolbachia .…”

Section: Methodsmentioning

confidence: 99%

Wolbachia and Sirtuin-4 interaction is associated with alterations in host glucose metabolism and bacterial titer

2020

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Wolbachia is an intracellular bacterial symbiont of arthropods notorious for inducing many reproductive manipulations that foster its dissemination. Wolbachia affects many aspects of host biology, including metabolism, longevity and physiology, being described as a nutrient provisioning or metabolic parasite, depending on the host-microbe association. Sirtuins (SIRTs) are a family of NAD + -dependent post-translational regulatory enzymes known to affect many of the same processes altered by Wolbachia , including aging and metabolism, among others. Despite a clear overlap in control of host-derived pathways and physiology, no work has demonstrated a link between these two regulators. We used genetically tractable Drosophila melanogaster to explore the role of sirtuins in shaping signaling pathways in the context of a host-symbiont model. By using transcriptional profiling and metabolic assays in the context of genetic knockouts/over-expressions, we examined the effect of several Wolbachia strains on host sirtuin expression across distinct tissues and timepoints. We also quantified the downstream effects of the sirtuin x Wolbachia interaction on host glucose metabolism, and in turn, how it impacted Wolbachia titer. Our results indicate that the presence of Wolbachia is associated with (1) reduced sirt-4 expression in a strain-specific manner, and (2) alterations in host glutamate dehydrogenase expression and ATP levels, key components of glucose metabolism. We detected high glucose levels in Wolbachia- infected flies, which further increased when sirt-4 was over-expressed. However, under sirt-4 knockout, flies displayed a hypoglycemic state not rescued to normal levels in the presence of Wolbachia . Finally, whole body sirt-4 over-expression resulted in reduced Wolbachia ovarian titer. Our results expand knowledge of Wolbachia -host associations in the context of a yet unexplored class of host post-translational regulatory enzymes with implications for conserved host signaling pathways and bacterial titer, factors known to impact host biology and the symbiont’s ability to spread through populations.

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“…Last, it has been shown that overexpression of sirt-4 in the fat body increases D . melanogaster lifespan [ 118 ], a trait also affected by Wolbachia .…”

Section: Methodsmentioning

confidence: 99%

Wolbachia and Sirtuin-4 interaction is associated with alterations in host glucose metabolism and bacterial titer

2020

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“…Additionally, the interaction of MCD and SIRT4 in the mitochondrial matrix was demonstrated by coimmunoprecipitation. SIRT4 lacked detectable histone deacetylase activity, but it deacetylated MCD in a substrate-specific manner (37, 38). Further, mitochondrial located SIRT3 was confirmed and excluded the possibility of deacetylation activity, because interaction between SIRT3 and SIRT4.…”

Section: Sirt4 Inhibits Fatty Acid Oxidation In Muscle and Fat Cellsmentioning

confidence: 99%

The Roles of Mitochondrial SIRT4 in Cellular Metabolism

2019

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Sirtuins comprise a family of nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacylases that regulate the life span, aging, and metabolism. Seven sirtuin family members (SIRT1-7) have been identified in mammals, including humans. Despite the indispensable role of mitochondrial sirtuin 4 (SIRT4) in metabolic regulation, the primary enzymatic activity of SIRT4 remains enigmatic. SIRT4 possesses ADP-ribosyltransferase, lipoamidase and deacylase activities. Interestingly, the enzymatic activities and substrates of SIRT4 vary in different tissues and cells. SIRT4 inhibits insulin secretion in pancreatic β cells and regulates insulin sensitivity as a deacylase in the pancreas. SIRT4 represses fatty acid oxidation (FAO) in muscle and liver cells differently. SIRT4 has also been identified as a mitochondrial-localized tumor suppressor. A comprehensive understanding of the enzymology of SIRT4 in metabolism is essential for developing novel therapeutic agents for human metabolic diseases. This review will update the roles of SIRT4 in cellular and organismal metabolic homeostasis.

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“…Drosophila melanogaster has five Sirtuins ( dSirt1 , dSirt2 , dSirt4 , dSirt6 , and dSirt7 ), of which Sirt1 (better known as dSir2 ) is most similar to S. cerevisiae SIR2 (9), and high levels are found in the nuclei and/or cytoplasm of neurons and fat bodies (10). Although recently reported that fly dSirt4 contains a mitochondrial targeting sequence (11), the dSirt4 knockout fly appeared healthy, and the mitochondria respiratory function was not disrupted (11). In mammals, there are seven Sirtuins ( SIRT1-SIRT7 ) having different profiles of enzymatic activity and subcellular compartmentation (12).…”

Section: Introductionmentioning

confidence: 99%

Sirtuin signaling in cellular senescence and aging

et al. 2019

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Sirtuin is an essential factor that delays cellular senescence and extends the organismal lifespan through the regulation of diverse cellular processes. Suppression of cellular senescence by Sirtuin is mainly mediated through delaying the age-related telomere attrition, sustaining genome integrity and promotion of DNA damage repair. In addition, Sirtuin modulates the organismal lifespan by interacting with several lifespan regulating signaling pathways including insulin/IGF-1 signaling pathway, AMP-activated protein kinase, and forkhead box O. Although still controversial, it is suggested that the prolongevity effect of Sirtuin is dependent with the level of and with the tissue expression of Sirtuin. Since Sirtuin is also believed to mediate the prolongevity effect of calorie restriction, activators of Sirtuin have attracted the attention of researchers to develop therapeutics for age-related diseases. Resveratrol, a phytochemical rich in the skin of red grapes and wine, has been actively investigated to activate Sirtuin activity with consequent beneficial effects on aging. This article reviews the evidences and controversies regarding the roles of Sirtuin on cellular senescence and lifespan extension, and summarizes the activators of Sirtuin including Sirtuin-activating compounds and compounds that increase the cellular level of nicotinamide dinucleotide.

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Sirt4 is a mitochondrial regulator of metabolism and lifespan in Drosophila melanogaster

Cited by 73 publications

References 35 publications

Wolbachia and Sirtuin-4 interaction is associated with alterations in host glucose metabolism and bacterial titer

Wolbachia and Sirtuin-4 interaction is associated with alterations in host glucose metabolism and bacterial titer

The Roles of Mitochondrial SIRT4 in Cellular Metabolism

Sirtuin signaling in cellular senescence and aging

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