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https://www.readbyqxmd.com/read/28340937/sirtuin-5-protects-mitochondria-from-fragmentation-and-degradation-during-starvation
#1
Hala Guedouari, Tanya Daigle, Luca Scorrano, Etienne Hebert-Chatelain
During starvation, intra-mitochondrial sirtuins, NAD(+) sensitive deacylating enzymes that modulate metabolic homeostasis and survival, directly adjust mitochondrial function to nutrient availability; concomitantly, mitochondria elongate to escape autophagic degradation. However, whether sirtuins also impinge on mitochondrial dynamics is still uncharacterized. Here we show that the mitochondrial Sirtuin 5 (Sirt5) is essential for starvation induced mitochondrial elongation. Deletion of Sirt5 in mouse embryonic fibroblasts increased levels of mitochondrial dynamics of 51kDa protein and mitochondrial fission protein 1, leading to mitochondrial accumulation of the pro-fission dynamin related protein 1 and to mitochondrial fragmentation...
January 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28050792/alpha-synuclein-alters-differently-gene-expression-of-sirts-parps-and-other-stress-response-proteins-implications-for-neurodegenerative-disorders
#2
J Motyl, P L Wencel, M Cieślik, R P Strosznajder, J B Strosznajder
Alpha-synuclein (ASN) is a presynaptic protein that can easily change its conformation under different types of stress. It's assumed that ASN plays an important role in the pathogenesis of Parkinson's and Alzheimer's disease. However, the molecular mechanism of ASN toxicity has not been elucidated. This study focused on the role of extracellular ASN (eASN) in regulation of transcription of sirtuins (Sirts) and DNA-bound poly(ADP-ribose) polymerases (PARPs) - proteins crucial for cells' survival/death. Our results indicate that eASN enhanced the free radicals level, decreased mitochondria membrane potential, cells viability and activated cells' death...
January 3, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28042700/a-versatile-approach-for-site-specific-lysine-acylation-in-proteins
#3
Zhipeng A Wang, Yadagiri Kurra, Xin Wang, Yu Zeng, Yan-Jiun Lee, Vangmayee Sharma, Hening Lin, Susie Y Dai, Wenshe R Liu
Using amber suppression in coordination with a mutant pyrrolysyl-tRNA synthetase-tRNA(Pyl) pair, azidonorleucine is genetically encoded in E. coli. Its genetic incorporation followed by traceless Staudinger ligation with a phosphinothioester allows the convenient synthesis of a protein with a site-specifically installed lysine acylation. By simply changing the phosphinothioester identity, any lysine acylation type could be introduced. Using this approach, we demonstrated that both lysine acetylation and lysine succinylation can be installed selectively in ubiquitin and synthesized histone H3 with succinylation at its K4 position (H3K4su)...
January 2, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28036303/desuccinylation-of-pyruvate-kinase-m2-by-sirt5-contributes-to-antioxidant-response-and-tumor-growth
#4
Ye Xiangyun, Niu Xiaomin, Gu Linping, Xu Yunhua, Li Ziming, Yu Yongfeng, Chen Zhiwei, Lu Shun
Tumor cells trends to express high level of pyruvate kinase M2 (PKM2). The inhibition of PKM2 activity is needed for antioxidant response by diverting glucose flux into the pentose phosphate pathway and thus generating sufficient reducing potential. Here we report that PKM2 is succinylated at lysine 498 (K498) and succinylation increases its activity. SIRT5 binds to, desuccinylates and inhibits PKM2 activity. Increased level of reactive oxygen species (ROS) decreases both the succinylation and activity of PKM2 by increasing its binding to SIRT5...
January 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28004755/stat3-undergoes-acetylation-dependent-mitochondrial-translocation-to-regulate-pyruvate-metabolism
#5
Yan S Xu, Jinyuan J Liang, Yumei Wang, Xiang-Zhong J Zhao, Li Xu, Ye-Yang Xu, Quanli C Zou, Junxun M Zhang, Cheng-E Tu, Yan-Ge Cui, Wei-Hong Sun, Chao Huang, Jing-Hua Yang, Y Eugene Chin
Cytoplasmic STAT3, after activation by growth factors, translocates to different subcellular compartments, including nuclei and mitochondria, where it carries out different biological functions. However, the precise mechanism by which STAT3 undergoes mitochondrial translocation and subsequently regulates the tricarboxylic acid (TCA) cycle-electron transport chain (ETC) remains poorly understood. Here, we clarify this process by visualizing STAT3 acetylation in starved cells after serum reintroduction or insulin stimulation...
December 22, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27858336/sirtuin-5-a-review-of-structure-known-inhibitors-and-clues-for-developing-new-inhibitors
#6
REVIEW
Lingling Yang, Xiaobo Ma, Yanying He, Chen Yuan, Quanlong Chen, Guobo Li, Xianggui Chen
Sirtuins (SIRTs) are nicotinamide adenine dinucleotide (NAD(+))-dependent protein deacetylases, which regulate important biological processes ranging from apoptosis, age-associated pathophysiologies, adipocyte and muscle differentiation, and energy expenditure to gluconeogenesis. Very recently, sirtuin 5 (SIRT5) has received considerable attention due to that it was found to have weak deacetylase activity but strong desuccinylase, demalonylase and deglutarylase activities, and it was also found to be associated with several human diseases such as cancer, Alzheimer's disease, and Parkinson's disease...
November 17, 2016: Science China. Life Sciences
https://www.readbyqxmd.com/read/27763519/segmental-aging-underlies-the-development-of-a-parkinson-phenotype-in-the-as-agu-rat
#7
Sohair M Khojah, Anthony P Payne, Dagmara McGuinness, Paul G Shiels
There is a paucity of information on the molecular biology of aging processes in the brain. We have used biomarkers of aging (SA β-Gal, p16(Ink4a), Sirt5, Sirt6, and Sirt7) to demonstrate the presence of an accelerated aging phenotype across different brain regions in the AS/AGU rat, a spontaneous Parkinsonian mutant of PKCγ derived from a parental AS strain. P16(INK4a) expression was significantly higher in AS/AGU animals compared to age-matched AS controls (p < 0.001) and displayed segmental expression across various brain regions...
October 17, 2016: Cells
https://www.readbyqxmd.com/read/27686746/in-low-protein-diets-microrna-19b-regulates-urea-synthesis-by-targeting-sirt5
#8
Rui-Ping Sun, Qian-Yun Xi, Jia-Jie Sun, Xiao Cheng, Yan-Ling Zhu, Ding-Ze Ye, Ting Chen, Li-Min Wei, Rui-Song Ye, Qing-Yan Jiang, Yong-Liang Zhang
Ammonia detoxification, which takes place via the hepatic urea cycle, is essential for nitrogen homeostasis and physiological well-being. It has been reported that a reduction in dietary protein reduces urea nitrogen. MicroRNAs (miRNAs) are major regulatory non-coding RNAs that have significant effects on several metabolic pathways; however, little is known on whether miRNAs regulate hepatic urea synthesis. The objective of this study was to assess the miRNA expression profile in a low protein diet and identify miRNAs involved in the regulation of the hepatic urea cycle using a porcine model...
September 30, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27681422/nampt-mediated-nad-biosynthesis-is-essential-for-vision-in-mice
#9
Jonathan B Lin, Shunsuke Kubota, Norimitsu Ban, Mitsukuni Yoshida, Andrea Santeford, Abdoulaye Sene, Rei Nakamura, Nicole Zapata, Miyuki Kubota, Kazuo Tsubota, Jun Yoshino, Shin-Ichiro Imai, Rajendra S Apte
Photoreceptor death is the endpoint of many blinding diseases. Identifying unifying pathogenic mechanisms in these diseases may offer global approaches for facilitating photoreceptor survival. We found that rod or cone photoreceptor-specific deletion of nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in the major NAD(+) biosynthetic pathway beginning with nicotinamide, caused retinal degeneration. In both cases, we could rescue vision with nicotinamide mononucleotide (NMN). Significantly, retinal NAD(+) deficiency was an early feature of multiple mouse models of retinal dysfunction, including light-induced degeneration, streptozotocin-induced diabetic retinopathy, and age-associated dysfunction...
September 27, 2016: Cell Reports
https://www.readbyqxmd.com/read/27628218/a-novel-role-for-sirt3-in-regulating-mediators-involved-in-the-terminal-pathways-of-human-labor-and-delivery
#10
Ratana Lim, Gillian Barker, Ramkumar Menon, Martha Lappas
Preterm birth remains the major cause of neonatal mortality and morbidity, mediated largely by an inflammatory process. The sirtuin (SIRT) family of cellular regulators has been implicated as key inhibitors of inflammation. We have previously reported a role for SIRT1, SIRT2, and SIRT6 in regulating inflammation-induced prolabor mediators. In this study, we determined the effect of term labor and pro-inflammatory cytokines on SIRT3, SIRT4, SIRT5, and SIRT7 expression in human myometrium. Functional studies were also used to investigate the effect of small interfering RNA (siRNA) knockdown of SIRTs in regulating inflammation-induced prolabor mediators...
November 2016: Biology of Reproduction
https://www.readbyqxmd.com/read/27626398/a-selective-cyclic-peptidic-human-sirt5-inhibitor
#11
Jiajia Liu, Yajun Huang, Weiping Zheng
In the current study, we discovered that a side chain-to-side chain cyclic pentapeptide harboring a central N(ε)-carboxyethyl-thiocarbamoyl-lysine residue behaved as a strong and selective (versus human SIRT1/2/3/6) inhibitor against human SIRT5-catalyzed deacylation reaction. This compound was also found to be proteolytically much more stable than its linear counterpart. This compound could be a valuable lead for developing stronger, selective, metabolically stable, and cell permeable human SIRT5 inhibitors...
September 10, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/27577743/sirtuin-5-is-anti-apoptotic-and-anti-oxidative-in-cultured-sh-ep-neuroblastoma-cells
#12
Fengyi Liang, Xie Wang, Suet Hui Ow, Wangxue Chen, Wei Chen Ong
As a nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase, demalonylase, and desuccinylase, sirtuin 5 (SIRT5) in host cells has been reportedly observed in the mitochondria, in the cytosol/cytoplasm or in the nucleus. Various functional roles of SIRT5 have also been described in cellular metabolism, energy production, detoxification, oxidative stress, and apoptosis, but some of the reported results are seemingly inconsistent or even contradictory to one another. Using immunocytochemistry, molecular biology, gene transfection, and flow cytometry, we investigated the expression, subcellular distribution, and possible functional roles of SIRT5 in regulating apoptosis and oxidative stress of cultured SH-EP neuroblastoma cells...
January 2017: Neurotoxicity Research
https://www.readbyqxmd.com/read/27445698/sirt5-deficiency-enhances-susceptibility-to-kainate-induced-seizures-and-exacerbates-hippocampal-neurodegeneration-not-through-mitochondrial-antioxidant-enzyme-sod2
#13
Fengling Li, Lei Liu
Epilepsy is a common and serious neurological disorder characterized by occurrence of recurrent spontaneous seizures, and emerging evidences support the association of mitochondrial dysfunction with epilepsy. Sirtuin 5 (SIRT5), localized in mitochondrial matrix, has been considered as an important functional modulator of mitochondria that contributes to ageing and neurological diseases. Our data shows that SIRT5 deficiency strikingly increased mortality rate and severity of response to epileptic seizures, dramatically exacerbated hippocampal neuronal loss and degeneration in mice exposed to Kainate (KA), and triggered more severe reactive astrogliosis...
2016: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/27435822/protein-kinase-c-epsilon-promotes-cerebral-ischemic-tolerance-via-modulation-of-mitochondrial-sirt5
#14
Kahlilia C Morris-Blanco, Kunjan R Dave, Isabel Saul, Kevin B Koronowski, Holly M Stradecki, Miguel A Perez-Pinzon
Sirtuin 5 (SIRT5) is a mitochondrial-localized NAD(+)-dependent lysine desuccinylase and a major regulator of the mitochondrial succinylome. We wanted to determine whether SIRT5 is activated by protein kinase C epsilon (PKCε)-mediated increases in mitochondrial Nampt and whether SIRT5 regulates mitochondrial bioenergetics and neuroprotection against cerebral ischemia. In isolated mitochondria from rat cortical cultures, PKCε activation increased SIRT5 levels and desuccinylation activity in a Nampt-dependent manner...
July 20, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27246219/generation-and-purification-of-catalytically-active-recombinant-sirtuin5-sirt5-protein
#15
Surinder Kumar, David B Lombard
Sirtuin-family deacylases promote health and longevity in mammals. The sirtuin SIRT5 localizes predominantly to the mitochondrial matrix. SIRT5 preferentially removes negatively charged modifications from its target lysines: succinylation, malonylation, and glutarylation. It regulates protein substrates involved in glucose oxidation, ketone body formation, ammonia detoxification, fatty acid oxidation, and ROS management. Like other sirtuins, SIRT5 has recently been linked with neoplasia. Therefore, targeting SIRT5 pharmacologically could conceivably provide new avenues for treatment of metabolic disease and cancer, necessitating development of SIRT5-selective modulators...
2016: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27246218/identification-of-sirtuin4-sirt4-protein-interactions-uncovering-candidate-acyl-modified-mitochondrial-substrates-and-enzymatic-regulators
#16
Rommel A Mathias, Todd M Greco, Ileana M Cristea
Recent studies have highlighted the three mitochondrial human sirtuins (SIRT3, SIRT4, and SIRT5) as critical regulators of a wide range of cellular metabolic pathways. A key factor to understanding their impact on metabolism has been the discovery that, in addition to their ability to deacetylate substrates, mitochondrial sirtuins can have other prominent enzymatic activities. SIRT4, one of the least characterized mitochondrial sirtuins, was shown to be the first known cellular lipoamidase, removing lipoyl modifications from lysine residues of substrates...
2016: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27164052/the-role-of-mitochondrial-sirtuins-in-health-and-disease
#17
REVIEW
Brenna Osborne, Nicholas L Bentley, Magdalene K Montgomery, Nigel Turner
Mitochondria play a critical role in energy production, cell signalling and cell survival. Defects in mitochondrial function contribute to the ageing process and ageing-related disorders such as metabolic disease, cancer, and neurodegeneration. The sirtuin family of deacylase enzymes have a variety of subcellular localisations and have been found to remove a growing list of post-translational acyl modifications from target proteins. SIRT3, SIRT4, and SIRT5 are found primarily located in the mitochondria, and are involved in many of the key processes of this organelle...
November 2016: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/27113762/sirt5-promotes-idh2-desuccinylation-and-g6pd-deglutarylation-to-enhance-cellular-antioxidant-defense
#18
Lisha Zhou, Fang Wang, Renqiang Sun, Xiufei Chen, Mengli Zhang, Qi Xu, Yi Wang, Shiwen Wang, Yue Xiong, Kun-Liang Guan, Pengyuan Yang, Hongxiu Yu, Dan Ye
Excess in mitochondrial reactive oxygen species (ROS) is considered as a major cause of cellular oxidative stress. NADPH, the main intracellular reductant, has a key role in keeping glutathione in its reduced form GSH, which scavenges ROS and thus protects the cell from oxidative damage. Here, we report that SIRT5 desuccinylates and deglutarylates isocitrate dehydrogenase 2 (IDH2) and glucose-6-phosphate dehydrogenase (G6PD), respectively, and thus activates both NADPH-producing enzymes. Moreover, we show that knockdown or knockout of SIRT5 leads to high levels of cellular ROS SIRT5 inactivation leads to the inhibition of IDH2 and G6PD, thereby decreasing NADPH production, lowering GSH, impairing the ability to scavenge ROS, and increasing cellular susceptibility to oxidative stress...
June 2016: EMBO Reports
https://www.readbyqxmd.com/read/27080717/high-throughput-screening-of-sirtuin-family-of-genes-in-breast-cancer
#19
Mehri Igci, Mehmet Emin Kalender, Ersin Borazan, Ibrahim Bozgeyik, Recep Bayraktar, Esra Bozgeyik, Celaletdin Camci, Ahmet Arslan
Mammalian Sirtuins have been shown to perform distinct cellular functions and deregulated expression of these genes was reported to be involved in the development of various malignancies including breast cancer. An increasing number of evidence indicates that Sirtuins have both tumor promoter and tumor suppressor functions. However, the roles of Sirtuins have not been well-reported in breast cancer. In the present study, quantitative expression levels of Sirtuins (SIRT1-7) in breast cancer patients and breast cancer cell lines (MCF-7 and SKBR3) and control cell line (CRL-4010) were assessed by using a high-throughput real-time PCR method...
July 15, 2016: Gene
https://www.readbyqxmd.com/read/27052737/pgc-1%C3%AE-promotes-ureagenesis-in-mouse-periportal-hepatocytes-through-sirt3-and-sirt5-in-response-to-glucagon
#20
Lulu Li, Ping Zhang, Zhengxi Bao, Tongxin Wang, Shuang Liu, Feiruo Huang
Excess ammonia is produced during fasting when amino acids are used for glucogenesis. Together with ureagenesis, glucogenesis occurs in periportal hepatocytes mediated mainly through the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). In vivo experiments showed that fasting strongly stimulated mice glucagon secretion, hepatic PGC-1α, sirtuin 3 (SIRT3) and sirtuin 5 (SIRT5) expression and ureagenesis enzymatic activity such as carbamoyl phosphate synthetase 1 (CPS1) and ornithine transcarbamoylase (OTC)...
April 7, 2016: Scientific Reports
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