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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
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
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
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 have been implicated as key inhibitors of inflammation. We have previously reported a role for SIRT1, SIRT2 and SIRT6 in regulating inflammation-induced pro-labor 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 employed to investigate the effect of siRNA knockdown of SIRTs in regulating inflammation-induced pro-labor mediators...
September 14, 2016: Biology of Reproduction
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...
2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
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...
August 30, 2016: Neurotoxicity Research
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
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...
2016: Scientific Reports
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
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
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...
May 6, 2016: Free Radical Biology & Medicine
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
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
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)...
2016: Scientific Reports
Sushabhan Sadhukhan, Xiaojing Liu, Dongryeol Ryu, Ornella D Nelson, John A Stupinski, Zhi Li, Wei Chen, Sheng Zhang, Robert S Weiss, Jason W Locasale, Johan Auwerx, Hening Lin
Cellular metabolites, such as acyl-CoA, can modify proteins, leading to protein posttranslational modifications (PTMs). One such PTM is lysine succinylation, which is regulated by sirtuin 5 (SIRT5). Although numerous proteins are modified by lysine succinylation, the physiological significance of lysine succinylation and SIRT5 remains elusive. Here, by profiling acyl-CoA molecules in various mouse tissues, we have discovered that different tissues have different acyl-CoA profiles and that succinyl-CoA is the most abundant acyl-CoA molecule in the heart...
April 19, 2016: Proceedings of the National Academy of Sciences of the United States of America
Sira Karvinen, Mika Silvennoinen, Petra Vainio, Lea Sistonen, Lauren G Koch, Steven L Britton, Heikki Kainulainen
AIM: Sirtuins are proteins that connect energy metabolism, oxidative stress and aging. Expression of heat shock proteins (Hsps) is regulated by heat shock factors (HSFs) in response to various environmental and physiological stresses, such as oxidative stress. Oxidative stress accumulates during aging which makes cells more prone to DNA damage. Although many experimental animal models have been designed to study the effects of knockdown or overexpression of sirtuins, HSFs and Hsps, little is known about how aging per se affects their expression...
June 15, 2016: Experimental Gerontology
Junru Yu, Manas Haldar, Sanku Mallik, D K Srivastava
Sirtuins are emerging as the key regulators of metabolism and aging, and their potential activators and inhibitors are being explored as therapeutics for improving health and treating associated diseases. Despite the global structural similarity among all seven isoforms of sirtuins (of which most of them catalyze the deacetylation reaction), SIRT5 is the only isoform that catalyzes the cleavage of negatively charged acylated substrates, and the latter feature appears to be encoded by the presence of Tyr102 and Arg105 residues at the active site pocket of the enzyme...
2016: PloS One
Yujiro Kida, Michael S Goligorsky
The sirtuins (SIRTs) constitute a class of proteins with nicotinamide adenine dinucleotide-dependent deacetylase or adenosine diphosphate-ribosyltransferase activity. Seven SIRT family members have been identified in mammals, from SIRT1, the best studied for its role in vascular aging, to SIRT7. SIRT1 and SIRT2 are localized in the nucleus and cytoplasm. SIRT3, SIRT4, and SIRT5 are mitochondrial, and SIRT6 and SIRT7 are nuclear. Extensive studies have clearly revealed that SIRT proteins regulate diverse cell functions and responses to stressors...
May 2016: Canadian Journal of Cardiology
Yi-Chao Hsu, Yu-Ting Wu, Ting-Hsien Yu, Yau-Huei Wei
Mesenchymal stem cells (MSCs) are characterized to have the capacity of self-renewal and the potential to differentiate into mesoderm, ectoderm-like and endoderm-like cells. MSCs hold great promise for cell therapies due to their multipotency in vitro and therapeutic advantage of hypo-immunogenicity and lower tumorigenicity. Moreover, it has been shown that MSCs can serve as a vehicle to transfer mitochondria into cells after cell transplantation. Mitochondria produce most of the energy through oxidative phosphorylation in differentiated cells...
April 2016: Seminars in Cell & Developmental Biology
Yue Chen
Lysine (Lys) succinylation is a recently discovered protein posttranslational modification pathway that is evolutionarily conserved from bacteria to mammals. It is regulated by Sirt5, a member of the class III histone deacetylases (HDACs) or the Sirtuins. Recent studies demonstrated that Lys succinylation and Sirt5 are involved in diverse cellular metabolic processes including urea cycle, ammonia transfer, and glucose metabolism. In this chapter, we describe the general protocol to identify Sirt5-regulated Lys succinylation substrates and a computational method to calculate the absolute modification stoichiometries of Lys succinylation sites...
2016: Methods in Molecular Biology
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