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Dong TR, Li YJ, Jin SY, Yang FL, Xiong RX, Dai YQ, Song XZ, Guan CP. Progress on mitochondria and hair follicle development in androgenetic alopecia: relationships and therapeutic perspectives. Stem Cell Res Ther 2025; 16:44. [PMID: 39901201 PMCID: PMC11792644 DOI: 10.1186/s13287-025-04182-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 01/23/2025] [Indexed: 02/05/2025] Open
Abstract
Hair loss has long been a significant concern for many individuals. Recent studies have indicated that mitochondria play a more crucial role in hair loss than previously recognized. This review summarizes the connection between mitochondrial dysfunction and hair follicle development, outlines the links between diseases related to mitochondrial disorders and hair issues, and highlights the influence of mitochondrial dysfunction on androgenetic alopecia. We discuss the cellular and signaling mechanisms associated with hair loss and examine how mitochondrial dysfunction, such as insufficient energy supply, signaling irregularities, protein/gene abnormalities, and programmed cell death, can hinder the normal proliferation, differentiation, and growth of hair follicle cells. Furthermore, we discuss current treatment approaches and potential innovative therapies, including mitochondrion-targeting drugs and advanced techniques that directly target hair follicle cells, providing fresh insights into the crucial role of mitochondria in maintaining hair follicle health and managing hair disorders. Furthermore, this review explores future therapeutic strategies and proposes that mitochondrial research could lead to groundbreaking treatments for hair loss, thus providing optimism and new avenues for the treatment of individuals experiencing hair loss. This review not only underscores the central importance of mitochondria in hair health but also emphasizes the importance of advancing research and treatment in this field.
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Affiliation(s)
- Ting-Ru Dong
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
| | - Yu-Jie Li
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
| | - Shi-Yu Jin
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
| | - Feng-Lan Yang
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
| | - Ren-Xue Xiong
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
- Department of Dermatology, Hangzhou Third People's Hospital, No 38 Xihu Rd, Hangzhou, 310009, China
| | - Ye-Qin Dai
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
- Department of Dermatology, Hangzhou Third People's Hospital, No 38 Xihu Rd, Hangzhou, 310009, China
| | - Xiu-Zu Song
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
- Department of Dermatology, Hangzhou Third People's Hospital, No 38 Xihu Rd, Hangzhou, 310009, China
| | - Cui-Ping Guan
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China.
- Department of Dermatology, Hangzhou Third People's Hospital, No 38 Xihu Rd, Hangzhou, 310009, China.
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Ke Z, Shen K, Wang L, Xu H, Pan X, Qian Z, Wen Y, Lv T, Zhang X, Song Y. Emerging roles of mitochondrial sirtuin SIRT5 in succinylation modification and cancer development. Front Immunol 2025; 16:1531246. [PMID: 39944690 PMCID: PMC11814216 DOI: 10.3389/fimmu.2025.1531246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 01/13/2025] [Indexed: 05/09/2025] Open
Abstract
Succinylation represents an emerging class of post-translational modifications (PTMs), characterized by the enzymatic or non-enzymatic transfer of a negatively charged four-carbon succinyl group to the ϵ-amino group of lysine residues, mediated by succinyl-coenzyme A. Recent studies have highlighted the involvement of succinylation in various diseases, particularly cancer progression. Sirtuin 5 (SIRT5), a member of the sirtuin family, has been extensively studied for its robust desuccinylase activity, alongside its deacetylase function. To date, only a limited number of SIRT5 substrates have been identified. These substrates mediate diverse physiological processes such as glucose oxidation, fatty acid oxidation, ammonia detoxification, reactive oxygen species scavenging, anti-apoptosis, and inflammatory responses. The regulation of these activities can occur through either the same enzymatic activity acting on different substrates or distinct enzymatic activities targeting the same substrate. Aberrant expression of SIRT5 has been closely linked to tumorigenesis and disease progression; however, its role remains controversial. SIRT5 exhibits dual functionalities: it can promote tumor proliferation, metastasis, drug resistance, and metabolic reprogramming, thereby acting as an oncogene; conversely, it can also inhibit tumor cell growth and induce apoptosis, functioning as a tumor suppressor gene. This review aims to provide a comprehensive overview of the current research status of SIRT5. We discuss its structural characteristics and regulatory mechanisms, compare its functions with other sirtuin family members, and elucidate the mechanisms regulating SIRT5 activity. Specifically, we focus on the role of succinylation modification mediated by SIRT5 in tumor progression, highlighting how desuccinylation by SIRT5 modulates tumor development and delineating the underlying mechanisms involved.
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Affiliation(s)
- Zhangmin Ke
- Department of Respiratory and Critical Care Medicine, Affiliated Jiangning Hospital of Nanjing Medicine University, Nanjing, China
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, China
| | - Kaikai Shen
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Li Wang
- Department of Respiratory and Critical Care Medicine, Affiliated Jiangning Hospital of Nanjing Medicine University, Nanjing, China
| | - Hao Xu
- Department of Respiratory and Critical Care Medicine, The People’s Hospital of Danyang, Affiliated Danyang Hospital of Nantong University, Zhenjiang, China
| | - Xia Pan
- Department of Respiratory and Critical Care Medicine, Affiliated Jiangning Hospital of Nanjing Medicine University, Nanjing, China
| | - Zhenjue Qian
- Department of Respiratory and Critical Care Medicine, Affiliated Jiangning Hospital of Nanjing Medicine University, Nanjing, China
| | - Yuting Wen
- Department of Respiratory and Critical Care Medicine, Affiliated Jiangning Hospital of Nanjing Medicine University, Nanjing, China
| | - Tangfeng Lv
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, China
| | - Xiuwei Zhang
- Department of Respiratory and Critical Care Medicine, Affiliated Jiangning Hospital of Nanjing Medicine University, Nanjing, China
| | - Yong Song
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, China
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Liang L, Huang Y, Wang Q, Hong Y, Zhen H, Chen Y. SIRT5 prevents mitochondrial dysfunction and cardiac hypertrophy induced by RIP140. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2025; 28:477-485. [PMID: 39968093 PMCID: PMC11831744 DOI: 10.22038/ijbms.2024.80343.17390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 09/29/2024] [Indexed: 02/20/2025]
Abstract
Objectives To investigate the effect and mechanism of sirtuin5 (SIRT5) on mitochondrial dysfunction and cardiac hypertrophy induced by receptor-interacting protein 140 (RIP140). Materials and Methods The neonatal rat cardiomyocytes (NRCMs) and SD rats were treated with Angiotensin II (Ang II) to induce in vitro and in vivo model of cardiac hypertrophy. RIP140 was overexpressed by adenovirus infection, and SIRT5 was overexpressed by plasmid transfection. RIP140 and SIRT5 were knocked down by siRNA interference. The expression of RIP140, SIRT5, and biomarkers of cardiac hypertrophy were measured by qRT-PCR and western blot. The transcription levels of mitochondrial DNA-encoded genes were detected by qRT-PCR. Cell surface area and mitochondrial membrane potential were respectively detected by rhodamine-phalloidin and tetramethylrhodamine ethyl ester (TMRE) fluorescence analysis. Cellular oxygen consumption and ATP production were investigated using assay kits. All data are from at least three independent experiments. Results The expression of SIRT5 was down-regulated in NRCMs and hearts treated with Ang II. Overexpression of SIRT5 protected cardiomyocytes from AngII-induced hypertrophy, whereas knockdown of SIRT5 resulted in cardiac hypertrophy. Moreover, since SIRT5 was regulated by the transcriptional coactivator, we also found that SIRT5 could be negatively regulated by the transcriptional corepressor RIP140 in cardiomyocytes. Furthermore, SIRT5 significantly attenuated energy metabolic dysregulation and mitochondrial dysfunction and exerted its protective role on myocardial hypertrophy under the regulation of RIP140. Conclusion SIRT5 exerts a protective role in mitochondrial dysfunction and cardiac hypertrophy induced by RIP140.
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Affiliation(s)
- Liying Liang
- Department of Pharmacy, Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
- These authors contributed equally to this work
| | - Yi Huang
- Guangzhou Special Service Recuperation Center of PLA Rocket Force, Guangzhou, Guangdong, China
- These authors contributed equally to this work
| | - Qiujuan Wang
- Department of Pharmacy, Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
- These authors contributed equally to this work
| | - Ye Hong
- Department of Pharmacy, Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Honghui Zhen
- Department of Pharmacy, Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yanfang Chen
- Department of Pharmacy, Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
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4
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Yang Y, Chen Q, Fan S, Lu Y, Huang Q, Liu X, Peng X. Glutamine sustains energy metabolism and alleviates liver injury in burn sepsis by promoting the assembly of mitochondrial HSP60-HSP10 complex via SIRT4 dependent protein deacetylation. Redox Rep 2024; 29:2312320. [PMID: 38329114 PMCID: PMC10854458 DOI: 10.1080/13510002.2024.2312320] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2024] Open
Abstract
Burns and burn sepsis, characterized by persistent and profound hypercatabolism, cause energy metabolism dysfunction that worsens organ injury and systemic disorders. Glutamine (Gln) is a key nutrient that remarkably replenishes energy metabolism in burn and sepsis patients, but its exact roles beyond substrate supply is unclear. In this study, we demonstrated that Gln alleviated liver injury by sustaining energy supply and restoring redox balance. Meanwhile, Gln also rescued the dysfunctional mitochondrial electron transport chain (ETC) complexes, improved ATP production, reduced oxidative stress, and protected hepatocytes from burn sepsis injury. Mechanistically, we revealed that Gln could activate SIRT4 by upregulating its protein synthesis and increasing the level of Nicotinamide adenine dinucleotide (NAD+), a co-enzyme that sustains the activity of SIRT4. This, in turn, reduced the acetylation of shock protein (HSP) 60 to facilitate the assembly of the HSP60-HSP10 complex, which maintains the activity of ETC complex II and III and thus sustain ATP generation and reduce reactive oxygen species release. Overall, our study uncovers a previously unknown pharmacological mechanism involving the regulation of HSP60-HSP10 assembly by which Gln recovers mitochondrial complex activity, sustains cellular energy metabolism and exerts a hepato-protective role in burn sepsis.
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Affiliation(s)
- Yongjun Yang
- Clinical Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China
| | - Qian Chen
- Clinical Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China
| | - Shijun Fan
- Clinical Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China
| | - Yongling Lu
- Clinical Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China
| | - Qianyin Huang
- Clinical Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China
| | - Xin Liu
- Clinical Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China
| | - Xi Peng
- Clinical Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China
- State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), ChongqingPeople’s Republic of China
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5
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Zhuang Y, Zhang Y, Liu C, Zhong Y. Interplay Between the Circadian Clock and Sirtuins. Int J Mol Sci 2024; 25:11469. [PMID: 39519022 PMCID: PMC11545976 DOI: 10.3390/ijms252111469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 10/18/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024] Open
Abstract
The circadian clock is an autonomous timekeeping system evolved by organisms to adapt to external changes, regulating a variety of important physiological and behavioral processes. Recent studies have shown that the sirtuin family of histone deacetylases is involved in regulating the expression of clock genes and plays an important role in maintaining the normal rhythm of clock gene expression and behavior. Moreover, sirtuins are regulated directly or indirectly by the circadian clock system. The mutual regulation between the circadian clock and sirtuins is likely involved in a variety of signal transduction and metabolism processes. In this review, we discuss the molecular mechanisms and research progress on the intertwined relationship between the circadian clock and sirtuins, mainly in mammals, highlighting sirtuins as molecular links between metabolic control and circadian rhythms and offering our perspectives on future developments in the field.
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Affiliation(s)
- Yan Zhuang
- School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Yantong Zhang
- School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Chao Liu
- School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Yingbin Zhong
- School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou 215123, China
- MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou 215123, China
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Jana S, Shang J, Hong JY, Fenwick MK, Puri R, Lu X, Melnick AM, Li M, Lin H. A Mitochondria-Targeting SIRT3 Inhibitor with Activity against Diffuse Large B Cell Lymphoma. J Med Chem 2024; 67:15428-15437. [PMID: 39191393 PMCID: PMC11403614 DOI: 10.1021/acs.jmedchem.4c01053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 07/19/2024] [Accepted: 07/22/2024] [Indexed: 08/29/2024]
Abstract
Diffuse large B-cell lymphomas (DLBCLs) are heterogeneous cancers that still require better and less toxic treatments. SIRT3, a member of the sirtuin family of NAD+-dependent protein deacylase, is critical for DLBCL growth and survival. A mitochondria-targeted SIRT3 small-molecule inhibitor, YC8-02, exhibits promising activity against DLBCL. However, YC8-02 has several limitations including poor solubility. Here, we report our medicinal chemistry efforts that led to an improved mitochondria-targeted SIRT3 inhibitor, SJ-106C, achieved by using a triethylammonium group, which helps to increase both solubility and SIRT3 inhibition potency. SJ-106C, while still inhibiting SIRT1 and SIRT2, is enriched in the mitochondria to help with SIRT3 inhibition. It is more active against DLBCL than other solid tumor cells and effectively inhibits DLBCL xenograft tumor growth. The findings provide useful insights for the development of SIRT3 inhibitors and mitochondrial targeting agents and further support the notion that SIRT3 is a promising druggable target for DLBCL.
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Affiliation(s)
- Sadhan Jana
- Department
of Chemistry and Chemical Biology, Cornell
University, Ithaca, New York 14853, United States
| | - Jialin Shang
- Department
of Chemistry and Chemical Biology, Cornell
University, Ithaca, New York 14853, United States
| | - Jun Young Hong
- Department
of Chemistry and Chemical Biology, Cornell
University, Ithaca, New York 14853, United States
| | - Michael K. Fenwick
- Department
of Chemistry and Chemical Biology, Cornell
University, Ithaca, New York 14853, United States
| | - Rishi Puri
- College
of Veterinary Medicine, Cornell University, Ithaca, New York 14853, United States
| | - Xuan Lu
- Department
of Chemistry and Chemical Biology, Cornell
University, Ithaca, New York 14853, United States
| | - Ari M. Melnick
- Department
of Medicine, Division of Hematology &
Medical Oncology, Weill Cornell Medicine, New York, New York 10065, United States
| | - Meng Li
- Department
of Medicine, Division of Hematology &
Medical Oncology, Weill Cornell Medicine, New York, New York 10065, United States
| | - Hening Lin
- Department
of Chemistry and Chemical Biology, Cornell
University, Ithaca, New York 14853, United States
- Howard
Hughes Medical Institute; Department of Chemistry and Chemical Biology;
Department of Molecular Biology and Genetics Cornell University Ithaca New York 14853 United States
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7
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Jin X, Sun X, Ma X, Qin Z, Gao X, Kang X, Li H, Sun H. SIRT1 maintains bone homeostasis by regulating osteoblast glycolysis through GOT1. Cell Mol Life Sci 2024; 81:204. [PMID: 38700532 PMCID: PMC11072260 DOI: 10.1007/s00018-023-05043-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 10/02/2023] [Accepted: 11/07/2023] [Indexed: 05/24/2024]
Abstract
The silent information regulator T1 (SIRT1) is linked to longevity and is a crucial mediator of osteoblast function. We investigated the direct role of Sirt1 during bone modeling and remodeling stages in vivo using Tamoxifen-inducible osteoblast-specific Sirt1 conditional knockout (cKO) mice. cKO mice exhibited lower trabecular and cortical bone mass in the distal femur. These phenotypes were coupled with lower bone formation and bone resorption. Metabolomics analysis revealed that the metabolites involved in glycolysis were significantly decreased in cKO mice. Further analysis of the quantitative acetylome revealed 11 proteins with upregulated acetylation levels in both the femur and calvaria of cKO mice. Cross-analysis identified four proteins with the same upregulated lysine acetylation site in both the femur and calvaria of cKO mice. A combined analysis of the metabolome and acetylome, as well as immunoprecipitation, gene knockout, and site-mutation experiments, revealed that Sirt1 deletion inhibited glycolysis by directly binding to and increasing the acetylation level of Glutamine oxaloacetic transaminase 1 (GOT1). In conclusion, our study suggested that Sirt1 played a crucial role in regulating osteoblast metabolism to maintain bone homeostasis through its deacetylase activity on GOT1. These findings provided a novel insight into the potential targeting of osteoblast metabolism for the treatment of bone-related diseases.
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Affiliation(s)
- Xinxin Jin
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China.
| | - Xulei Sun
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Xiao Ma
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Zixuan Qin
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China
| | - Xin Gao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China
| | - Xiaomin Kang
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Huixia Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China
| | - Hongzhi Sun
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China.
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8
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Liu R, Li L, Wang Z, Zhu J, Ji Y. Acetylated Histone Modifications: Intersection of Diabetes and Atherosclerosis. J Cardiovasc Pharmacol 2024; 83:207-219. [PMID: 37989137 DOI: 10.1097/fjc.0000000000001516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 11/09/2023] [Indexed: 11/23/2023]
Abstract
ABSTRACT Worldwide, type 2 diabetes is predominant form of diabetes, and it is mainly affected by the environment. Furthermore, the offspring of patients with type 2 diabetes and metabolic disorder syndrome may have a higher risk of diabetes and cardiovascular disease, which indicates that the environmental impact on diabetes prevalence can be transmitted across generations. In the process of diabetes onset and intergenerational transmission, the genetic structure of the individual is not directly changed but is regulated by epigenetics. In this process, genes or histones are modified, resulting in selective expression of proteins. This modification will affect not only the onset of diabetes but also the related onset of atherosclerosis. Acetylation and deacetylation may be important regulatory factors for the above lesions. Therefore, in this review, based on the whole process of atherosclerosis evolution, we explored the possible existence of acetylation/deacetylation caused by diabetes. However, because of the lack of atherosclerosis-related acetylation studies directly based on diabetic models, we also used a small number of experiments involving nondiabetic models of related molecular mechanisms.
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Affiliation(s)
| | | | - Zhongqun Wang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China; and
| | - Jie Zhu
- Department of Cardiology, The Lu'an Hospital Affiliated to Anhui Medical University, The Lu' an People's Hospital, Lu'an, China
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Pannek M, Alhalabi Z, Tomaselli D, Menna M, Fiorentino F, Robaa D, Weyand M, Puhlmann M, Tomassi S, Barreca F, Tafani M, Zaganjor E, Haigis MC, Sippl W, Rotili D, Mai A, Steegborn C. Specific Inhibitors of Mitochondrial Deacylase Sirtuin 4 Endowed with Cellular Activity. J Med Chem 2024; 67:1843-1860. [PMID: 38253001 DOI: 10.1021/acs.jmedchem.3c01496] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
Sirtuins are NAD+-dependent protein lysine deacylases implicated in aging-related diseases. Mammalian Sirtuin 4 (Sirt4) is located in mitochondria and a potential therapeutic target for cancer and metabolic diseases, but no potent and selective Sirt4 inhibitors have been reported. Here, we describe the identification of potent Sirt4-specific small-molecule inhibitors. Testing hits from a target-based virtual screen revealed 12 active compounds. A focused screen based on two top compounds, followed by structure-assisted design of derivatives, yielded four first-in-class potent Sirt4 inhibitors. Kinetic analyses indicate compound competition with the acyl peptide substrate, consistent with the docking models and implicating Sirt4's unique acyl binding site. The compounds indeed show preference for Sirt4 over other isoforms, with one of them (69) being highly isoform selective, and they are active in cells. Our results provide first lead compounds and mechanistic insights for optimization toward Sirt4-specific inhibitors useful as experimental tools and potential therapeutics.
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Affiliation(s)
- Martin Pannek
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
| | - Zayan Alhalabi
- Department of Pharmaceutical Chemistry, Martin-Luther-University Halle-Wittenberg, 06108 Halle, Germany
| | - Daniela Tomaselli
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, 00185 Rome, Italy
| | - Martina Menna
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, 00185 Rome, Italy
| | - Francesco Fiorentino
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, 00185 Rome, Italy
| | - Dina Robaa
- Department of Pharmaceutical Chemistry, Martin-Luther-University Halle-Wittenberg, 06108 Halle, Germany
| | - Michael Weyand
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
| | | | - Stefano Tomassi
- Department of Pharmacy, University of Naples "Federico II", 80131 Naples, Italy
| | - Federica Barreca
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Marco Tafani
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Elma Zaganjor
- Department of Cell Biology, Harvard Medical School, Boston, 02115 Massachusetts, United States
| | - Marcia C Haigis
- Department of Cell Biology, Harvard Medical School, Boston, 02115 Massachusetts, United States
| | - Wolfgang Sippl
- Department of Pharmaceutical Chemistry, Martin-Luther-University Halle-Wittenberg, 06108 Halle, Germany
| | - Dante Rotili
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, 00185 Rome, Italy
| | - Antonello Mai
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, 00185 Rome, Italy
- Pasteur Institute Italy, Cenci-Bolognetti Foundation, Sapienza University of Rome, 00185 Rome, Italy
| | - Clemens Steegborn
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
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Tao Z, Jin Z, Wu J, Cai G, Yu X. Sirtuin family in autoimmune diseases. Front Immunol 2023; 14:1186231. [PMID: 37483618 PMCID: PMC10357840 DOI: 10.3389/fimmu.2023.1186231] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 06/15/2023] [Indexed: 07/25/2023] Open
Abstract
In recent years, epigenetic modifications have been widely researched. As humans age, environmental and genetic factors may drive inflammation and immune responses by influencing the epigenome, which can lead to abnormal autoimmune responses in the body. Currently, an increasing number of studies have emphasized the important role of epigenetic modification in the progression of autoimmune diseases. Sirtuins (SIRTs) are class III nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases and SIRT-mediated deacetylation is an important epigenetic alteration. The SIRT family comprises seven protein members (namely, SIRT1-7). While the catalytic core domain contains amino acid residues that have remained stable throughout the entire evolutionary process, the N- and C-terminal regions are structurally divergent and contribute to differences in subcellular localization, enzymatic activity and substrate specificity. SIRT1 and SIRT2 are localized in the nucleus and cytoplasm. SIRT3, SIRT4, and SIRT5 are mitochondrial, and SIRT6 and SIRT7 are predominantly found in the nucleus. SIRTs are key regulators of various physiological processes such as cellular differentiation, apoptosis, metabolism, ageing, immune response, oxidative stress, and mitochondrial function. We discuss the association between SIRTs and common autoimmune diseases to facilitate the development of more effective therapeutic strategies.
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Affiliation(s)
- Zhengjie Tao
- Science and Education Section, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
- Department of Ultrasonics, The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, China
| | - Zihan Jin
- Clinical Lab, Changzhou Second People’s Hospital Affiliated to Nanjing Medical University, Changzhou, China
| | - Jiabiao Wu
- Department of Immunology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
| | - Gaojun Cai
- Cardiology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
| | - Xiaolong Yu
- Science and Education Section, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
- Department of Ultrasonics, The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, China
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11
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Park JW, Tyl MD, Cristea IM. Orchestration of Mitochondrial Function and Remodeling by Post-Translational Modifications Provide Insight into Mechanisms of Viral Infection. Biomolecules 2023; 13:biom13050869. [PMID: 37238738 DOI: 10.3390/biom13050869] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 05/17/2023] [Accepted: 05/18/2023] [Indexed: 05/28/2023] Open
Abstract
The regulation of mitochondria structure and function is at the core of numerous viral infections. Acting in support of the host or of virus replication, mitochondria regulation facilitates control of energy metabolism, apoptosis, and immune signaling. Accumulating studies have pointed to post-translational modification (PTM) of mitochondrial proteins as a critical component of such regulatory mechanisms. Mitochondrial PTMs have been implicated in the pathology of several diseases and emerging evidence is starting to highlight essential roles in the context of viral infections. Here, we provide an overview of the growing arsenal of PTMs decorating mitochondrial proteins and their possible contribution to the infection-induced modulation of bioenergetics, apoptosis, and immune responses. We further consider links between PTM changes and mitochondrial structure remodeling, as well as the enzymatic and non-enzymatic mechanisms underlying mitochondrial PTM regulation. Finally, we highlight some of the methods, including mass spectrometry-based analyses, available for the identification, prioritization, and mechanistic interrogation of PTMs.
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Affiliation(s)
- Ji Woo Park
- Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544, USA
| | - Matthew D Tyl
- Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544, USA
| | - Ileana M Cristea
- Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544, USA
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12
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Paula Ceballos M, Darío Quiroga A, Palma NF. Role of sirtuins in hepatocellular carcinoma progression and multidrug resistance: Mechanistical and pharmacological perspectives. Biochem Pharmacol 2023; 212:115573. [PMID: 37127248 DOI: 10.1016/j.bcp.2023.115573] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 04/20/2023] [Accepted: 04/24/2023] [Indexed: 05/03/2023]
Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer worldwide. Therapeutic strategies are still challenging due to the high relapse rate after surgery and multidrug resistance (MDR). It is essential to better understand the mechanisms for HCC progression and MDR for the development of new therapeutic strategies. Mammalian sirtuins (SIRTs), a family of seven members, are related to tumor progression, MDR and prognosis and were proposed as potential prognostic markers, as well as therapeutic targets for treating cancer. SIRT1 is the most studied member and is overexpressed in HCC, playing an oncogenic role and predicting poor prognosis. Several manuscripts describe the role of SIRTs2-7 in HCC; most of them report an oncogenic role for SIRT2 and -7 and a suppressive role for SIRT3 and -4. The scenario is more confusing for SIRT5 and -6, since information is contradictory and scarce. For SIRT1 many inhibitors are available and they seem to hold therapeutic promise in HCC. For the other members the development of specific modulators has just started. This review is aimed to describe the features of SIRTs1-7 in HCC, and the role they play in the onset and progression of the disease. Also, when possible, we will depict the information related to the SIRTs modulators that have been tested in HCC and their possible implication in MDR. With this, we hope to clarify the role of each member in HCC and to shed some light on the most successful strategies to overcome MDR.
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Affiliation(s)
- María Paula Ceballos
- Instituto de Fisiología Experimental (IFISE), Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET, UNR, Suipacha 70 (S2002LRL), Rosario, Argentina.
| | - Ariel Darío Quiroga
- Instituto de Fisiología Experimental (IFISE), Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET, UNR, Suipacha 70 (S2002LRL), Rosario, Argentina; Área Morfología, Facultad de Ciencias Bioquímicas y Farmacéuticas, UNR, Suipachs 570 (S2002LRL), Rosario, Argentina; Centro de Altos Estudios en Ciencias Humanas y de la Salud (CAECIHS) Sede Regional Rosario, Universidad Abierta Interamericana, Av. Pellegrini 1618 (S2000BUG), Rosario, Argentina
| | - Nicolás Francisco Palma
- Instituto de Fisiología Experimental (IFISE), Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET, UNR, Suipacha 70 (S2002LRL), Rosario, Argentina; Área Morfología, Facultad de Ciencias Bioquímicas y Farmacéuticas, UNR, Suipachs 570 (S2002LRL), Rosario, Argentina
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13
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Adolph RS, Beck E, Schweimer K, Di Fonzo A, Weyand M, Rösch P, Wöhrl BM, Steegborn C. Molecular Mechanism of Sirtuin 1 Inhibition by Human Immunodeficiency Virus 1 Tat Protein. Life (Basel) 2023; 13:life13040949. [PMID: 37109478 PMCID: PMC10144703 DOI: 10.3390/life13040949] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 03/20/2023] [Accepted: 03/30/2023] [Indexed: 04/08/2023] Open
Abstract
Sirtuins are NAD+-dependent protein lysine deacylases implicated in metabolic regulation and aging-related dysfunctions. The nuclear isoform Sirt1 deacetylates histones and transcription factors and contributes, e.g., to brain and immune cell functions. Upon infection by human immunodeficiency virus 1 (HIV1), Sirt1 deacetylates the viral transactivator of transcription (Tat) protein to promote the expression of the viral genome. Tat, in turn, inhibits Sirt1, leading to the T cell hyperactivation associated with HIV infection. Here, we describe the molecular mechanism of Tat-dependent sirtuin inhibition. Using Tat-derived peptides and recombinant Tat protein, we mapped the inhibitory activity to Tat residues 34–59, comprising Tat core and basic regions and including the Sirt1 deacetylation site Lys50. Tat binds to the sirtuin catalytic core and inhibits Sirt1, Sirt2, and Sirt3 with comparable potencies. Biochemical data and crystal structures of sirtuin complexes with Tat peptides reveal that Tat exploits its intrinsically extended basic region for binding to the sirtuin substrate binding cleft through substrate-like β-strand interactions, supported by charge complementarity. Tat Lys50 is positioned in the sirtuin substrate lysine pocket, although binding and inhibition do not require prior acetylation and rely on subtle differences to the binding of regular substrates. Our results provide mechanistic insights into sirtuin regulation by Tat, improving our understanding of physiological sirtuin regulation and the role of this interaction during HIV1 infection.
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Affiliation(s)
- Ramona S. Adolph
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
| | - Eileen Beck
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
| | - Kristian Schweimer
- Department of Biopolymers, University of Bayreuth, 95440 Bayreuth, Germany
| | - Andrea Di Fonzo
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
| | - Michael Weyand
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
| | - Paul Rösch
- Department of Biopolymers, University of Bayreuth, 95440 Bayreuth, Germany
| | - Birgitta M. Wöhrl
- Department of Biopolymers, University of Bayreuth, 95440 Bayreuth, Germany
| | - Clemens Steegborn
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
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14
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Suenkel B, Valente S, Zwergel C, Weiss S, Di Bello E, Fioravanti R, Aventaggiato M, Amorim JA, Garg N, Kumar S, Lombard DB, Hu T, Singh PK, Tafani M, Palmeira CM, Sinclair D, Mai A, Steegborn C. Potent and Specific Activators for Mitochondrial Sirtuins Sirt3 and Sirt5. J Med Chem 2022; 65:14015-14031. [PMID: 36228194 PMCID: PMC9653166 DOI: 10.1021/acs.jmedchem.2c01215] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Sirtuins are NAD+-dependent protein deacylases involved in metabolic regulation and aging-related diseases. Specific activators for seven human Sirtuin isoforms would be important chemical tools and potential therapeutic drugs. Activators have been described for Sirt1 and act via a unique N-terminal domain of this isoform. For most other Sirtuin isoforms, including mitochondrial Sirt3-5, no potent and specific activators have yet been identified. We here describe the identification and characterization of 1,4-dihydropyridine-based compounds that either act as pan Sirtuin activators or specifically stimulate Sirt3 or Sirt5. The activators bind to the Sirtuin catalytic cores independent of NAD+ and acylated peptides and stimulate turnover of peptide and protein substrates. The compounds also activate Sirt3 or Sirt5 in cellular systems regulating, e.g., apoptosis and electron transport chain. Our results provide a scaffold for potent Sirtuin activation and derivatives specific for Sirt3 and Sirt5 as an excellent basis for further drug development.
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Affiliation(s)
- Benjamin Suenkel
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
| | - Sergio Valente
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, and Pasteur Institute, Cenci-Bolognetti Foundation, 00185 Rome, Italy
| | - Clemens Zwergel
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, and Pasteur Institute, Cenci-Bolognetti Foundation, 00185 Rome, Italy
| | - Sandra Weiss
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
| | - Elisabetta Di Bello
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, and Pasteur Institute, Cenci-Bolognetti Foundation, 00185 Rome, Italy
| | - Rossella Fioravanti
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, and Pasteur Institute, Cenci-Bolognetti Foundation, 00185 Rome, Italy
| | - Michele Aventaggiato
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - João A. Amorim
- Department of Life Sciences, University of Coimbra, 3004-504 Coimbra, Portugal
- Center for Neurosciences and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
- Genetics Department, Blavatnik Institute, Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA 02115, USA
| | - Neha Garg
- Genetics Department, Blavatnik Institute, Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA 02115, USA
| | - Surinder Kumar
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109-2800, USA
| | - David B. Lombard
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109-2800, USA
- Institute of Gerontology, University of Michigan, Ann Arbor, MI 48109-2800, USA
| | - Tuo Hu
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA
| | - Pankaj K. Singh
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA
| | - Marco Tafani
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Carlos M. Palmeira
- Department of Life Sciences, University of Coimbra, 3004-504 Coimbra, Portugal
- Center for Neurosciences and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
| | - David Sinclair
- Genetics Department, Blavatnik Institute, Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA 02115, USA
| | - Antonello Mai
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, and Pasteur Institute, Cenci-Bolognetti Foundation, 00185 Rome, Italy
| | - Clemens Steegborn
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
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15
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Fagerli E, Escobar I, Ferrier FJ, Jackson CW, Perez-Lao EJ, Perez-Pinzon MA. Sirtuins and cognition: implications for learning and memory in neurological disorders. Front Physiol 2022; 13:908689. [PMID: 35936890 PMCID: PMC9355297 DOI: 10.3389/fphys.2022.908689] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 06/30/2022] [Indexed: 11/18/2022] Open
Abstract
Sirtuins are an evolutionarily conserved family of regulatory proteins that function in an NAD+ -dependent manner. The mammalian family of sirtuins is composed of seven histone deacetylase and ADP-ribosyltransferase proteins (SIRT1-SIRT7) that are found throughout the different cellular compartments of the cell. Sirtuins in the brain have received considerable attention in cognition due to their role in a plethora of metabolic and age-related diseases and their ability to induce neuroprotection. More recently, sirtuins have been shown to play a role in normal physiological cognitive function, and aberrant sirtuin function is seen in pathological cellular states. Sirtuins are believed to play a role in cognition through enhancing synaptic plasticity, influencing epigenetic regulation, and playing key roles in molecular pathways involved with oxidative stress affecting mitochondrial function. This review aims to discuss recent advances in the understanding of the role of mammalian sirtuins in cognitive function and the therapeutic potential of targeting sirtuins to ameliorate cognitive deficits in neurological disorders.
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Affiliation(s)
| | | | | | | | | | - Miguel A. Perez-Pinzon
- Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, United States
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16
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Development of hetero-triaryls as a new chemotype for subtype-selective and potent Sirt5 inhibition. Eur J Med Chem 2022; 240:114594. [PMID: 35853430 DOI: 10.1016/j.ejmech.2022.114594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 12/23/2021] [Accepted: 07/05/2022] [Indexed: 11/21/2022]
Abstract
In contrast to other sirtuins (NAD+-dependent class III lysine deacylases), inhibition of Sirt5 is poorly investigated, yet. Our present work is based on the recently identified Sirt5 inhibitor balsalazide, an approved drug with negligible bioavailability after oral administration. After gaining first insights into its structure-activity relationship in previous work, we were able to now develop heteroaryl-triaryls as a novel chemotype of drug-like, potent and subtype-selective Sirt5 inhibitors. The unfavourable azo group of the lead structure was modified in a systematic and comprehensive manner, leading us to a few open-chained and, most importantly, five-membered heteroaromatic substitutes (isoxazole CG_209, triazole CG_220, pyrazole CG_232) with very encouraging in vitro activities (IC50 on Sirt5 in the low micromolar range, <10 μM). These advanced inhibitors were free of cytotoxicity and showed favourable pharmacokinetic properties, as confirmed by permeability into mitochondria using live cell imaging experiments. Furthermore, results from calculations of the relative free binding affinities of the analogues compared to balsalazide as reference compound agreed well with the trends for inhibitory activities obtained in the in vitro experiments. Therefore, this method can be used to predict the affinity of closely related future potential Sirt5 inhibitors. Encouraged by our findings, we employed chemoproteomic selectivity profiling to confirm Sirt5 as main target of balsalazide and one of its improved analogues. An immobilised balsalazide-analogue specifically pulled down Sirt5 from whole cell lysates and competition experiments identified glutaryl-CoA dehydrogenase (GCDH) and nucleotide diphosphate kinase (NME4) as potential off-targets, once again confirming the selectivity of the novel balsalazide-derived Sirt5 inhibitors. In summary, a combination of targeted chemical synthesis, biological work, and computational studies led to a new generation of tailored Sirt5 inhibitors, which represent valuable chemical tools for the investigation of the physiological role of Sirt5, but could also serve as advanced lead structures for drug candidates for systemic use.
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17
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Gandhirajan A, Roychowdhury S, Vachharajani V. Sirtuins and Sepsis: Cross Talk between Redox and Epigenetic Pathways. Antioxidants (Basel) 2021; 11:antiox11010003. [PMID: 35052507 PMCID: PMC8772830 DOI: 10.3390/antiox11010003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 12/09/2021] [Accepted: 12/11/2021] [Indexed: 12/19/2022] Open
Abstract
Sepsis and septic shock are the leading causes of death among hospitalized patients in the US. The immune response in sepsis transitions from a pro-inflammatory and pro-oxidant hyper-inflammation to an anti-inflammatory and cytoprotective hypo-inflammatory phase. While 1/3rd sepsis-related deaths occur during hyper-, a vast majority of sepsis-mortality occurs during the hypo-inflammation. Hyper-inflammation is cytotoxic for the immune cells and cannot be sustained. As a compensatory mechanism, the immune cells transition from cytotoxic hyper-inflammation to a cytoprotective hypo-inflammation with anti-inflammatory/immunosuppressive phase. However, the hypo-inflammation is associated with an inability to clear invading pathogens, leaving the host susceptible to secondary infections. Thus, the maladaptive immune response leads to a marked departure from homeostasis during sepsis-phases. The transition from hyper- to hypo-inflammation occurs via epigenetic programming. Sirtuins, a highly conserved family of histone deacetylators and guardians of homeostasis, are integral to the epigenetic programming in sepsis. Through their anti-inflammatory and anti-oxidant properties, the sirtuins modulate the immune response in sepsis. We review the role of sirtuins in orchestrating the interplay between the oxidative stress and epigenetic programming during sepsis.
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Affiliation(s)
- Anugraha Gandhirajan
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (A.G.); (S.R.)
| | - Sanjoy Roychowdhury
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (A.G.); (S.R.)
| | - Vidula Vachharajani
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (A.G.); (S.R.)
- Department of Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195, USA
- Correspondence:
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18
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Zhang N, Song L, Xu Y, Pei X, Luisi BF, Liang W. The decrotonylase FoSir5 facilitates mitochondrial metabolic state switching in conidial germination of Fusarium oxysporum. eLife 2021; 10:75583. [PMID: 34927582 PMCID: PMC8730727 DOI: 10.7554/elife.75583] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 12/15/2021] [Indexed: 11/13/2022] Open
Abstract
Fusarium oxysporum is one of the most important pathogenic fungi with a broad range of plant and animal hosts. The first key step of its infection cycle is conidial germination, but there is limited information available on the molecular events supporting this process. We show here that germination is accompanied by a sharp decrease in expression of FoSir5, an ortholog of the human lysine deacetylase SIRT5. We observe that FoSir5 decrotonylates a subunit of the fungal pyruvate dehydrogenase complex (FoDLAT) at K148, resulting in inhibition of the activity of the complex in mitochondria. Moreover, FoSir5 decrotonylates histone H3K18, leading to a downregulation of transcripts encoding enzymes of aerobic respiration pathways. Thus, the activity of FoSir5 coordinates regulation in different organelles to steer metabolic flux through respiration. As ATP content is positively related to fungal germination, we propose that FoSir5 negatively modulates conidial germination in F. oxysporum through its metabolic impact. These findings provide insights into the multifaceted roles of decrotonylation, catalyzed by FoSir5, that support conidial germination in F. oxysporum.
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Affiliation(s)
- Ning Zhang
- Key Lab of Integrated Crop Pest Management of Shandong Province, College of Plant Health and Medicine, Qingdao Agricultural University, Qingdao, China
| | - Limin Song
- Key Lab of Integrated Crop Pest Management of Shandong Province, College of Plant Health and Medicine, Qingdao Agricultural University, Qingdao, China
| | - Yang Xu
- Key Lab of Integrated Crop Pest Management of Shandong Province, College of Plant Health and Medicine, Qingdao Agricultural University, Qingdao, China
| | - Xueyuan Pei
- Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
| | - Ben F Luisi
- Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
| | - Wenxing Liang
- Key Lab of Integrated Crop Pest Management of Shandong Province, College of Plant Health and Medicine, Qingdao Agricultural University, Qingdao, China
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19
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Ji Z, Liu GH, Qu J. Mitochondrial sirtuins, metabolism, and aging. J Genet Genomics 2021; 49:287-298. [PMID: 34856390 DOI: 10.1016/j.jgg.2021.11.005] [Citation(s) in RCA: 112] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 11/09/2021] [Accepted: 11/10/2021] [Indexed: 02/06/2023]
Abstract
Maintaining metabolic homeostasis is essential for cellular and organismal health throughout life. Of the multiple signaling pathways that regulate metabolism, such as PI3K/AKT, mTOR, AMPK, and sirtuins, mammalian sirtuins also play unique roles in aging. By understanding how sirtuins regulate metabolic processes, we can start to understand how they slow down or accelerate biological aging. Here, we review the biology of SIRT3, SIRT4, and SIRT5, known as the mitochondrial sirtuins due to their localization in the mitochondrial matrix. First, we will focus on canonical pathways that regulate metabolism more broadly and how these are integrated with aging regulation. Then, we will summarize the current knowledge about functional differences between SIRT3, SIRT4, and SIRT5 in metabolic control and integration in signaling networks. Finally, we will discuss how mitochondrial sirtuins regulate processes associated with aging and oxidative stress, calorie restriction and disease.
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Affiliation(s)
- Zhejun Ji
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Guang-Hui Liu
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China.
| | - Jing Qu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
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20
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Mani S, Swargiary G, Ralph SJ. Targeting the redox imbalance in mitochondria: A novel mode for cancer therapy. Mitochondrion 2021; 62:50-73. [PMID: 34758363 DOI: 10.1016/j.mito.2021.11.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 10/14/2021] [Accepted: 11/01/2021] [Indexed: 12/19/2022]
Abstract
Changes in reactive oxygen species (ROS) levels affect many aspects of cell behavior. During carcinogenesis, moderate ROS production modifies gene expression to alter cell function, elevating metabolic activity and ROS. To avoid extreme ROS-activated death, cancer cells increase antioxidative capacity, regulating sustained ROS levels that promote growth. Anticancer therapies are exploring inducing supranormal, cytotoxic oxidative stress levels either inhibiting antioxidative capacity or promoting excess ROS to selectively destroy cancer cells, triggering mechanisms such as apoptosis, autophagy, necrosis, or ferroptosis. This review exemplifies pro-oxidants (natural/synthetic/repurposed drugs) and their clinical significance as cancer therapies providing revolutionary approaches.
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Affiliation(s)
- Shalini Mani
- Centre for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, Noida, India.
| | - Geeta Swargiary
- Centre for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, Noida, India
| | - Stephen J Ralph
- School of Medical Science, Griffith University, Southport, Australia.
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21
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Ding YQ, Zhang YH, Lu J, Li B, Yu WJ, Yue ZB, Hu YH, Wang PX, Li JY, Cai SD, Ye JT, Liu PQ. MicroRNA-214 contributes to Ang II-induced cardiac hypertrophy by targeting SIRT3 to provoke mitochondrial malfunction. Acta Pharmacol Sin 2021; 42:1422-1436. [PMID: 33247214 PMCID: PMC8379271 DOI: 10.1038/s41401-020-00563-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Accepted: 10/21/2020] [Indexed: 12/21/2022]
Abstract
Reduction of expression and activity of sirtuin 3 (SIRT3) contributes to the pathogenesis of cardiomyopathy via inducing mitochondrial injury and energy metabolism disorder. However, development of effective ways and agents to modulate SIRT3 remains a big challenge. In this study we explored the upstream suppressor of SIRT3 in angiotensin II (Ang II)-induced cardiac hypertrophy in mice. We first found that SIRT3 deficiency exacerbated Ang II-induced cardiac hypertrophy, and resulted in the development of spontaneous heart failure. Since miRNAs play crucial roles in the pathogenesis of cardiac hypertrophy, we performed miRNA sequencing on myocardium tissues from Ang II-infused Sirt3-/- and wild type mice, and identified microRNA-214 (miR-214) was significantly up-regulated in Ang II-infused mice. Similar results were also obtained in Ang II-treated neonatal mouse cardiomyocytes (NMCMs). Using dual-luciferase reporter assay we demonstrated that SIRT3 was a direct target of miR-214. Overexpression of miR-214 in vitro and in vivo decreased the expression of SIRT3, which resulted in extensive mitochondrial damages, thereby facilitating the onset of hypertrophy. In contrast, knockdown of miR-214 counteracted Ang II-induced detrimental effects via restoring SIRT3, and ameliorated mitochondrial morphology and respiratory activity. Collectively, these results demonstrate that miR-214 participates in Ang II-induced cardiac hypertrophy by directly suppressing SIRT3, and subsequently leading to mitochondrial malfunction, suggesting the potential of miR-214 as a promising intervention target for antihypertrophic therapy.
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Affiliation(s)
- Yan-Qing Ding
- Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou, 510006, China
| | - Yu-Hong Zhang
- Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou, 510006, China
| | - Jing Lu
- Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou, 510006, China
| | - Bai Li
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Wen-Jing Yu
- Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou, 510006, China
| | - Zhong-Bao Yue
- Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou, 510006, China
| | - Yue-Huai Hu
- Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou, 510006, China
| | - Pan-Xia Wang
- Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou, 510006, China
| | - Jing-Yan Li
- International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Si-Dong Cai
- Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou, 510006, China
| | - Jian-Tao Ye
- Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou, 510006, China.
| | - Pei-Qing Liu
- Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou, 510006, China.
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22
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VHL regulates the sensitivity of clear cell renal cell carcinoma to SIRT4-mediated metabolic stress via HIF-1α/HO-1 pathway. Cell Death Dis 2021; 12:621. [PMID: 34135317 PMCID: PMC8209205 DOI: 10.1038/s41419-021-03901-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 06/02/2021] [Accepted: 06/03/2021] [Indexed: 02/05/2023]
Abstract
Clear cell renal cell carcinomas (ccRCC) reprogram carbon metabolism responses to hypoxia, thereby promoting utilization of glutamine. Recently, sirtuin 4 (SIRT4), a novel molecular has turned out to be related to alternating glutamine metabolism and modulating the tumor microenvironment. However, the role of SIRT4 in ccRCC remains poorly understood. Here, we illustrated that the expression of SIRT4 is markedly reduced in cancerous tissues, and closely associated with malignancy stage, grade, and prognosis. In ccRCC cells, SIRT4 exerted its proapoptotic activity through enhancing intracellular reactive oxygen species (ROS). Heme oxygenase-1 (HO-1) is part of an endogenous defense system against oxidative stress. Nevertheless, overexpression of SIRT4 hindered the upregulation of HO-1 in von Hippel-Lindau (VHL)-proficient cells and repressed its expression in VHL-deficient cells. This discrepancy indicated that competent VHL withstands the inhibitory role of SIRT4 on HIF-1α/HO-1. Functionally, overexpression of HO-1 counteracted the promotional effects of SIRT4 on ROS accumulation and apoptosis. Mechanistically, SIRT4 modulates ROS and HO-1 expression via accommodating p38-MAPK phosphorylation. By contrast, downregulation of p38-MAPK by SB203580 decreased intracellular ROS level and enhanced the expression of HO-1. Collectively, this work revealed a potential role for SIRT4 in the stimulation of ROS and the modulation of apoptosis. SIRT4/HO-1 may act as a potential therapeutic target, especially in VHL-deficient ccRCCs.
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23
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Bharadwaj S, Dubey A, Kamboj NK, Sahoo AK, Kang SG, Yadava U. Drug repurposing for ligand-induced rearrangement of Sirt2 active site-based inhibitors via molecular modeling and quantum mechanics calculations. Sci Rep 2021; 11:10169. [PMID: 33986372 PMCID: PMC8119977 DOI: 10.1038/s41598-021-89627-0] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 04/29/2021] [Indexed: 12/14/2022] Open
Abstract
Sirtuin 2 (Sirt2) nicotinamide adenine dinucleotide-dependent deacetylase enzyme has been reported to alter diverse biological functions in the cells and onset of diseases, including cancer, aging, and neurodegenerative diseases, which implicate the regulation of Sirt2 function as a potential drug target. Available Sirt2 inhibitors or modulators exhibit insufficient specificity and potency, and even partially contradictory Sirt2 effects were described for the available inhibitors. Herein, we applied computational screening and evaluation of FDA-approved drugs for highly selective modulation of Sirt2 activity via a unique inhibitory mechanism as reported earlier for SirReal2 inhibitor. Application of stringent molecular docking results in the identification of 48 FDA-approved drugs as selective putative inhibitors of Sirt2, but only top 10 drugs with docking scores > - 11 kcal/mol were considered in reference to SirReal2 inhibitor for computational analysis. The molecular dynamics simulations and post-simulation analysis of Sirt2-drug complexes revealed substantial stability for Fluphenazine and Nintedanib with Sirt2. Additionally, developed 3D-QSAR-models also support the inhibitory potential of drugs, which exclusively revealed highest activities for Nintedanib (pIC50 ≥ 5.90 µM). Conclusively, screened FDA-approved drugs were advocated as promising agents for Sirt2 inhibition and required in vitro investigation for Sirt2 targeted drug development.
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Affiliation(s)
- Shiv Bharadwaj
- Department of Biotechnology, Institute of Biotechnology, College of Life and Applied Sciences, Yeungnam University, 280 Daehak-Ro, Gyeongsan, Gyeongbuk, 38541, Republic of Korea
| | - Amit Dubey
- Computational Chemistry and Drug Discovery Division, Quanta Calculus Pvt. Ltd., Kushinagar, 274203, India
| | - Nitin Kumar Kamboj
- School of Physical Sciences, DIT University, Dehradun, UK, 248001, India
| | - Amaresh Kumar Sahoo
- Department of Applied Sciences, Indian Institute of Information Technology Allahabad, Allahabad, Uttar Pradesh, 211015, India.
| | - Sang Gu Kang
- Department of Biotechnology, Institute of Biotechnology, College of Life and Applied Sciences, Yeungnam University, 280 Daehak-Ro, Gyeongsan, Gyeongbuk, 38541, Republic of Korea.
| | - Umesh Yadava
- Department of Physics, Deen Dayal Upadhyaya Gorakhpur University, Gorakhpur, India.
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24
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Poltronieri P, Celetti A, Palazzo L. Mono(ADP-ribosyl)ation Enzymes and NAD + Metabolism: A Focus on Diseases and Therapeutic Perspectives. Cells 2021; 10:128. [PMID: 33440786 PMCID: PMC7827148 DOI: 10.3390/cells10010128] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 01/05/2021] [Accepted: 01/05/2021] [Indexed: 12/19/2022] Open
Abstract
Mono(ADP-ribose) transferases and mono(ADP-ribosyl)ating sirtuins use NAD+ to perform the mono(ADP-ribosyl)ation, a simple form of post-translational modification of proteins and, in some cases, of nucleic acids. The availability of NAD+ is a limiting step and an essential requisite for NAD+ consuming enzymes. The synthesis and degradation of NAD+, as well as the transport of its key intermediates among cell compartments, play a vital role in the maintenance of optimal NAD+ levels, which are essential for the regulation of NAD+-utilizing enzymes. In this review, we provide an overview of the current knowledge of NAD+ metabolism, highlighting the functional liaison with mono(ADP-ribosyl)ating enzymes, such as the well-known ARTD10 (also named PARP10), SIRT6, and SIRT7. To this aim, we discuss the link of these enzymes with NAD+ metabolism and chronic diseases, such as cancer, degenerative disorders and aging.
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Affiliation(s)
- Palmiro Poltronieri
- Institute of Sciences of Food Productions, National Research Council of Italy, via Monteroni 7, 73100 Lecce, Italy
| | - Angela Celetti
- Institute for the Experimental Endocrinology and Oncology, National Research Council of Italy, Via Sergio Pansini 5, 80131 Naples, Italy
| | - Luca Palazzo
- Institute for the Experimental Endocrinology and Oncology, National Research Council of Italy, Via Tommaso de Amicis 95, 80145 Naples, Italy
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25
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Bai Y, Yang J, Cui Y, Yao Y, Wu F, Liu C, Fan X, Zhang Y. Research Progress of Sirtuin4 in Cancer. Front Oncol 2021; 10:562950. [PMID: 33585187 PMCID: PMC7874138 DOI: 10.3389/fonc.2020.562950] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 11/03/2020] [Indexed: 12/29/2022] Open
Abstract
Sirtuins (SIRTs) are members of the silent information regulator-2 family. They are a conserved family of nicotinamide adenine dinucleotide-dependent protein lysine deacylases. SIRTS are involved in intricate cellular processes. There are seven subtypes of SIRTs (1–7) in mammals. SIRT4 is located mainly in mitochondria and has various catalytic activities. These enzyme activities give it a diverse range of important biologic functions, such as energy metabolism, oxidative stress, and aging. Cancer is characterized as reprogramming of energy metabolism and redox imbalance, and SIRT4 can affect tumorigenesis. Here, we review the structure, localization, and enzyme activity of SIRT4 and its role in various neoplasms.
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Affiliation(s)
- Yibing Bai
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Jiani Yang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Ying Cui
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.,Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yuanfei Yao
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Feng Wu
- Department of Gastroenterology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Caiqi Liu
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xiaona Fan
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yanqiao Zhang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
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26
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Identification of the subtype-selective Sirt5 inhibitor balsalazide through systematic SAR analysis and rationalization via theoretical investigations. Eur J Med Chem 2020; 206:112676. [PMID: 32858418 DOI: 10.1016/j.ejmech.2020.112676] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 07/17/2020] [Accepted: 07/18/2020] [Indexed: 12/30/2022]
Abstract
We report here an extensive structure-activity relationship study of balsalazide, which was previously identified in a high-throughput screening as an inhibitor of Sirt5. To get a closer understanding why this compound is able to inhibit Sirt5, we initially performed docking experiments comparing the binding mode of a succinylated peptide as the natural substrate and balsalazide with Sirt5 in the presence of NAD+. Based on the evidence gathered here, we designed and synthesized 13 analogues of balsalazide, in which single functional groups were either deleted or slightly altered to investigate which of them are mandatory for high inhibitory activity. Our study confirms that balsalazide with all its given functional groups is an inhibitor of Sirt5 in the low micromolar concentration range and structural modifications presented in this study did not increase potency. While changes on the N-aroyl-β-alanine side chain eliminated potency, the introduction of a truncated salicylic acid part minimally altered potency. Calculations of the associated reaction paths showed that the inhibition potency is very likely dominated by the stability of the inhibitor-enzyme complex and not the type of inhibition (covalent vs. non-covalent). Further in-vitro characterization in a trypsin coupled assay determined that the tested inhibitors showed no competition towards NAD+ or the synthetic substrate analogue ZKsA. In addition, investigations for subtype selectivity revealed that balsalazide is a subtype-selective Sirt5 inhibitor, and our initial SAR and docking studies pave the way for further optimization.
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27
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Tomaselli D, Steegborn C, Mai A, Rotili D. Sirt4: A Multifaceted Enzyme at the Crossroads of Mitochondrial Metabolism and Cancer. Front Oncol 2020; 10:474. [PMID: 32373514 PMCID: PMC7177044 DOI: 10.3389/fonc.2020.00474] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Accepted: 03/16/2020] [Indexed: 01/02/2023] Open
Abstract
Sirtuins are NAD+-dependent deacylases that play crucial roles in the regulation of cellular metabolism, and as a result, are implicated in several diseases. The mitochondrial sirtuin Sirt4, for a long time considered as mainly a mono-ADP-ribosyltransferase, recently has shown a robust deacylase activity in addition to the already accepted substrate-dependent lipoamidase and deacetylase properties. Through these and likely other enzymatic and non-enzymatic activities, Sirt4 closely controls various metabolic events, and its dysregulation is linked to various aging-related disorders, including type 2 diabetes, cardiac hypertrophy, non-alcoholic fatty liver disease, obesity, and cancer. For its capability to inhibit glutamine catabolism and for the modulation of genome stability in cancer cells in response to different DNA-damaging conditions, Sirt4 is proposed as either a mitochondrial tumor suppressor or a tumor-promoting protein in a context-dependent manner. In addition to what is already known about the roles of Sirt4 in different biological settings, further studies are certainly still needed in order to validate this enzyme as a new potential target for various aging diseases.
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Affiliation(s)
- Daniela Tomaselli
- Department of Chemistry and Technology of Drugs, "Sapienza" University of Rome, Rome, Italy
| | - Clemens Steegborn
- Department of Biochemistry, University of Bayreuth, Bayreuth, Germany
| | - Antonello Mai
- Department of Chemistry and Technology of Drugs, "Sapienza" University of Rome, Rome, Italy
| | - Dante Rotili
- Department of Chemistry and Technology of Drugs, "Sapienza" University of Rome, Rome, Italy
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28
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Liu J, Chen S, Biswas S, Nagrani N, Chu Y, Chakrabarti S, Feng B. Glucose-induced oxidative stress and accelerated aging in endothelial cells are mediated by the depletion of mitochondrial SIRTs. Physiol Rep 2020; 8:e14331. [PMID: 32026628 PMCID: PMC7002531 DOI: 10.14814/phy2.14331] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Diabetic complications cause significant morbidity and mortality. Dysfunction of vascular endothelial cells (ECs), caused by oxidative stress, is a main mechanism of cellular damage. Oxidative stress accelerates EC senescence and DNA damage. In this study, we examined the role of mitochondrial sirtuins (SIRTs) in glucose-induced oxidative stress, EC senescence, and their regulation by miRNAs. Human retinal microvascular endothelial cells (HRECs) were exposed to 5 mmol/L (normoglycemia; NG) or 25 mmol/L glucose (hyperglycemia; HG) with or without transfection of miRNA antagomirs (miRNA-1, miRNA-19b, and miRNA-320; specific SIRT-targeting miRNAs). Expressions of SIRT3, 4 and 5 and their targeting miRNAs were examined using qRT-PCR and ELISAs were used to study SIRT proteins. Cellular senescence was investigated using senescence-associated β-gal stain; while, oxidative stress and mitochondrial alterations were examined using 8-OHdG staining and cytochrome B expressions, respectively. A streptozotocin-induced diabetic mouse model was also used and animal retinas and hearts were collected at 2 months of diabetes. In HRECs, HG downregulated the mRNAs of SIRTs, while SIRT-targeting miRNAs were upregulated. ELISA analyses confirmed such downregulation of SIRTs at the protein level. HG additionally caused early senescence, endothelial-to-mesenchymal transition and oxidative DNA damage in ECs. These changes were prevented by the transfection of specific miRNA antagomirs and by resveratrol. Retinal and cardiac tissues from diabetic mice also showed similar reductions of mitochondrial SIRTs. Collectively, these findings demonstrate a novel mechanism in which mitochondrial SIRTs regulate glucose-induced cellular aging through oxidative stress and how these SIRTs are regulated by specific miRNAs. Identifying such mechanisms may lead to the discovery of novel treatments for diabetic complications.
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Affiliation(s)
- Jieting Liu
- Department of Pathology and Laboratory MedicineWestern UniversityLondonONCanada
- Mudanjiang Medical UniversityHeilongjiangPR China
| | - Shali Chen
- Department of Pathology and Laboratory MedicineWestern UniversityLondonONCanada
| | - Saumik Biswas
- Department of Pathology and Laboratory MedicineWestern UniversityLondonONCanada
| | - Niharika Nagrani
- Department of Pathology and Laboratory MedicineWestern UniversityLondonONCanada
| | - Yanhui Chu
- Mudanjiang Medical UniversityHeilongjiangPR China
| | - Subrata Chakrabarti
- Department of Pathology and Laboratory MedicineWestern UniversityLondonONCanada
| | - Biao Feng
- Department of Pathology and Laboratory MedicineWestern UniversityLondonONCanada
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29
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Anaizi N. Nicotinamide adenine dinucleotide, the sirtuins, and the secret of a long health span. IBNOSINA JOURNAL OF MEDICINE AND BIOMEDICAL SCIENCES 2020. [DOI: 10.4103/ijmbs.ijmbs_6_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
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30
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Structural basis for the activation and inhibition of Sirtuin 6 by quercetin and its derivatives. Sci Rep 2019; 9:19176. [PMID: 31844103 PMCID: PMC6914789 DOI: 10.1038/s41598-019-55654-1] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 11/27/2019] [Indexed: 02/06/2023] Open
Abstract
Mammalian Sirtuin 6 (Sirt6) is an NAD+-dependent protein deacylase regulating metabolism and chromatin homeostasis. Sirt6 activation protects against metabolic and aging-related diseases, and Sirt6 inhibition is considered a cancer therapy. Available Sirt6 modulators show insufficient potency and specificity, and even partially contradictory Sirt6 effects were reported for the plant flavone quercetin. To understand Sirt6 modulation by quercetin-based compounds, we analysed their binding and activity effects on Sirt6 and other Sirtuin isoforms and solved crystal structures of compound complexes with Sirt6 and Sirt2. We find that quercetin activates Sirt6 via the isoform-specific binding site for pyrrolo[1,2-a]quinoxalines. Its inhibitory effect on other isoforms is based on an alternative binding site at the active site entrance. Based on these insights, we identified isoquercetin as a ligand that can discriminate both sites and thus activates Sirt6 with increased specificity. Furthermore, we find that quercetin derivatives that inhibit rather than activate Sirt6 exploit the same general Sirt6 binding site as the activators, identifying it as a versatile allosteric site for Sirt6 modulation. Our results thus provide a structural basis for Sirtuin effects of quercetin-related compounds and helpful insights for Sirt6-targeted drug development.
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31
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Heinonen T, Ciarlo E, Le Roy D, Roger T. Impact of the Dual Deletion of the Mitochondrial Sirtuins SIRT3 and SIRT5 on Anti-microbial Host Defenses. Front Immunol 2019; 10:2341. [PMID: 31632409 PMCID: PMC6781768 DOI: 10.3389/fimmu.2019.02341] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 09/17/2019] [Indexed: 12/15/2022] Open
Abstract
The sirtuins SIRT3 and SIRT5 are the main mitochondrial lysine deacetylase and desuccinylase, respectively. SIRT3 and SIRT5 regulate metabolism and redox homeostasis and have been involved in age-associated metabolic, neurologic and oncologic diseases. We have previously shown that single deficiency in either SIRT3 or SIRT5 had no impact on host defenses in a large panel of preclinical models of sepsis. However, SIRT3 and SIRT5 may compensate each other considering that they share subcellular location and targets. Here, we generated a SIRT3/5 double knockout mouse line. SIRT3/5 deficient mice multiplied and developed without abnormalities. Hematopoiesis and immune cell development were largely unaffected in SIRT3/5 deficient mice. Whole blood, macrophages and neutrophils from SIRT3/5 deficient mice displayed enhanced inflammatory and bactericidal responses. In agreement, SIRT3/5 deficient mice showed somewhat improved resistance to Listeria monocytogenes infection. Overall, the double deficiency in SIRT3 and SIRT5 has rather subtle impacts on immune cell development and anti-microbial host defenses unseen in single deficient mice, indicating a certain degree of overlap between SIRT3 and SIRT5. These data support the assumption that therapies directed against mitochondrial sirtuins, at least SIRT3 and SIRT5, should not impair antibacterial host defenses.
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Affiliation(s)
- Tytti Heinonen
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Epalinges, Switzerland
| | - Eleonora Ciarlo
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Epalinges, Switzerland
| | - Didier Le Roy
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Epalinges, Switzerland
| | - Thierry Roger
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Epalinges, Switzerland
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32
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Han Y, Zhou S, Coetzee S, Chen A. SIRT4 and Its Roles in Energy and Redox Metabolism in Health, Disease and During Exercise. Front Physiol 2019; 10:1006. [PMID: 31447696 PMCID: PMC6695564 DOI: 10.3389/fphys.2019.01006] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Accepted: 07/22/2019] [Indexed: 01/25/2023] Open
Abstract
NAD+-dependent SIRT4 has been reported to be a key regulator of metabolic enzymes and antioxidant defense mechanisms in mitochondria. It also plays an important role in regulation of mitochondrial metabolism in response to exercise. Recent studies have shown that SIRT4 is involved in a wide range of mitochondrial metabolic processes, including depressing insulin secretion in pancreatic beta cells, promoting lipid synthesis, regulating mitochondrial adenosine triphosphate (ATP) homeostasis, controlling apoptosis and regulating redox. SIRT4 also appears to have enzymatic functions involved in posttranslational modifications such as ADP-ribosylation, lysine deacetylation and lipoamidation. However, the effects on SIRT4 by metabolic diseases and changes in metabolic homeostasis such as during exercise, along with the roles of SIRT4 in the regulation of metabolism during disease, are not well understood. The main goal of this review is to critically analyse and summarise the current research evidence on the significance of the SIRT4 as a metabolic regulator and in mitochondrial function and its putative roles in relation to metabolic diseases and exercise.
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Affiliation(s)
- Yumei Han
- School of Physical Education, Shanxi University, Taiyuan, China
| | - Shi Zhou
- School of Health and Human Sciences, Southern Cross University, Lismore, NSW, Australia
| | - Sonja Coetzee
- School of Health and Human Sciences, Southern Cross University, Lismore, NSW, Australia
| | - Anping Chen
- School of Physical Education, Shanxi University, Taiyuan, China
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33
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Montserrat-de la Paz S, Naranjo MC, Millan-Linares MC, Lopez S, Abia R, Biessen EAL, Muriana FJG, Bermudez B. Monounsaturated Fatty Acids in a High-Fat Diet and Niacin Protect from White Fat Dysfunction in the Metabolic Syndrome. Mol Nutr Food Res 2019; 63:e1900425. [PMID: 31343843 DOI: 10.1002/mnfr.201900425] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 06/26/2019] [Indexed: 12/14/2022]
Abstract
SCOPE Obesity is a principal causative factor of metabolic syndrome. Niacin potently regulates lipid metabolism. Replacement of saturated fatty acids by MUFAs or inclusion of omega-3 long-chain PUFAs in the diet improves plasma lipid levels. However, the potential benefits of niacin in combination with MUFAs or omega-3 long-chain PUFAs against white adipose tissue (WAT) dysfunction in the high fat diet (HFD)-induced metabolic syndrome are unknown. METHODS AND RESULTS Male Lepob/ob LDLR-/- mice are fed a chow diet or HFDs based on milk cream (21% kcal), olive oil (21% kcal), or olive oil (20% kcal) plus 1% kcal from eicosapentaenoic and docosahexaenoic acids, including immediate-release niacin (1% w/v) in drinking water, for 8 weeks. Mice are then phenotyped. Dietary MUFAs are identified as positive regulators of adipose NAD+ signaling pathways by triggering NAD+ biosynthesis via the salvage pathway. This coexists with overexpression of genes involved in recognition of NAD+ and fatty acids, a surrounding lipid environment dominated by exogenous oleic acid and an alternatively activated macrophage profile, which culminate in a healthy expansion of WAT and improvement of several hallmarks that typify the metabolic syndrome. CONCLUSION Niacin in combination with dietary MUFAs can favor WAT homeostasis in the development of HFD-induced obesity and metabolic syndrome.
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Affiliation(s)
- Sergio Montserrat-de la Paz
- Laboratory of Cellular and Molecular Nutrition, Instituto de la Grasa, CSIC, 41013, Seville, Spain.,Department of Medical Biochemistry, Molecular Biology and Immunology, School of Medicine, University of Seville, 41009, Seville, Spain
| | - Maria C Naranjo
- Laboratory of Cellular and Molecular Nutrition, Instituto de la Grasa, CSIC, 41013, Seville, Spain
| | | | - Sergio Lopez
- Laboratory of Cellular and Molecular Nutrition, Instituto de la Grasa, CSIC, 41013, Seville, Spain.,Department of Cell Biology, School of Biology, University of Seville, 41012, Seville, Spain
| | - Rocio Abia
- Laboratory of Cellular and Molecular Nutrition, Instituto de la Grasa, CSIC, 41013, Seville, Spain
| | - Erik A L Biessen
- Experimental Vascular Pathology Group, Cardiovascular Research Institute of Maastricht (CARIM), University of Maastricht, 6200, Maastricht, The Netherlands
| | - Francisco J G Muriana
- Laboratory of Cellular and Molecular Nutrition, Instituto de la Grasa, CSIC, 41013, Seville, Spain
| | - Beatriz Bermudez
- Laboratory of Cellular and Molecular Nutrition, Instituto de la Grasa, CSIC, 41013, Seville, Spain.,Department of Cell Biology, School of Biology, University of Seville, 41012, Seville, Spain
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Biasutto L, Mattarei A, La Spina M, Azzolini M, Parrasia S, Szabò I, Zoratti M. Strategies to target bioactive molecules to subcellular compartments. Focus on natural compounds. Eur J Med Chem 2019; 181:111557. [PMID: 31374419 DOI: 10.1016/j.ejmech.2019.07.060] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 07/04/2019] [Accepted: 07/21/2019] [Indexed: 02/06/2023]
Abstract
Many potential pharmacological targets are present in multiple subcellular compartments and have different pathophysiological roles depending on location. In these cases, selective targeting of a drug to the relevant subcellular domain(s) may help to sharpen its impact by providing topological specificity, thus limiting side effects, and to concentrate the compound where needed, thus increasing its effectiveness. We review here the state of the art in precision subcellular delivery. The major approaches confer "homing" properties to the active principle via permanent or reversible (in pro-drug fashion) modifications, or through the use of special-design nanoparticles or liposomes to ferry a drug(s) cargo to its desired destination. An assortment of peptides, substituents with delocalized positive charges, custom-blended lipid mixtures, pH- or enzyme-sensitive groups provide the main tools of the trade. Mitochondria, lysosomes and the cell membrane may be mentioned as the fronts on which the most significant advances have been made. Most of the examples presented here have to do with targeting natural compounds - in particular polyphenols, known as pleiotropic agents - to one or the other subcellular compartment.
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Affiliation(s)
- Lucia Biasutto
- CNR Neuroscience Institute, Viale G. Colombo 3, 35121, Padova, Italy; Dept. Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35121, Padova, Italy.
| | - Andrea Mattarei
- Dept. Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131, Padova, Italy
| | - Martina La Spina
- Dept. Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35121, Padova, Italy
| | - Michele Azzolini
- Dept. Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35121, Padova, Italy
| | - Sofia Parrasia
- Dept. Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35121, Padova, Italy
| | - Ildikò Szabò
- CNR Neuroscience Institute, Viale G. Colombo 3, 35121, Padova, Italy; Dept. Biology, University of Padova, Viale G. Colombo 3, 35121, Padova, Italy
| | - Mario Zoratti
- CNR Neuroscience Institute, Viale G. Colombo 3, 35121, Padova, Italy; Dept. Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35121, Padova, Italy
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Yu H, Pan W, Huang H, Chen J, Sun B, Yang L, Zhu P. Screening Analysis of Sirtuins Family Expression on Anti-Inflammation of Resveratrol in Endothelial Cells. Med Sci Monit 2019; 25:4137-4148. [PMID: 31158122 PMCID: PMC6561145 DOI: 10.12659/msm.913240] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background Resveratrol has been shown to possess beneficial activities including antioxidant, anti-inflammatory, and cardioprotective effects through activating a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase family member sirtuin-1 (SIRT1) protein. The current study was undertaken to investigate the role of sirtuin family members (SIRT1–SIRT7) on the anti-inflammation activities of resveratrol in endothelial cells. Material/Methods Primary human umbilical vein endothelial cells (HUVECs) were pretreated with resveratrol before tumor necrosis factor (TNF)-α (10–20 μg/L) stimulation. Cell viability was measured using the Cell Counting Kit-8 method. Total RNA was extracted after different treatments and the NimbleGen Human 12×135K Gene Expression Array was applied to screen and analyze SIRTs expression. Quantitative real-time polymerase chain reaction and western blot were applied to verify the results of the gene expression microarrays. Reactive oxygen species (ROS) production was examined using flow cytometry analysis. Results Microarray analysis showed that the expressions of SIRT1, SIRT2, SIRT3, SIRT5, SIRT6, and SIRT7 showed the tendency to increase while SIRT4 showed the tendency to decrease. SIRT1, SIRT2, SIRT5, and SIRT7 gene expression could be upregulated by pretreatment with resveratrol compared with TNF-α alone while there were no obvious differences of SIRT3, SIRT4, and SIRT6 expressions observed in TNF-α alone treated cells and resveratrol-TNF-α co-treated cells. Interestingly, SIRT1, SIRT2, SIRT3, SIRT4, and SIRT5 siRNA could reverse the effect of resveratrol on ROS production; SIRT1 and SIRT5 siRNA could significantly increase CD40 expression inhibited by resveratrol in TNF-α treated cells. Conclusions Our results suggest that resveratrol inhibiting oxidative stress production is associated with SIRT1, SIRT2, SIRT3, SIRT4, and SIRT5 pathways; attenuating CD40 expression was only associated with SIRT1 and SIRT5 pathways in TNF-α-induced endothelial cells injury.
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Affiliation(s)
- Huizhen Yu
- Key Laboratory of Geriatrics, Provincial Clinical Medicine College of Fujian Medical University, Fujian Institute of Clinical Geriatrics, Fuzhou, Fujian, China (mainland).,Department of Medicine, Fujian Provincial Hospital South Branch, Fuzhou, Fujian, China (mainland)
| | - Wei Pan
- Key Laboratory of Geriatrics, Provincial Clinical Medicine College of Fujian Medical University, Fujian Institute of Clinical Geriatrics, Fuzhou, Fujian, China (mainland).,Department of Cardiology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China (mainland)
| | - Huashan Huang
- Key Laboratory of Geriatrics, Provincial Clinical Medicine College of Fujian Medical University, Fujian Institute of Clinical Geriatrics, Fuzhou, Fujian, China (mainland)
| | - Junming Chen
- Key Laboratory of Geriatrics, Provincial Clinical Medicine College of Fujian Medical University, Fujian Institute of Clinical Geriatrics, Fuzhou, Fujian, China (mainland)
| | - Baohua Sun
- Department of Medicine, Fujian Provincial Hospital South Branch, Fuzhou, Fujian, China (mainland)
| | - Linxin Yang
- Key Laboratory of Geriatrics, Provincial Clinical Medicine College of Fujian Medical University, Fujian Institute of Clinical Geriatrics, Fuzhou, Fujian, China (mainland)
| | - Pengli Zhu
- Key Laboratory of Geriatrics, Provincial Clinical Medicine College of Fujian Medical University, Fujian Institute of Clinical Geriatrics, Fuzhou, Fujian, China (mainland)
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Kanwal A. Functional and therapeutic potential of mitochondrial SIRT3 deacetylase in disease conditions. Expert Rev Clin Pharmacol 2018; 11:1151-1155. [DOI: 10.1080/17512433.2018.1546119] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Abhinav Kanwal
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal, India
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You W, Steegborn C. Structural Basis of Sirtuin 6 Inhibition by the Hydroxamate Trichostatin A: Implications for Protein Deacylase Drug Development. J Med Chem 2018; 61:10922-10928. [PMID: 30395713 DOI: 10.1021/acs.jmedchem.8b01455] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Protein lysine deacylases comprise three zinc-dependent families and the NAD+-dependent sirtuins Sirt1-7, which contribute to aging-related diseases. Few Sirt6-specific inhibitors are available. Trichostatin A, which belongs to the potent, zinc-chelating hydroxamate inhibitors of zinc-dependent deacylases, was recently found to potently and isoform-specifically inhibit Sirt6. We solved a crystal structure of a Sirt6/ADP-ribose/trichostatin A complex, which reveals nicotinamide pocket and acyl channel as binding site and provides interaction details supporting the development of improved deacylase inhibitors.
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Affiliation(s)
- Weijie You
- Department of Biochemistry , University of Bayreuth , Universitätsstraße 30 , 95445 Bayreuth , Germany
| | - Clemens Steegborn
- Department of Biochemistry , University of Bayreuth , Universitätsstraße 30 , 95445 Bayreuth , Germany
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Kumar S, Lombard DB. Functions of the sirtuin deacylase SIRT5 in normal physiology and pathobiology. Crit Rev Biochem Mol Biol 2018; 53:311-334. [PMID: 29637793 DOI: 10.1080/10409238.2018.1458071] [Citation(s) in RCA: 184] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Sirtuins are NAD+-dependent protein deacylases/ADP-ribosyltransferases that have emerged as candidate targets for new therapeutics to treat metabolic disorders and other diseases, including cancer. The sirtuin SIRT5 resides primarily in the mitochondrial matrix and catalyzes the removal of negatively charged lysine acyl modifications; succinyl, malonyl, and glutaryl groups. Evidence has now accumulated to document the roles of SIRT5 as a significant regulator of cellular homeostasis, in a context- and cell-type specific manner, as has been observed previously for other sirtuin family members. SIRT5 regulates protein substrates involved in glycolysis, the TCA cycle, fatty acid oxidation, electron transport chain, ketone body formation, nitrogenous waste management, and ROS detoxification, among other processes. SIRT5 plays pivotal roles in cardiac physiology and stress responses and is involved in the regulation of numerous aspects of myocardial energy metabolism. SIRT5 is implicated in neoplasia, as both a tumor promoter and suppressor in a context-specific manner, and may serve a protective function in the setting of neurodegenerative disorders. Here, we review the current understanding of functional impacts of SIRT5 on its metabolic targets, and its molecular functions in both normal and pathological conditions. Finally, we will discuss the potential utility of SIRT5 as a drug target and also summarize the current status, progress, and challenges in developing small molecule compounds to modulate SIRT5 activity with high potency and specificity.
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Affiliation(s)
- Surinder Kumar
- a Department of Pathology , University of Michigan , Ann Arbor , MI , USA
| | - David B Lombard
- a Department of Pathology , University of Michigan , Ann Arbor , MI , USA.,b Institute of Gerontology , University of Michigan , Ann Arbor , MI , USA
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Dai H, Sinclair DA, Ellis JL, Steegborn C. Sirtuin activators and inhibitors: Promises, achievements, and challenges. Pharmacol Ther 2018; 188:140-154. [PMID: 29577959 DOI: 10.1016/j.pharmthera.2018.03.004] [Citation(s) in RCA: 339] [Impact Index Per Article: 48.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The NAD+-dependent protein lysine deacylases of the Sirtuin family regulate various physiological functions, from energy metabolism to stress responses. The human Sirtuin isoforms, SIRT1-7, are considered attractive therapeutic targets for aging-related diseases, such as type 2 diabetes, inflammatory diseases and neurodegenerative disorders. We review the status of Sirtuin-targeted drug discovery and development. Potent and selective pharmacological Sirt1 activators and inhibitors are available, and initial clinical trials have been carried out. Several promising inhibitors and activators have also been described for other isoforms. Progress in understanding the mechanisms of Sirtuin modulation by such compounds provides a rational basis for further drug development.
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Affiliation(s)
- Han Dai
- GlaxoSmithKline, 1250S. Collegeville Road, Collegeville, PA 19426, USA
| | - David A Sinclair
- Department of Genetics, Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, Boston, MA 02115, USA
| | - James L Ellis
- GlaxoSmithKline, 1250S. Collegeville Road, Collegeville, PA 19426, USA
| | - Clemens Steegborn
- Department of Biochemistry and Research Center for Bio-Macromolecules, University of Bayreuth, 95440 Bayreuth, Germany.
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40
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Khoury N, Koronowski KB, Young JI, Perez-Pinzon MA. The NAD +-Dependent Family of Sirtuins in Cerebral Ischemia and Preconditioning. Antioxid Redox Signal 2018; 28:691-710. [PMID: 28683567 PMCID: PMC5824497 DOI: 10.1089/ars.2017.7258] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2017] [Accepted: 07/04/2017] [Indexed: 12/11/2022]
Abstract
SIGNIFICANCE Sirtuins are an evolutionarily conserved family of NAD+-dependent lysine deacylases and ADP ribosylases. Their requirement for NAD+ as a cosubstrate allows them to act as metabolic sensors that couple changes in the energy status of the cell to changes in cellular physiological processes. NAD+ levels are affected by several NAD+-producing and NAD+-consuming pathways as well as by cellular respiration. Thus their intracellular levels are highly dynamic and are misregulated in a spectrum of metabolic disorders including cerebral ischemia. This, in turn, compromises several NAD+-dependent processes that may ultimately lead to cell death. Recent Advances: A number of efforts have been made to replenish NAD+ in cerebral ischemic injuries as well as to understand the functions of one its important mediators, the sirtuin family of proteins through the use of pharmacological modulators or genetic manipulation approaches either before or after the insult. Critical Issues and Future Directions: The results of these studies have regarded the sirtuins as promising therapeutic targets for cerebral ischemia. Yet, additional efforts are needed to understand the role of some of the less characterized members and to address the sex-specific effects observed with some members. Sirtuins also exhibit cell-type-specific expression in the brain as well as distinct subcellular and regional localizations. As such, they are involved in diverse and sometimes opposing cellular processes that can either promote neuroprotection or further contribute to the injury; which also stresses the need for the development and use of sirtuin-specific pharmacological modulators. Antioxid. Redox Signal. 28, 691-710.
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Affiliation(s)
- Nathalie Khoury
- Department of Neurology; Cerebral Vascular Research Laboratories; and Neuroscience Program, Miller School of Medicine, University of Miami, Miami, Florida
| | - Kevin B. Koronowski
- Department of Neurology; Cerebral Vascular Research Laboratories; and Neuroscience Program, Miller School of Medicine, University of Miami, Miami, Florida
| | - Juan I. Young
- Dr. John T. Macdonald Foundation Department of Human Genetics; Hussman Institute for Human Genomics, and Neuroscience Program, Miller School of Medicine, University of Miami, Miami, Florida
| | - Miguel A. Perez-Pinzon
- Department of Neurology; Cerebral Vascular Research Laboratories; and Neuroscience Program, Miller School of Medicine, University of Miami, Miami, Florida
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Abstract
Sirtuins (SIRTs) are NAD(+)-dependent enzymes that catalyze deacylation of protein lysine residues. In mammals, seven sirtuins have been identified, SIRT1-7. SIRT3-5 are mainly or exclusively localized within mitochondria and mainly participate in the regulation of energy metabolic pathways. Since mitochondrial ATP regeneration is inevitably linked to the maintenance of cardiac pump function, it is not surprising that recent studies revealed a role for mitochondrial sirtuins in the regulation of myocardial energetics and function. In addition, mitochondrial sirtuins modulate the extent of myocardial ischemia reperfusion injury and the development of cardiac hypertrophy and failure. Thus, targeting mitochondrial sirtuins has been proposed as a novel approach to improve myocardial mitochondrial energetics, which is frequently impaired in cardiac disease and considered an important underlying cause contributing to several cardiac pathologies, including myocardial ischemia reperfusion injury and heart failure. In the current review, we present and discuss the available literature on mitochondrial sirtuins and their potential roles in cardiac physiology and disease.
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Affiliation(s)
- Heiko Bugger
- Department of Cardiology and Angiology I, Heart Center Freiburg University, Hugstetter Str. 55, 79106, Freiburg, Germany.
| | - Constantin N Witt
- Department of Cardiology and Angiology I, Heart Center Freiburg University, Hugstetter Str. 55, 79106, Freiburg, Germany
| | - Christoph Bode
- Department of Cardiology and Angiology I, Heart Center Freiburg University, Hugstetter Str. 55, 79106, Freiburg, Germany
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SIRT3: A New Regulator of Cardiovascular Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:7293861. [PMID: 29643974 PMCID: PMC5831850 DOI: 10.1155/2018/7293861] [Citation(s) in RCA: 121] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 12/20/2017] [Accepted: 01/04/2018] [Indexed: 01/13/2023]
Abstract
Cardiovascular diseases (CVDs) are the leading causes of death worldwide, and defects in mitochondrial function contribute largely to the occurrence of CVDs. Recent studies suggest that sirtuin 3 (SIRT3), the mitochondrial NAD+-dependent deacetylase, may regulate mitochondrial function and biosynthetic pathways such as glucose and fatty acid metabolism and the tricarboxylic acid (TCA) cycle, oxidative stress, and apoptosis by reversible protein lysine deacetylation. SIRT3 regulates glucose and lipid metabolism and maintains myocardial ATP levels, which protects the heart from metabolic disturbances. SIRT3 can also protect cardiomyocytes from oxidative stress-mediated cell damage and block the development of cardiac hypertrophy. Recent reports show that SIRT3 is involved in the protection of several heart diseases. This review discusses the progress in SIRT3-related research and the role of SIRT3 in the prevention and treatment of CVDs.
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Min Z, Gao J, Yu Y. The Roles of Mitochondrial SIRT4 in Cellular Metabolism. Front Endocrinol (Lausanne) 2018; 9:783. [PMID: 30666234 PMCID: PMC6330279 DOI: 10.3389/fendo.2018.00783] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2018] [Accepted: 12/12/2018] [Indexed: 12/14/2022] Open
Abstract
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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Affiliation(s)
- Zheying Min
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology and Key Laboratory of Assisted Reproduction, Ministry of Education, Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Peking University Third Hospital, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Jiangman Gao
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology and Key Laboratory of Assisted Reproduction, Ministry of Education, Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Peking University Third Hospital, Beijing, China
| | - Yang Yu
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology and Key Laboratory of Assisted Reproduction, Ministry of Education, Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Peking University Third Hospital, Beijing, China
- *Correspondence: Yang Yu
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Rajabi N, Galleano I, Madsen AS, Olsen CA. Targeting Sirtuins: Substrate Specificity and Inhibitor Design. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2018; 154:25-69. [PMID: 29413177 DOI: 10.1016/bs.pmbts.2017.11.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Lysine residues across the proteome are modified by posttranslational modifications (PTMs) that significantly enhance the structural and functional diversity of proteins. For lysine, the most abundant PTM is ɛ-N-acetyllysine (Kac), which plays numerous roles in regulation of important cellular functions, such as gene expression (epigenetic effects) and metabolism. A family of enzymes, namely histone deacetylases (HDACs), removes these PTMs. A subset of these enzymes, the sirtuins (SIRTs), represent class III HDAC and, unlike the rest of the family, these hydrolases are NAD+-dependent. Although initially described as deacetylases, alternative deacylase functions for sirtuins have been reported, which expands the potential cellular roles of this class of enzymes. Currently, sirtuins are investigated as therapeutic targets for the treatment of diseases that span from cancers to neurodegenerative disorders. In the present book chapter, we review and discuss the current literature on novel ɛ-N-acyllysine PTMs, targeted by sirtuins, as well as mechanism-based sirtuin inhibitors inspired by their substrates.
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Affiliation(s)
- Nima Rajabi
- Center for Biopharmaceuticals, University of Copenhagen, Copenhagen, Denmark
| | - Iacopo Galleano
- Center for Biopharmaceuticals, University of Copenhagen, Copenhagen, Denmark
| | - Andreas S Madsen
- Center for Biopharmaceuticals, University of Copenhagen, Copenhagen, Denmark
| | - Christian A Olsen
- Center for Biopharmaceuticals, University of Copenhagen, Copenhagen, Denmark.
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Rajabi N, Auth M, Troelsen KR, Pannek M, Bhatt DP, Fontenas M, Hirschey MD, Steegborn C, Madsen AS, Olsen CA. Mechanism-Based Inhibitors of the Human Sirtuin 5 Deacylase: Structure-Activity Relationship, Biostructural, and Kinetic Insight. Angew Chem Int Ed Engl 2017. [DOI: 10.1002/ange.201709050] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Nima Rajabi
- Center for Biopharmaceuticals & Department of Drug Design and Pharmacology; University of Copenhagen; Universitetsparken 2 2100 Copenhagen Denmark
| | - Marina Auth
- Center for Biopharmaceuticals & Department of Drug Design and Pharmacology; University of Copenhagen; Universitetsparken 2 2100 Copenhagen Denmark
| | - Kathrin R. Troelsen
- Center for Biopharmaceuticals & Department of Drug Design and Pharmacology; University of Copenhagen; Universitetsparken 2 2100 Copenhagen Denmark
| | - Martin Pannek
- Universität Bayreuth; Lehrstuhl Biochemie und Forschungszentrum für Biomakromoleküle; Universitätsstrasse 30 95447 Bayreuth Germany
| | - Dhaval P. Bhatt
- Duke University Medical Center; Sarah W. Stedman Nutrition and Metabolism Center; 4321 Medical Park Drive Durham NC 27704 USA
| | - Martin Fontenas
- Center for Biopharmaceuticals & Department of Drug Design and Pharmacology; University of Copenhagen; Universitetsparken 2 2100 Copenhagen Denmark
| | - Matthew D. Hirschey
- Duke University Medical Center; Sarah W. Stedman Nutrition and Metabolism Center; 4321 Medical Park Drive Durham NC 27704 USA
| | - Clemens Steegborn
- Universität Bayreuth; Lehrstuhl Biochemie und Forschungszentrum für Biomakromoleküle; Universitätsstrasse 30 95447 Bayreuth Germany
| | - Andreas S. Madsen
- Center for Biopharmaceuticals & Department of Drug Design and Pharmacology; University of Copenhagen; Universitetsparken 2 2100 Copenhagen Denmark
| | - Christian A. Olsen
- Center for Biopharmaceuticals & Department of Drug Design and Pharmacology; University of Copenhagen; Universitetsparken 2 2100 Copenhagen Denmark
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Rajabi N, Auth M, Troelsen KR, Pannek M, Bhatt DP, Fontenas M, Hirschey MD, Steegborn C, Madsen AS, Olsen CA. Mechanism-Based Inhibitors of the Human Sirtuin 5 Deacylase: Structure-Activity Relationship, Biostructural, and Kinetic Insight. Angew Chem Int Ed Engl 2017; 56:14836-14841. [PMID: 29044784 PMCID: PMC5814306 DOI: 10.1002/anie.201709050] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Indexed: 12/18/2022]
Abstract
The sirtuin enzymes are important regulatory deacylases in a variety of biochemical contexts and may therefore be potential therapeutic targets through either activation or inhibition by small molecules. Here, we describe the discovery of the most potent inhibitor of sirtuin 5 (SIRT5) reported to date. We provide rationalization of the mode of binding by solving co-crystal structures of selected inhibitors in complex with both human and zebrafish SIRT5, which provide insight for future optimization of inhibitors with more "drug-like" properties. Importantly, enzyme kinetic evaluation revealed a slow, tight-binding mechanism of inhibition, which is unprecedented for SIRT5. This is important information when applying inhibitors to probe mechanisms in biology.
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Affiliation(s)
- Nima Rajabi
- Center for Biopharmaceuticals & Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark
| | - Marina Auth
- Center for Biopharmaceuticals & Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark
| | - Kathrin R Troelsen
- Center for Biopharmaceuticals & Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark
| | - Martin Pannek
- Universität Bayreuth, Lehrstuhl Biochemie und Forschungszentrum für Biomakromoleküle, Universitätsstrasse 30, 95447, Bayreuth, Germany
| | - Dhaval P Bhatt
- Duke University Medical Center, Sarah W. Stedman Nutrition and Metabolism Center, 4321 Medical Park Drive, Durham, NC, 27704, USA
| | - Martin Fontenas
- Center for Biopharmaceuticals & Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark
| | - Matthew D Hirschey
- Duke University Medical Center, Sarah W. Stedman Nutrition and Metabolism Center, 4321 Medical Park Drive, Durham, NC, 27704, USA
| | - Clemens Steegborn
- Universität Bayreuth, Lehrstuhl Biochemie und Forschungszentrum für Biomakromoleküle, Universitätsstrasse 30, 95447, Bayreuth, Germany
| | - Andreas S Madsen
- Center for Biopharmaceuticals & Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark
| | - Christian A Olsen
- Center for Biopharmaceuticals & Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark
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Pannek M, Simic Z, Fuszard M, Meleshin M, Rotili D, Mai A, Schutkowski M, Steegborn C. Crystal structures of the mitochondrial deacylase Sirtuin 4 reveal isoform-specific acyl recognition and regulation features. Nat Commun 2017; 8:1513. [PMID: 29138502 PMCID: PMC5686155 DOI: 10.1038/s41467-017-01701-2] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 10/07/2017] [Indexed: 12/22/2022] Open
Abstract
Sirtuins are evolutionary conserved NAD+-dependent protein lysine deacylases. The seven human isoforms, Sirt1-7, regulate metabolism and stress responses and are considered therapeutic targets for aging-related diseases. Sirt4 locates to mitochondria and regulates fatty acid metabolism and apoptosis. In contrast to the mitochondrial deacetylase Sirt3 and desuccinylase Sirt5, no prominent deacylase activity and structural information are available for Sirt4. Here we describe acyl substrates and crystal structures for Sirt4. The enzyme shows isoform-specific acyl selectivity, with significant activity against hydroxymethylglutarylation. Crystal structures of Sirt4 from Xenopus tropicalis reveal a particular acyl binding site with an additional access channel, rationalizing its activities. The structures further identify a conserved, isoform-specific Sirt4 loop that folds into the active site to potentially regulate catalysis. Using these results, we further establish efficient Sirt4 activity assays, an unusual Sirt4 regulation by NADH, and Sirt4 effects of pharmacological modulators.
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Affiliation(s)
- Martin Pannek
- Department of Biochemistry, University of Bayreuth, 95440, Bayreuth, Germany
| | - Zeljko Simic
- Department of Enzymology, Institute of Biochemistry and Biotechnology, Martin-Luther-University Halle-Wittenberg, 06108, Halle, Germany
| | - Matthew Fuszard
- Department of Biochemistry, University of Bayreuth, 95440, Bayreuth, Germany
| | - Marat Meleshin
- Department of Enzymology, Institute of Biochemistry and Biotechnology, Martin-Luther-University Halle-Wittenberg, 06108, Halle, Germany
| | - Dante Rotili
- Department of Chemistry and Technologies of Drugs, Pasteur Institute Italy, Cenci-Bolognetti Foundation, Sapienza University of Rome, 00185, Rome, Italy
| | - Antonello Mai
- Department of Chemistry and Technologies of Drugs, Pasteur Institute Italy, Cenci-Bolognetti Foundation, Sapienza University of Rome, 00185, Rome, Italy
| | - Mike Schutkowski
- Department of Enzymology, Institute of Biochemistry and Biotechnology, Martin-Luther-University Halle-Wittenberg, 06108, Halle, Germany
| | - Clemens Steegborn
- Department of Biochemistry, University of Bayreuth, 95440, Bayreuth, Germany.
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Lu J, Zhang H, Chen X, Zou Y, Li J, Wang L, Wu M, Zang J, Yu Y, Zhuang W, Xia Q, Wang J. A small molecule activator of SIRT3 promotes deacetylation and activation of manganese superoxide dismutase. Free Radic Biol Med 2017; 112:287-297. [PMID: 28711502 DOI: 10.1016/j.freeradbiomed.2017.07.012] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2017] [Accepted: 07/10/2017] [Indexed: 01/04/2023]
Abstract
The modulation of protein acetylation network is a promising strategy for life span extension and disease treatment (Sabari et al., 2016; Giblin et al., 2014) [1,2]. A variety of small molecules have been developed to target deacetylases, but extremely few of these molecules are capable of activating the mitochondrial NAD-dependent deacetylase sirtuin-3 (SIRT3) (Gertz and Steegborn, 2016; Scholz et al., 2015) [3,4]. Manganese superoxide dismutase (MnSOD) is the major superoxide scavenger in mitochondria, whose activity is regulated by SIRT3-mediated deacetylation, particularly at the Lys68 site (Chen et al., 2011) [5]. To investigate the influence of Lys68 acetylation on MnSOD activity, we produced a mutant MnSOD protein-bearing N-acetyllysine (AcK) at its Lys68 position through the genetic code expansion approach. We solved the crystal structure of this acetylated MnSOD (MnSODK68AcK), thus revealing the structural and electrostatic basis for the significant activity decrease upon Lys68 acetylation. On the basis of an assay we developed for the SIRT3-mediated deacetylation of MnSODK68AcK, we identified a novel SIRT3 activator, 7-hydroxy-3-(4'-methoxyphenyl) coumarin (C12), which binds to SIRT3 with high affinity and can promote the deacetylation and activation of MnSOD. C12 adds to the current repertoire of extremely few SIRT3 activators, which are potentially valuable for treating a wide array of diseases via modulating the cellular acetylome.
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Affiliation(s)
- Jiaqi Lu
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Hua Zhang
- Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China; State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Inner Mongolia University, Huhhot, 010021,China
| | - Xian Chen
- Department of Physics, Jilin University, Changchun 130012, China
| | - Yong Zou
- Guangzhou Institute of Chemistry, Chinese Academy of Sciences, Tianhe District, Guangzhou 510650, China
| | - Jiasong Li
- Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China
| | - Li Wang
- Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China
| | - Minhao Wu
- School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Jianye Zang
- School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Yang Yu
- Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China
| | - Wei Zhuang
- Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China.
| | - Qing Xia
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
| | - Jiangyun Wang
- Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China.
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Tang BL. Could Sirtuin Activities Modify ALS Onset and Progression? Cell Mol Neurobiol 2017; 37:1147-1160. [PMID: 27942908 PMCID: PMC11482121 DOI: 10.1007/s10571-016-0452-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 11/30/2016] [Indexed: 12/11/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a complex etiology. Sirtuins have been implicated as disease-modifying factors in several neurological disorders, and in the past decade, attempts have been made to check if manipulating Sirtuin activities and levels could confer benefit in terms of neuroprotection and survival in ALS models. The efforts have largely focused on mutant SOD1, and while limited in scope, the results were largely positive. Here, the body of work linking Sirtuins with ALS is reviewed, with discussions on how Sirtuins and their activities may impact on the major etiological mechanisms of ALS. Moving forward, it is important that the potentially beneficial effect of Sirtuins in ALS disease onset and progression are assessed in ALS models with TDP-43, FUS, and C9orf72 mutations.
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Affiliation(s)
- Bor Luen Tang
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, MD7, 8 Medical Drive, Singapore, 117597, Singapore.
- NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, 28 Medical Drive, Singapore, 117456, Singapore.
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50
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Assiri MA, Roy SR, Harris PS, Ali H, Liang Y, Shearn CT, Orlicky DJ, Roede JR, Hirschey MD, Backos DS, Fritz KS. Chronic Ethanol Metabolism Inhibits Hepatic Mitochondrial Superoxide Dismutase via Lysine Acetylation. Alcohol Clin Exp Res 2017; 41:1705-1714. [PMID: 28804911 DOI: 10.1111/acer.13473] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 08/04/2017] [Indexed: 12/25/2022]
Abstract
BACKGROUND Chronic ethanol (EtOH) consumption is a major cause of liver disease worldwide. Oxidative stress is a known consequence of EtOH metabolism and is thought to contribute significantly to alcoholic liver disease (ALD). Therefore, elucidating pathways leading to sustained oxidative stress and downstream redox imbalances may reveal how EtOH consumption leads to ALD. Recent studies suggest that EtOH metabolism impacts mitochondrial antioxidant processes through a number of proteomic alterations, including hyperacetylation of key antioxidant proteins. METHODS To elucidate mechanisms of EtOH-induced hepatic oxidative stress, we investigate a role for protein hyperacetylation in modulating mitochondrial superoxide dismutase (SOD2) structure and function in a 6-week Lieber-DeCarli murine model of EtOH consumption. Our experimental approach includes immunoblotting immunohistochemistry (IHC), activity assays, mass spectrometry, and in silico modeling. RESULTS We found that EtOH metabolism significantly increased the acetylation of SOD2 at 2 functionally relevant lysine sites, K68 and K122, resulting in a 40% decrease in enzyme activity while overall SOD2 abundance was unchanged. In vitro studies also reveal which lysine residues are more susceptible to acetylation. IHC analysis demonstrates that SOD2 hyperacetylation occurs near zone 3 within the liver, which is the main EtOH-metabolizing region of the liver. CONCLUSIONS Overall, the findings presented in this study support a role for EtOH-induced lysine acetylation as an adverse posttranslational modification within the mitochondria that directly impacts SOD2 charge state and activity. Last, the data presented here indicate that protein hyperacetylation may be a major factor contributing to an imbalance in hepatic redox homeostasis due to chronic EtOH metabolism.
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Affiliation(s)
- Mohammed A Assiri
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Samantha R Roy
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Peter S Harris
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Hadi Ali
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Yongliang Liang
- Clinical Biomarkers Laboratory, Department of Medicine, Emory University, Atlanta, Georgia
| | - Colin T Shearn
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - David J Orlicky
- Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - James R Roede
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Matthew D Hirschey
- Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, North Carolina.,Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina
| | - Donald S Backos
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Kristofer S Fritz
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
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