Role of Nadгѕ in Regulating Cellular and Metabolic Signaling Pathways
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Nicotinamide Adenine Dinucleotide Is Transported Into Mammalian
RESEARCH ARTICLE Nicotinamide adenine dinucleotide is transported into mammalian mitochondria Antonio Davila1,2†, Ling Liu3†, Karthikeyani Chellappa1, Philip Redpath4, Eiko Nakamaru-Ogiso5, Lauren M Paolella1, Zhigang Zhang6, Marie E Migaud4,7, Joshua D Rabinowitz3, Joseph A Baur1* 1Department of Physiology, Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States; 2PARC, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States; 3Lewis-Sigler Institute for Integrative Genomics, Department of Chemistry, Princeton University, Princeton, United States; 4School of Pharmacy, Queen’s University Belfast, Belfast, United Kingdom; 5Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States; 6College of Veterinary Medicine, Northeast Agricultural University, Harbin, China; 7Mitchell Cancer Institute, University of South Alabama, Mobile, United States Abstract Mitochondrial NAD levels influence fuel selection, circadian rhythms, and cell survival under stress. It has alternately been argued that NAD in mammalian mitochondria arises from import of cytosolic nicotinamide (NAM), nicotinamide mononucleotide (NMN), or NAD itself. We provide evidence that murine and human mitochondria take up intact NAD. Isolated mitochondria preparations cannot make NAD from NAM, and while NAD is synthesized from NMN, it does not localize to the mitochondrial matrix or effectively support oxidative phosphorylation. Treating cells *For correspondence: with nicotinamide riboside that is isotopically labeled on the nicotinamide and ribose moieties [email protected] results in the appearance of doubly labeled NAD within mitochondria. Analogous experiments with †These authors contributed doubly labeled nicotinic acid riboside (labeling cytosolic NAD without labeling NMN) demonstrate equally to this work that NAD(H) is the imported species. -
Metabolism and Biochemical Properties of Nicotinamide
www.nature.com/scientificreports OPEN Metabolism and biochemical properties of nicotinamide adenine dinucleotide (NAD) analogs, Received: 11 December 2018 Accepted: 27 August 2019 nicotinamide guanine dinucleotide Published: xx xx xxxx (NGD) and nicotinamide hypoxanthine dinucleotide (NHD) Keisuke Yaku1, Keisuke Okabe1,2, Maryam Gulshan1, Kiyoshi Takatsu3,4, Hiroshi Okamoto5,6 & Takashi Nakagawa 1,7 Nicotinamide adenine dinucleotide (NAD) is an important coenzyme that regulates various metabolic pathways, including glycolysis, β-oxidation, and oxidative phosphorylation. Additionally, NAD serves as a substrate for poly(ADP-ribose) polymerase (PARP), sirtuin, and NAD glycohydrolase, and it regulates DNA repair, gene expression, energy metabolism, and stress responses. Many studies have demonstrated that NAD metabolism is deeply involved in aging and aging-related diseases. Previously, we demonstrated that nicotinamide guanine dinucleotide (NGD) and nicotinamide hypoxanthine dinucleotide (NHD), which are analogs of NAD, are signifcantly increased in Nmnat3- overexpressing mice. However, there is insufcient knowledge about NGD and NHD in vivo. In the present study, we aimed to investigate the metabolism and biochemical properties of these NAD analogs. We demonstrated that endogenous NGD and NHD were found in various murine tissues, and their synthesis and degradation partially rely on Nmnat3 and CD38. We have also shown that NGD and NHD serve as coenzymes for alcohol dehydrogenase (ADH) in vitro, although their afnity is much lower than that of NAD. On the other hand, NGD and NHD cannot be used as substrates for SIRT1, SIRT3, and PARP1. These results reveal the basic metabolism of NGD and NHD and also highlight their biological function as coenzymes. Nicotinamide adenine dinucleotide (NAD) is an essential cofactor that mediates various redox reactions through the transfer of electrons between NAD+ (oxidized form of NAD, hereafer referred to as NAD) and NADH (reduced form of NAD, hereafer referred to as NADH). -
Roles of Mitochondrial Respiratory Complexes During Infection Pedro Escoll, Lucien Platon, Carmen Buchrieser
Roles of Mitochondrial Respiratory Complexes during Infection Pedro Escoll, Lucien Platon, Carmen Buchrieser To cite this version: Pedro Escoll, Lucien Platon, Carmen Buchrieser. Roles of Mitochondrial Respiratory Complexes during Infection. Immunometabolism, Hapres, 2019, Immunometabolism and Inflammation, 1, pp.e190011. 10.20900/immunometab20190011. pasteur-02593579 HAL Id: pasteur-02593579 https://hal-pasteur.archives-ouvertes.fr/pasteur-02593579 Submitted on 15 May 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution| 4.0 International License ij.hapres.com Review Roles of Mitochondrial Respiratory Complexes during Infection Pedro Escoll 1,2,*, Lucien Platon 1,2,3, Carmen Buchrieser 1,2,* 1 Institut Pasteur, Unité de Biologie des Bactéries Intracellulaires, 75015 Paris, France 2 CNRS-UMR 3525, 75015 Paris, France 3 Faculté des Sciences, Université de Montpellier, 34095 Montpellier, France * Correspondence: Pedro Escoll, Email: [email protected]; Tel.: +33-0-1-44-38-9540; Carmen Buchrieser, Email: [email protected]; Tel.: +33-0-1-45-68-8372. ABSTRACT Beyond oxidative phosphorylation (OXPHOS), mitochondria have also immune functions against infection, such as the regulation of cytokine production, the generation of metabolites with antimicrobial proprieties and the regulation of inflammasome-dependent cell death, which seem in turn to be regulated by the metabolic status of the organelle. -
Gene Section Review
Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL INIST-CNRS Gene Section Review NDUFA13 (NADH:ubiquinone oxidoreductase subunit A13) Mafalda Pinto, Valdemar Máximo IPATIMUP Institute of Molecular Pathology and Immunology of the University of Porto, Portugal (MP, VM); I3S - Institute for Innovation and Helath Research, University of Porto, Portugal (MP, VM); Department of Pathology and Oncology, Medical Faculty of the University of Porto, Porto, Portugal (VM); [email protected]; [email protected] Published in Atlas Database: November 2015 Online updated version : http://AtlasGeneticsOncology.org/Genes/NDUFA13ID50482ch19p13.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/66061/11-2015-NDUFA13ID50482ch19p13.pdf DOI: 10.4267/2042/66061 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract Location: 19p13.11 (Chromosome 19: 19,626,545- 19,644,285 forward strand.) (Chidambaram et al., Short communication on NDUFA13, with data on 2000). DNA/RNA, on the protein encoded and where this Location (base pair) : Starts at 19515989 and ends gene is implicated. at 19528126 bp (according to COSMIC) Keywords Local order: Orientation: Forward Strand. Between NDUFA13; GRIM-19; mitochondria complex I; theGATAD2A and YJEFN3 genes. apoptosis. DNA/RNA Identity Note Other names: B16.6, CDA016, CGI-39, GRIM-19, NDUFA13 is a protein-coding gene, which encodes GRIM19, complex I B16.6 subunit a subunit of the mitochondrial respiratory chain HGNC (Hugo): NDUFA13 NADH dehydrogenase (Complex I). Atlas Genet Cytogenet Oncol Haematol. 2016; 20(8) 431 NDUFA13 (NADH:ubiquinone oxidoreductase subunit A13) Pinto M, Máximo V. -
Human CLPB) Is a Potent Mitochondrial Protein Disaggregase That Is Inactivated By
bioRxiv preprint doi: https://doi.org/10.1101/2020.01.17.911016; this version posted January 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Skd3 (human CLPB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations Ryan R. Cupo1,2 and James Shorter1,2* 1Department of Biochemistry and Biophysics, 2Pharmacology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, U.S.A. *Correspondence: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.01.17.911016; this version posted January 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. ABSTRACT Cells have evolved specialized protein disaggregases to reverse toxic protein aggregation and restore protein functionality. In nonmetazoan eukaryotes, the AAA+ disaggregase Hsp78 resolubilizes and reactivates proteins in mitochondria. Curiously, metazoa lack Hsp78. Hence, whether metazoan mitochondria reactivate aggregated proteins is unknown. Here, we establish that a mitochondrial AAA+ protein, Skd3 (human CLPB), couples ATP hydrolysis to protein disaggregation and reactivation. The Skd3 ankyrin-repeat domain combines with conserved AAA+ elements to enable stand-alone disaggregase activity. A mitochondrial inner-membrane protease, PARL, removes an autoinhibitory peptide from Skd3 to greatly enhance disaggregase activity. Indeed, PARL-activated Skd3 dissolves α-synuclein fibrils connected to Parkinson’s disease. Human cells lacking Skd3 exhibit reduced solubility of various mitochondrial proteins, including anti-apoptotic Hax1. -
Skd3 (Human CLPB) Is a Potent Mitochondrial Protein Disaggregase That Is Inactivated By
bioRxiv preprint first posted online Jan. 18, 2020; doi: http://dx.doi.org/10.1101/2020.01.17.911016. The copyright holder for this preprint (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Skd3 (human CLPB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations Ryan R. Cupo1,2 and James Shorter1,2* 1Department of Biochemistry and Biophysics, 2Pharmacology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, U.S.A. *Correspondence: [email protected] 1 bioRxiv preprint first posted online Jan. 18, 2020; doi: http://dx.doi.org/10.1101/2020.01.17.911016. The copyright holder for this preprint (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. ABSTRACT Cells have evolved specialized protein disaggregases to reverse toxic protein aggregation and restore protein functionality. In nonmetazoan eukaryotes, the AAA+ disaggregase Hsp78 resolubilizes and reactivates proteins in mitochondria. Curiously, metazoa lack Hsp78. Hence, whether metazoan mitochondria reactivate aggregated proteins is unknown. Here, we establish that a mitochondrial AAA+ protein, Skd3 (human CLPB), couples ATP hydrolysis to protein disaggregation and reactivation. The Skd3 ankyrin-repeat domain combines with conserved AAA+ elements to enable stand-alone disaggregase activity. A mitochondrial inner-membrane protease, PARL, removes an autoinhibitory peptide from Skd3 to greatly enhance disaggregase activity. Indeed, PARL-activated Skd3 dissolves α-synuclein fibrils connected to Parkinson’s disease. -
Coupling Mitochondrial Respiratory Chain to Cell Death: an Essential Role of Mitochondrial Complex I in the Interferon-B and Retinoic Acid-Induced Cancer Cell Death
Cell Death and Differentiation (2007) 14, 327–337 & 2007 Nature Publishing Group All rights reserved 1350-9047/07 $30.00 www.nature.com/cdd Coupling mitochondrial respiratory chain to cell death: an essential role of mitochondrial complex I in the interferon-b and retinoic acid-induced cancer cell death G Huang1, Y Chen1,HLu1 and X Cao*,1 Combination of retinoic acids (RAs) and interferons (IFNs) has synergistic apoptotic effects and is used in cancer treatment. However, the underlying mechanisms remain unknown. Here, we demonstrate that mitochondrial respiratory chain (MRC) plays an essential role in the IFN-b/RA-induced cancer cell death. We found that IFN-b/RA upregulates the expression of MRC complex subunits. Mitochondrial–nuclear translocation of these subunits was not observed, but overproduction of reactive oxygen species (ROS), which causes loss of mitochondrial function, was detected upon IFN-b/RA treatment. Knockdown of GRIM-19 (gene associated with retinoid-interferon-induced mortality-19) and NDUFS3 (NADH dehydrogenase (ubiquinone) Fe-S protein 3), two subunits of MRC complex I, by siRNA in two cancer cell lines conferred resistance to IFN-b/RA-induced apoptosis and reduced ROS production. In parallel, expression of late genes induced by IFN-b/RA that are directly involved in growth inhibition and cell death was also repressed in the knockdown cells. Our data suggest that the MRC regulates IFN-b/RA-induced cell death by modulating ROS production and late gene expression. Cell Death and Differentiation (2007) 14, 327–337. -
Nicotinamide Mononucleotide Preserves Mitochondrial Function and Increases Survival in Hemorrhagic Shock
RESEARCH ARTICLE Nicotinamide mononucleotide preserves mitochondrial function and increases survival in hemorrhagic shock Carrie A. Sims,1,2,3 Yuxia Guan,2 Sarmistha Mukherjee,1,4 Khushboo Singh,2 Paul Botolin,2 Antonio Davila Jr.,3 and Joseph A. Baur1,4 1Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 2The Trauma Center at Penn, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 3Penn Acute Research Collaboration (PARC) and 4Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Hemorrhagic shock depletes nicotinamide adenine dinucleotide (NAD) and causes metabolic derangements that, in severe cases, cannot be overcome, even after restoration of blood volume and pressure. However, current strategies to treat acute blood loss do not target cellular metabolism. We hypothesized that supplemental nicotinamide mononucleotide (NMN), the immediate biosynthetic precursor to NAD, would support cellular energetics and enhance physiologic resilience to hemorrhagic shock. In a rodent model of decompensated hemorrhagic shock, rats receiving NMN displayed significantly reduced lactic acidosis and serum IL-6 levels, two strong predictors of mortality in human patients. In both livers and kidneys, NMN increased NAD levels and prevented mitochondrial dysfunction. Moreover, NMN preserved mitochondrial function in isolated hepatocytes cocultured with proinflammatory cytokines, indicating a cell-autonomous protective effect that is independent from the reduction in circulating IL-6. In kidneys, but not in livers, NMN was sufficient to prevent ATP loss following shock and resuscitation. Overall, NMN increased the time animals could sustain severe shock before requiring resuscitation by nearly 25% and significantly improved survival after resuscitation (P = 0.018), whether NMN was given as a pretreatment or only as an adjunct during resuscitation. -
Nmnat3 Is Dispensable in Mitochondrial NAD Level Maintenance in Vivo
RESEARCH ARTICLE Nmnat3 Is Dispensable in Mitochondrial NAD Level Maintenance In Vivo Masashi Yamamoto1,2, Keisuke Hikosaka1, Arshad Mahmood1,3, Kazuyuki Tobe3, Hideo Shojaku4, Hidenori Inohara2, Takashi Nakagawa1* 1 Frontier Research Core for Life Sciences, University of Toyama, Toyama 930–0194, Japan, 2 Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Osaka 565–0871, Japan, 3 First Department of Internal Medicine, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama 930–0194, Japan, 4 Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama 930–0194, Japan * [email protected] Abstract Nicotinamide adenine dinucleotide (NAD) is an essential co-enzyme mediating various OPEN ACCESS enzymatic reactions. Mitochondrial NAD particularly occupies a considerable amount of total NAD in cells, and serves as a co-enzyme in tricarboxylic acid cycle (TCA cycle), β-oxi- Citation: Yamamoto M, Hikosaka K, Mahmood A, Tobe K, Shojaku H, Inohara H, et al. (2016) Nmnat3 dation, and oxidative phosphorylation. Despite the importance of mitochondrial NAD, its Is Dispensable in Mitochondrial NAD Level synthesis pathway remains unknown. It has been proposed that NAD synthesis enzyme, Maintenance In Vivo. PLoS ONE 11(1): e0147037. Nmnat3, was localized in mitochondria, but its physiological relevance to the metabolism in doi:10.1371/journal.pone.0147037 mitochondria was not fully elucidated. Previously, we have reported that murine Nmnat3 Editor: Junichi Sadoshima, Rutgers New Jersey protein was strongly expressed in the cytoplasm of mature erythrocytes, in which mitochon- Medical School, UNITED STATES dria were absent, and Nmnat3-deficient mice (Nmnat3-KO mice) exhibited splenomegaly Received: July 29, 2015 and hemolytic anemia due to reduced NAD levels in mature erythrocytes. -
STAT3 Localizes in Mitochondria-Associated ER Membranes Instead of in Mitochondria
bioRxiv preprint doi: https://doi.org/10.1101/2019.12.18.880567; this version posted December 22, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. STAT3 localizes in mitochondria-associated ER membranes instead of in mitochondria Yixun Su1,2, Xiaomin Huang1, Zhangsen Huang1, Taida Huang1, Yunsheng Xu1, Chenju Yi1* 1 The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China; 2 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119615, Singapore *To whom correspondence should be addressed: Prof. Chenju Yi, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China; [email protected]. Keywords: MAM, transcription factors, mitochondrial localization. ABSTRACT Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor (TF) that regulates a variety of biological processes, including a key role in mediating mitochondrial metabolism. It has been shown that STAT3 performs this function by translocating in minute amounts into mitochondria and interacting with mitochondrial proteins and genome. However, whether STAT3 localizes in mitochondria is still up for debate. To decipher the role of mitochondrial STAT3 requires a detailed understanding of its cellular localization. Using Percoll density gradient centrifugation, we surprisingly found that STAT3 is not located in the mitochondrial fraction, but instead, in the mitochondria-associated endoplasmic reticulum membrane (MAM) fraction. This was confirmed by sub-diffraction image analysis of labeled mitochondria in embryonic astrocytes. Also, we find that other TFs that have been previously found to localize in mitochondria are also found instead in the MAM fraction. -
NMNAT3 Improves Mitochondrial Function and Enhances Bmscs Anti-Oxidative Stress Through the NAD+-Sirt3 Pathway
NMNAT3 improves mitochondrial function and enhances BMSCs anti-oxidative stress through the NAD+-Sirt3 pathway Tao Wang ( [email protected] ) Guizhou Medical University https://orcid.org/0000-0002-4918-3915 Wuxun Peng Guizhou Medical University Fei Zhang Guizhou Medical University Lei Wang Guiyang Maternity and Child Health Hospital Jian Zhang Guizhou Medical University Wentao Dong Guizhou Medical University Chuan Ye Guizhou Medical University Xiaobin Tian Guizhou Medical University Yanlin Li Kunming Medical University First Alliated Hospital Yuekun Gong Kunming Medical University First Alliated Hospital Research Keywords: oxidative stress, nicotinamide adenine dinucleotide, nicotinamide mononucleotide adenylyl transferase 3, mitochondrial function, bone marrow mesenchymal stem cells Posted Date: March 13th, 2020 DOI: https://doi.org/10.21203/rs.3.rs-17046/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/26 Abstract Background To investigate the effects of NMNAT3 on mitochondrial function and anti-oxidative stress in rabbit BMSCs and its underlying mechanisms. Methods Stable strains of NMNAT3 overexpressing rabbit BMSCs were obtained by lentivirus transfection; the Oxidative stress model in rabbit BMSCs was imitated by treating with H 2 O 2 ; Observe the changes in mitochondrial ultrastructure and mitochondrial function-related indicators (mitochondrial membrane potential, ATP and mitochondrial protein PGC-1α, NRF1 synthesis), to study the effect of NMNAT3 on -
Mitochondrial H2O2 Generated from Electron Transport Chain Complex I Stimulates Muscle Differentiation
Cell Research (2011) 21:817-834. © 2011 IBCB, SIBS, CAS All rights reserved 1001-0602/11 $ 32.00 npg ORIGINAL ARTICLE www.nature.com/cr Mitochondrial H2O2 generated from electron transport chain complex I stimulates muscle differentiation Seonmin Lee1, Eunyoung Tak1, Jisun Lee1, MA Rashid1, Michael P Murphy2, Joohun Ha1, Sung Soo Kim1 1Department of Biochemistry and Molecular Biology, Medical Science and Engineering Research Center for Bioreaction to Reac- tive Oxygen Species and Biomedical Science Institute (BK-21), School of Medicine, Kyung Hee University, #1, Hoegi-dong, Dong- daemoon-gu, Seoul 130-701, Korea; 2MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK Mitochondrial reactive oxygen species (mROS) have been considered detrimental to cells. However, their physi- ological roles as signaling mediators have not been thoroughly explored. Here, we investigated whether mROS gener- ated from mitochondrial electron transport chain (mETC) complex I stimulated muscle differentiation. Our results showed that the quantity of mROS was increased and that manganese superoxide dismutase (MnSOD) was induced via NF-κB activation during muscle differentiation. Mitochondria-targeted antioxidants (MitoQ and MitoTEMPOL) and mitochondria-targeted catalase decreased mROS quantity and suppressed muscle differentiation without af- fecting the amount of ATP. Mitochondrial alterations, including the induction of mitochondrial transcription factor A and an increase in the number and size of mitochondria, and functional activations were observed during muscle differentiation. In particular, increased expression levels of mETC complex I subunits and a higher activity of com- plex I than other complexes were observed. Rotenone, an inhibitor of mETC complex I, decreased the mitochondrial NADH/NAD+ ratio and mROS levels during muscle differentiation.