Markus Michael Bachschmid, PhD

Assistant Professor, Medicine

Markus Bachschmid
617.358.7811
650 Albany St Evans Biomed Research Ctr

Biography

Redox regulation of metabolism by Sirtuin-1 and glutaredoxin-1 in the cardiovascular system and liver.

What is redox signaling?
The cellular redox status and oxidants play an important role in regulating cell physiology and signaling through oxidative protein modifications. Reactive cysteines (thiolates) in proteins can react with oxidants and abundant intracellular glutathione to form glutathione adducts. Glutaredoxins, also known as thioltransferases, remove protein glutathione adducts and restore the reactive state of cysteines. This sequence is part of a redox regulatory cycle, which modulates activities of many important proteins including transcription factors, central metabolic regulators, and signal transduction cascades. Oxidative stress in disease, however, interrupts this cycle and causes irreversible oxidation and inactivation of regulatory protein cysteines.

Clinical significance of redox signaling
Cellular redox homeostasis is perturbed in numerous diseases, dysregulating cellular signaling pathways and metabolic redox processes. Consequently, oxidative protein modifications increase and can serve as specific disease biomarkers. Better understandings of redox signaling and novel strategies for intervention are needed.
Current research in the Bachschmid lab focuses on specific redox signaling cascades and novel strategies I) to analyze protein oxidation, II) to prevent protein oxidation, III) to create oxidation resistant mutant proteins, and IV) to specifically inhibit proteins rendered dysfunctional by oxidants.

Genetic mouse model of redox signaling
The Bachschmid lab works with glutaredoxin-1 knockout mice, which exhibit increased protein glutathione adducts and develop obesity, dyslipidemia, fatty liver, and metabolic cardiovascular disease. We discovered three cysteine residues of sirtuin-1 modified with glutathione adducts, which inactivate this enzyme in glutaredoxin-1 knockout mice. Sirtuin-1 is a NAD-dependent protein deacetylase and central regulator of metabolism. Several metabolic diseases including non-alcoholic fatty liver and metabolic cardiovascular disease are associated with inactivation or decreased Sirtuin-1 expression. Glutaredoxin-1 regulates sirtuin-1 activity through removing glutathione adducts and restores sirtuin-1 activity under oxidative stress. The Bachschmid lab created non-oxidizable mutant sirtuin-1, which retains full activity under oxidative stress. Using gene therapeutic approaches (adeno-associated and adenovirus mediated), over-expression of glutaredoxin-1 or our mutant sirtuin-1 normalized hepatic lipid metabolism and improved plasma dyslipidemia in glutaredoxin-1 knockout mice. We are currently identifying new target proteins of glutaredoxin-1 using omics platforms and systems biology. The lab also screens for small molecules to modify reactive cysteines and prevent protein inactivation by glutathione adducts.

Biochemistry, Pharmacology and Toxicology.

Other Positions

  • Boston Medical Center

Education

  • Universität Konstanz, PhD
  • Universität Konstanz, MS
  • Universität Konstanz, BS

Publications

  • Published on 8/1/2018

    Taylor E, Huang N, Bodde J, Ellison A, Killiany R, Bachschmid MM, Hamilton J. MRI of atherosclerosis and fatty liver disease in cholesterol fed rabbits. J Transl Med. 2018 Aug 01; 16(1):215. PMID: 30068362.

    Read at: PubMed
  • Published on 7/9/2018

    Anathy V, Lahue KG, Chapman DG, Chia SB, Casey DT, Aboushousha R, van der Velden JLJ, Elko E, Hoffman SM, McMillan DH, Jones JT, Nolin JD, Abdalla S, Schneider R, Seward DJ, Roberson EC, Liptak MD, Cousins ME, Butnor KJ, Taatjes DJ, Budd RC, Irvin CG, Ho YS, Hakem R, Brown KK, Matsui R, Bachschmid MM, Gomez JL, Kaminski N, van der Vliet A, Janssen-Heininger YMW. Reducing protein oxidation reverses lung fibrosis. Nat Med. 2018 Aug; 24(8):1128-1135. PMID: 29988126.

    Read at: PubMed
  • Published on 2/1/2018

    Luptak I, Sverdlov AL, Panagia M, Qin F, Pimentel DR, Croteau D, Siwik DA, Ingwall JS, Bachschmid MM, Balschi JA, Colucci WS. Decreased ATP production and myocardial contractile reserve in metabolic heart disease. J Mol Cell Cardiol. 2018 Mar; 116:106-114. PMID: 29409987.

    Read at: PubMed
  • Published on 1/1/2018

    Yoon S, Beermann ML, Yu B, Shao D, Bachschmid M, Miller JB. Aberrant Caspase Activation in Laminin-a2-Deficient Human Myogenic Cells is Mediated by p53 and Sirtuin Activity. J Neuromuscul Dis. 2018; 5(1):59-73. PMID: 29278895.

    Read at: PubMed
  • Published on 10/26/2017

    Egea J, Fabregat I, Frapart YM, Ghezzi P, Görlach A, Kietzmann T, Kubaichuk K, Knaus UG, Lopez MG, Olaso-Gonzalez G, Petry A, Schulz R, Vina J, Winyard P, Abbas K, Ademowo OS, Afonso CB, Andreadou I, Antelmann H, Antunes F, Aslan M, Bachschmid MM, Barbosa RM, Belousov V, Berndt C, Bernlohr D, Bertrán E, Bindoli A, Bottari SP, Brito PM, Carrara G, Casas AI, Chatzi A, Chondrogianni N, Conrad M, Cooke MS, Costa JG, Cuadrado A, My-Chan Dang P, De Smet B, Debelec-Butuner B, Dias IHK, Dunn JD, Edson AJ, El Assar M, El-Benna J, Ferdinandy P, Fernandes AS, Fladmark KE, Förstermann U, Giniatullin R, Giricz Z, Görbe A, Griffiths H, Hampl V, Hanf A, Herget J, Hernansanz-Agustín P, Hillion M, Huang J, Ilikay S, Jansen-Dürr P, Jaquet V, Joles JA, Kalyanaraman B, Kaminskyy D, Karbaschi M, Kleanthous M, Klotz LO, Korac B, Korkmaz KS, Koziel R, Kracun D, Krause KH, Kren V, Krieg T, Laranjinha J, Lazou A, Li H, Martínez-Ruiz A, Matsui R, McBean GJ, Meredith SP, Messens J, Miguel V, Mikhed Y, Milisav I, Milkovic L, Miranda-Vizuete A, Mojovic M, Monsalve M, Mouthuy PA, Mulvey J, Münzel T, Muzykantov V, Nguyen ITN, Oelze M, Oliveira NG, Palmeira CM, Papaevgeniou N, Pavicevic A, Pedre B, Peyrot F, Phylactides M, Pircalabioru GG, Pitt AR, Poulsen HE, Prieto I, Rigobello MP, Robledinos-Antón N, Rodríguez-Mañas L, Rolo AP, Rousset F, Ruskovska T, Saraiva N, Sasson S, Schröder K, Semen K, Seredenina T, Shakirzyanova A, Smith GL, Soldati T, Sousa BC, Spickett CM, Stancic A, Stasia MJ, Steinbrenner H, Stepanic V, Steven S, Tokatlidis K, Tuncay E, Turan B, Ursini F, Vacek J, Vajnerova O, Valentová K, Van Breusegem F, Varisli L, Veal EA, Yalçin AS, Yelisyeyeva O, Žarkovic N, Zatloukalová M, Zielonka J, Touyz RM, Papapetropoulos A, Grune T, Lamas S, Schmidt HHHW, Di Lisa F, Daiber A. Corrigendum to "European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS)" [Redox Biol. 13 (2017) 94-162]. Redox Biol. 2018 04; 14:694-696. PMID: 29107648.

    Read at: PubMed
  • Published on 5/18/2017

    Egea J, Fabregat I, Frapart YM, Ghezzi P, Görlach A, Kietzmann T, Kubaichuk K, Knaus UG, Lopez MG, Olaso-Gonzalez G, Petry A, Schulz R, Vina J, Winyard P, Abbas K, Ademowo OS, Afonso CB, Andreadou I, Antelmann H, Antunes F, Aslan M, Bachschmid MM, Barbosa RM, Belousov V, Berndt C, Bernlohr D, Bertrán E, Bindoli A, Bottari SP, Brito PM, Carrara G, Casas AI, Chatzi A, Chondrogianni N, Conrad M, Cooke MS, Costa JG, Cuadrado A, My-Chan Dang P, De Smet B, Debelec-Butuner B, Dias IHK, Dunn JD, Edson AJ, El Assar M, El-Benna J, Ferdinandy P, Fernandes AS, Fladmark KE, Förstermann U, Giniatullin R, Giricz Z, Görbe A, Griffiths H, Hampl V, Hanf A, Herget J, Hernansanz-Agustín P, Hillion M, Huang J, Ilikay S, Jansen-Dürr P, Jaquet V, Joles JA, Kalyanaraman B, Kaminskyy D, Karbaschi M, Kleanthous M, Klotz LO, Korac B, Korkmaz KS, Koziel R, Kracun D, Krause KH, Kren V, Krieg T, Laranjinha J, Lazou A, Li H, Martínez-Ruiz A, Matsui R, McBean GJ, Meredith SP, Messens J, Miguel V, Mikhed Y, Milisav I, Milkovic L, Miranda-Vizuete A, Mojovic M, Monsalve M, Mouthuy PA, Mulvey J, Münzel T, Muzykantov V, Nguyen ITN, Oelze M, Oliveira NG, Palmeira CM, Papaevgeniou N, Pavicevic A, Pedre B, Peyrot F, Phylactides M, Pircalabioru GG, Pitt AR, Poulsen HE, Prieto I, Rigobello MP, Robledinos-Antón N, Rodríguez-Mañas L, Rolo AP, Rousset F, Ruskovska T, Saraiva N, Sasson S, Schröder K, Semen K, Seredenina T, Shakirzyanova A, Smith GL, Soldati T, Sousa BC, Spickett CM, Stancic A, Stasia MJ, Steinbrenner H, Stepanic V, Steven S, Tokatlidis K, Tuncay E, Turan B, Ursini F, Vacek J, Vajnerova O, Valentová K, Van Breusegem F, Varisli L, Veal EA, Yalçin AS, Yelisyeyeva O, Žarkovic N, Zatloukalová M, Zielonka J, Touyz RM, Papapetropoulos A, Grune T, Lamas S, Schmidt HHHW, Di Lisa F, Daiber A. European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS). Redox Biol. 2017 10; 13:94-162. PMID: 28577489.

    Read at: PubMed
  • Published on 2/16/2017

    Shao D, Han J, Hou X, Fry J, Behring JB, Seta F, Long MT, Roy HK, Cohen RA, Matsui R, Bachschmid MM. Glutaredoxin-1 Deficiency Causes Fatty Liver and Dyslipidemia by Inhibiting Sirtuin-1. Antioxid Redox Signal. 2017 Aug 20; 27(6):313-327. PMID: 27958883.

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  • Published on 2/13/2017

    Vikram A, Lewarchik CM, Yoon JY, Naqvi A, Kumar S, Morgan GM, Jacobs JS, Li Q, Kim YR, Kassan M, Liu J, Gabani M, Kumar A, Mehdi H, Zhu X, Guan X, Kutschke W, Zhang X, Boudreau RL, Dai S, Matasic DS, Jung SB, Margulies KB, Kumar V, Bachschmid MM, London B, Irani K. Sirtuin 1 regulates cardiac electrical activity by deacetylating the cardiac sodium channel. Nat Med. 2017 Mar; 23(3):361-367. PMID: 28191886.

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  • Published on 1/30/2017

    Kumar S, Kim YR, Vikram A, Naqvi A, Li Q, Kassan M, Kumar V, Bachschmid MM, Jacobs JS, Kumar A, Irani K. Sirtuin1-regulated lysine acetylation of p66Shc governs diabetes-induced vascular oxidative stress and endothelial dysfunction. Proc Natl Acad Sci U S A. 2017 02 14; 114(7):1714-1719. PMID: 28137876.

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  • Published on 9/11/2016

    Han J, Weisbrod RM, Shao D, Watanabe Y, Yin X, Bachschmid MM, Seta F, Janssen-Heininger YMW, Matsui R, Zang M, Hamburg NM, Cohen RA. The redox mechanism for vascular barrier dysfunction associated with metabolic disorders: Glutathionylation of Rac1 in endothelial cells. Redox Biol. 2016 Oct; 9:306-319. PMID: 27693992.

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