Markus Michael Bachschmid, PhD

Assistant Professor, Medicine

Markus Bachschmid
617.638.2797
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 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 Apr; 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 Oct; 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.

    Read at: PubMed
  • 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.

    Read at: PubMed
  • 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.

    Read at: PubMed
  • 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.

    Read at: PubMed
  • Published on 7/18/2016

    Fry JL, Al Sayah L, Weisbrod RM, Van Roy I, Weng X, Cohen RA, Bachschmid MM, Seta F. Vascular Smooth Muscle Sirtuin-1 Protects Against Diet-Induced Aortic Stiffness. Hypertension. 2016 Sep; 68(3):775-84. PMID: 27432859.

    Read at: PubMed
  • Published on 6/27/2016

    Gorelenkova Miller O, Behring JB, Siedlak SL, Jiang S, Matsui R, Bachschmid MM, Zhu X, Mieyal JJ. Upregulation of Glutaredoxin-1 Activates Microglia and Promotes Neurodegeneration: Implications for Parkinson's Disease. Antioxid Redox Signal. 2016 Dec 20; 25(18):967-982. PMID: 27224303.

    Read at: PubMed

View 71 more publications: View full profile at BUMC

View all profiles