Reversal of mitochondrial transhydrogenase causes oxidative stress in heart failure

Alexander G. Nickel; Albrecht Von Hardenberg; Mathias Hohl; Joachim R. Löffler; Michael Kohlhaas; Janne Becker; Jan Christian Reil; Andrey Kazakov; Julia Bonnekoh; Moritz Stadelmaier; Sarah Lena Puhl; Michael Wagner; Ivan Bogeski; Sonia Cortassa; Reinhard Kappl; Bastian Pasieka; Michael Lafontaine; C. Roy D. Lancaster; Thomas S. Blacker; Andrew R. Hall; Michael R. Duchen; Lars Kästner; Peter Lipp; Tanja Zeller; Christian Müller; Andreas Knopp; Ulrich Laufs; Michael Böhm; Markus Hoth; Christoph Maack

doi:10.1016/j.cmet.2015.07.008

Reversal of mitochondrial transhydrogenase causes oxidative stress in heart failure

Alexander G. Nickel, Albrecht Von Hardenberg, Mathias Hohl, Joachim R. Löffler, Michael Kohlhaas, Janne Becker, Jan Christian Reil, Andrey Kazakov, Julia Bonnekoh, Moritz Stadelmaier, Sarah Lena Puhl, Michael Wagner, Ivan Bogeski, Sonia Cortassa, Reinhard Kappl, Bastian Pasieka, Michael Lafontaine, C. Roy D. Lancaster, Thomas S. Blacker, Andrew R. HallMichael R. Duchen, Lars Kästner, Peter Lipp, Tanja Zeller, Christian Müller, Andreas Knopp, Ulrich Laufs, Michael Böhm, Markus Hoth, Christoph Maack

School of Medicine

Research output: Contribution to journal › Article › peer-review

162 Scopus citations

Abstract

Mitochondrial reactive oxygen species (ROS) play a central role in most aging-related diseases. ROS are produced at the respiratory chain that demands NADH for electron transport and are eliminated by enzymes that require NADPH. The nicotinamide nucleotide transhydrogenase (Nnt) is considered a key antioxidative enzyme based on its ability to regenerate NADPH from NADH. Here, we show that pathological metabolic demand reverses the direction of the Nnt, consuming NADPH to support NADH and ATP production, but at the cost of NADPH-linked antioxidative capacity. In heart, reverse-mode Nnt is the dominant source for ROS during pressure overload. Due to a mutation of the Nnt gene, the inbred mouse strain C57BL/6J is protected from oxidative stress, heart failure, and death, making its use in cardiovascular research problematic. Targeting Nnt-mediated ROS with the tetrapeptide SS-31 rescued mortality in pressure overload-induced heart failure and could therefore have therapeutic potential in patients with this syndrome.

Original language	English (US)
Pages (from-to)	472-484
Number of pages	13
Journal	Cell Metabolism
Volume	22
Issue number	3
DOIs	https://doi.org/10.1016/j.cmet.2015.07.008
State	Published - Sep 1 2015

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

Access to Document

10.1016/j.cmet.2015.07.008

Cite this

Nickel, A. G., Von Hardenberg, A., Hohl, M., Löffler, J. R., Kohlhaas, M., Becker, J., Reil, J. C., Kazakov, A., Bonnekoh, J., Stadelmaier, M., Puhl, S. L., Wagner, M., Bogeski, I., Cortassa, S., Kappl, R., Pasieka, B., Lafontaine, M., Lancaster, C. R. D., Blacker, T. S., ... Maack, C. (2015). Reversal of mitochondrial transhydrogenase causes oxidative stress in heart failure. Cell Metabolism, 22(3), 472-484. https://doi.org/10.1016/j.cmet.2015.07.008

Nickel, AG, Von Hardenberg, A, Hohl, M, Löffler, JR, Kohlhaas, M, Becker, J, Reil, JC, Kazakov, A, Bonnekoh, J, Stadelmaier, M, Puhl, SL, Wagner, M, Bogeski, I, Cortassa, S, Kappl, R, Pasieka, B, Lafontaine, M, Lancaster, CRD, Blacker, TS, Hall, AR, Duchen, MR, Kästner, L, Lipp, P, Zeller, T, Müller, C, Knopp, A, Laufs, U, Böhm, M, Hoth, M & Maack, C 2015, 'Reversal of mitochondrial transhydrogenase causes oxidative stress in heart failure', Cell Metabolism, vol. 22, no. 3, pp. 472-484. https://doi.org/10.1016/j.cmet.2015.07.008

@article{6b505956f51847b3ba1921e549a10947,

title = "Reversal of mitochondrial transhydrogenase causes oxidative stress in heart failure",

abstract = "Mitochondrial reactive oxygen species (ROS) play a central role in most aging-related diseases. ROS are produced at the respiratory chain that demands NADH for electron transport and are eliminated by enzymes that require NADPH. The nicotinamide nucleotide transhydrogenase (Nnt) is considered a key antioxidative enzyme based on its ability to regenerate NADPH from NADH. Here, we show that pathological metabolic demand reverses the direction of the Nnt, consuming NADPH to support NADH and ATP production, but at the cost of NADPH-linked antioxidative capacity. In heart, reverse-mode Nnt is the dominant source for ROS during pressure overload. Due to a mutation of the Nnt gene, the inbred mouse strain C57BL/6J is protected from oxidative stress, heart failure, and death, making its use in cardiovascular research problematic. Targeting Nnt-mediated ROS with the tetrapeptide SS-31 rescued mortality in pressure overload-induced heart failure and could therefore have therapeutic potential in patients with this syndrome.",

author = "Nickel, {Alexander G.} and {Von Hardenberg}, Albrecht and Mathias Hohl and L{\"o}ffler, {Joachim R.} and Michael Kohlhaas and Janne Becker and Reil, {Jan Christian} and Andrey Kazakov and Julia Bonnekoh and Moritz Stadelmaier and Puhl, {Sarah Lena} and Michael Wagner and Ivan Bogeski and Sonia Cortassa and Reinhard Kappl and Bastian Pasieka and Michael Lafontaine and Lancaster, {C. Roy D.} and Blacker, {Thomas S.} and Hall, {Andrew R.} and Duchen, {Michael R.} and Lars K{\"a}stner and Peter Lipp and Tanja Zeller and Christian M{\"u}ller and Andreas Knopp and Ulrich Laufs and Michael B{\"o}hm and Markus Hoth and Christoph Maack",

note = "Funding Information: The study was supported by the Deutsche Forschungsgemeinschaft (Emmy Noether- and Heisenberg Programm to C. Maack; SFB 894 to M. Hoth and C. Maack; KFO 196 to C. Maack, U.L, A.K., M.B.; and SFB 1027 to M. Hoth (project A2) and I.B. (project C4); BO3643/3-1 to I.B.), the Deutsche Gesellschaft f{\"u}r Kardiologie (Otto Hess Stipendium to M.S.) and the Staatskanzlei Saarland (LFFP 11/02 and 15/04) (to C.R.D.L.). U.L. and C. Maack are supported by the Corona foundation. We thank Michelle Gulentz, Lisa Lang, Jeanette Zimolong, and Nina Schnellbach for technical assistance and Ting-Ting Huang (Stanford University, CA) for providing the antibody against Nnt. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = sep,

day = "1",

doi = "10.1016/j.cmet.2015.07.008",

language = "English (US)",

volume = "22",

pages = "472--484",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Cell Press",

number = "3",

}

TY - JOUR

T1 - Reversal of mitochondrial transhydrogenase causes oxidative stress in heart failure

AU - Nickel, Alexander G.

AU - Von Hardenberg, Albrecht

AU - Hohl, Mathias

AU - Löffler, Joachim R.

AU - Kohlhaas, Michael

AU - Becker, Janne

AU - Reil, Jan Christian

AU - Kazakov, Andrey

AU - Bonnekoh, Julia

AU - Stadelmaier, Moritz

AU - Puhl, Sarah Lena

AU - Wagner, Michael

AU - Bogeski, Ivan

AU - Cortassa, Sonia

AU - Kappl, Reinhard

AU - Pasieka, Bastian

AU - Lafontaine, Michael

AU - Lancaster, C. Roy D.

AU - Blacker, Thomas S.

AU - Hall, Andrew R.

AU - Duchen, Michael R.

AU - Kästner, Lars

AU - Lipp, Peter

AU - Zeller, Tanja

AU - Müller, Christian

AU - Knopp, Andreas

AU - Laufs, Ulrich

AU - Böhm, Michael

AU - Hoth, Markus

AU - Maack, Christoph

N1 - Funding Information: The study was supported by the Deutsche Forschungsgemeinschaft (Emmy Noether- and Heisenberg Programm to C. Maack; SFB 894 to M. Hoth and C. Maack; KFO 196 to C. Maack, U.L, A.K., M.B.; and SFB 1027 to M. Hoth (project A2) and I.B. (project C4); BO3643/3-1 to I.B.), the Deutsche Gesellschaft für Kardiologie (Otto Hess Stipendium to M.S.) and the Staatskanzlei Saarland (LFFP 11/02 and 15/04) (to C.R.D.L.). U.L. and C. Maack are supported by the Corona foundation. We thank Michelle Gulentz, Lisa Lang, Jeanette Zimolong, and Nina Schnellbach for technical assistance and Ting-Ting Huang (Stanford University, CA) for providing the antibody against Nnt. Publisher Copyright: © 2015 Elsevier Inc.

PY - 2015/9/1

Y1 - 2015/9/1

N2 - Mitochondrial reactive oxygen species (ROS) play a central role in most aging-related diseases. ROS are produced at the respiratory chain that demands NADH for electron transport and are eliminated by enzymes that require NADPH. The nicotinamide nucleotide transhydrogenase (Nnt) is considered a key antioxidative enzyme based on its ability to regenerate NADPH from NADH. Here, we show that pathological metabolic demand reverses the direction of the Nnt, consuming NADPH to support NADH and ATP production, but at the cost of NADPH-linked antioxidative capacity. In heart, reverse-mode Nnt is the dominant source for ROS during pressure overload. Due to a mutation of the Nnt gene, the inbred mouse strain C57BL/6J is protected from oxidative stress, heart failure, and death, making its use in cardiovascular research problematic. Targeting Nnt-mediated ROS with the tetrapeptide SS-31 rescued mortality in pressure overload-induced heart failure and could therefore have therapeutic potential in patients with this syndrome.

AB - Mitochondrial reactive oxygen species (ROS) play a central role in most aging-related diseases. ROS are produced at the respiratory chain that demands NADH for electron transport and are eliminated by enzymes that require NADPH. The nicotinamide nucleotide transhydrogenase (Nnt) is considered a key antioxidative enzyme based on its ability to regenerate NADPH from NADH. Here, we show that pathological metabolic demand reverses the direction of the Nnt, consuming NADPH to support NADH and ATP production, but at the cost of NADPH-linked antioxidative capacity. In heart, reverse-mode Nnt is the dominant source for ROS during pressure overload. Due to a mutation of the Nnt gene, the inbred mouse strain C57BL/6J is protected from oxidative stress, heart failure, and death, making its use in cardiovascular research problematic. Targeting Nnt-mediated ROS with the tetrapeptide SS-31 rescued mortality in pressure overload-induced heart failure and could therefore have therapeutic potential in patients with this syndrome.

UR - http://www.scopus.com/inward/record.url?scp=84940646298&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84940646298&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2015.07.008

DO - 10.1016/j.cmet.2015.07.008

M3 - Article

C2 - 26256392

AN - SCOPUS:84940646298

SN - 1550-4131

VL - 22

SP - 472

EP - 484

JO - Cell Metabolism

JF - Cell Metabolism

IS - 3

ER -

Reversal of mitochondrial transhydrogenase causes oxidative stress in heart failure

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this