Reversal of Mitochondrial Transhydrogenase Causes Oxidative Stress in Heart Failure
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Reversal of Mitochondrial Transhydrogenase Causes Oxidative Stress in Heart Failure. / Nickel, Alexander G; von Hardenberg, Albrecht; Hohl, Mathias; Löffler, Joachim R; Kohlhaas, Michael; Becker, Janne; Reil, Jan-Christian; Kazakov, Andrey; Bonnekoh, Julia; Stadelmaier, Moritz; Puhl, Sarah-Lena; Wagner, Michael; Bogeski, Ivan; Cortassa, Sonia; Kappl, Reinhard; Pasieka, Bastian; Lafontaine, Michael; Lancaster, C Roy D; Blacker, Thomas S; Hall, Andrew R; Duchen, Michael R; Kästner, Lars; Lipp, Peter; Zeller, Tanja; Müller, Christian; Knopp, Andreas; Laufs, Ulrich; Böhm, Michael; Hoth, Markus; Maack, Christoph.
In: CELL METAB, Vol. 22, No. 3, 01.09.2015, p. 472-484.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 - Copyright © 2015 Elsevier Inc. All rights reserved.
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.
KW - Adenosine Triphosphate/metabolism
KW - Animals
KW - Cells, Cultured
KW - Glutathione/metabolism
KW - Heart Failure/metabolism
KW - Mice, Inbred C57BL
KW - Mitochondria, Heart/metabolism
KW - NADP/metabolism
KW - NADP Transhydrogenases/metabolism
KW - Oxidative Stress
KW - Reactive Oxygen Species/metabolism
U2 - 10.1016/j.cmet.2015.07.008
DO - 10.1016/j.cmet.2015.07.008
M3 - SCORING: Journal article
C2 - 26256392
VL - 22
SP - 472
EP - 484
JO - CELL METAB
JF - CELL METAB
SN - 1550-4131
IS - 3
ER -