2020
DOI: 10.1007/s00395-020-0815-1
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Abstract: In heart failure, a functional block of complex I of the respiratory chain provokes superoxide generation, which is transformed to H2O2 by dismutation. The Krebs cycle produces NADH, which delivers electrons to complex I, and NADPH for H2O2 elimination via isocitrate dehydrogenase and nicotinamide nucleotide transhydrogenase (NNT). At high NADH levels, α-ketoglutarate dehydrogenase (α-KGDH) is a major source of superoxide in skeletal muscle mitochondria with low NNT activity. Here, we analyzed how α-KGDH and N… Show more

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Cited by 28 publications
(18 citation statements)
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References 38 publications
(69 reference statements)
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“…Therefore, greater percentage of oxygen in the blood is available to perivascular cardiomyocytes. Reactive oxygen species (ROS) are by-products of metabolism which function as secondary messengers to transmit physiological signals 32 , 33 . However, excessive ROS production compromises intracellular components such as phospholipids, proteins, and DNA.…”
Section: Pathology Of Coronary Microvascular Ecs Damage In MImentioning
confidence: 99%
“…Therefore, greater percentage of oxygen in the blood is available to perivascular cardiomyocytes. Reactive oxygen species (ROS) are by-products of metabolism which function as secondary messengers to transmit physiological signals 32 , 33 . However, excessive ROS production compromises intracellular components such as phospholipids, proteins, and DNA.…”
Section: Pathology Of Coronary Microvascular Ecs Damage In MImentioning
confidence: 99%
“…ROS production at Complex III, however, is regarded as inconsequential compared to rate of production at Complex I, unless pharmacologically induced by Antimycin A. Dihidrolipoamide dehydrogenase, a component of the metabolic enzymes α-ketoglutarate dehydrogenase (αKGDH) and pyruvate dehydrogenase (PDH), is also capable of ROS production in a NADH/NAD + -dependent manner [ 3 , 91 , 103 ]. However, under physiological conditions in working cardiac myocytes, α-KGDH is not a relevant source of ROS, but rather contributes to regeneration of reduced nicotinamide adenine dinucleotide phosphate (NADPH) through tight functional coupling to the nicotinamide nucleotide transhydrogenase [ 119 ]. Further potential sites for ROS production in the mitochondria have been suggested, as reviewed by Murphy [ 91 ].…”
Section: Mitochondrial Physiology In the Heartmentioning
confidence: 99%
“…H 2 O 2 , the main ROS signal, is eliminated by peroxiredoxin and glutathione peroxidase, which require NADPH for regeneration, and also by mitochondrial catalase [ 16 ]. NADH generated by the Krebs cycle, and in particular, by α-KGDH, is converted to NADPH by nicotinamide nucleotide transhydrogenase (NNT), a process coupled to the proton gradient across the IMM [ 97 , 119 ]. Furthermore, NADPH is regenerated by isocitrate dehydrogenase and malic enzyme, which also both derive substrates from the Krebs cycle (isocitrate and malate, respectively).…”
Section: Mitochondrial Physiology In the Heartmentioning
confidence: 99%
“…After TUNEL labeling and DAPI counterstain, images were captured by fluorescence microscopy. Apoptosis was expressed as a percentage relative to the control group [ 44 , 45 ].…”
Section: Methodsmentioning
confidence: 99%