ArticleThe Journal of biological chemistry2016
The Contribution of Nicotinamide Nucleotide Transhydrogenase to Peroxide Detoxification Is Dependent on the Respiratory State and Counterbalanced by Other Sources of NADPH in Liver Mitochondria.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 116 citations in OpenAlex.
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- Dissipation of the mitochondrial proton motive force drives sepsis pathogenesis and explains hyperlactatemia's predictive value in sepsis mortality.World journal of critical care medicine · 2026Review
- Receptor-Mitochondria Crosstalk in the Kynurenine Metabolic Pathway: Integrating Metabolomics and Clinical Mass Spectrometry.Antioxidants (Basel, Switzerland) · 2026Review
- Hallachrome, a marine anthraquinone, impairs cell proliferation by acting as a functional mitochondrial uncoupler in A375 melanoma cells.Frontiers in pharmacology · 2026Article
- Cystathionine γ-lyase is a major regulator of cognitive function through neurotrophin signaling and neurogenesis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Keeping up with the nicotinamides: NADP(H), the forgotten circadian cofactor that keeps metabolic time.Life metabolism · 2025Review
- Nicotinamide nucleotide transhydrogenase deficiency and genetic susceptibility to high glucose-mediated peritoneal injury in mice.Physiological reports · 2025Article
- Impact of Obesity Caused by a High-Fat Diet on the Heart's Redox Balance.Antioxidants (Basel, Switzerland) · 2025Article
- ApoM maintains cellular homeostasis between mitophagy and apoptosis by affecting the stability of Nnt mRNA through the Zic3-ApoM-Elavl2-Nnt axis during neural tube closure.Cell death & disease · 2025Article
- Cellular and molecular roles of reactive oxygen species in wound healing.Communications biology · 2024Review
- Combined Analysis of Metabolomics and Transcriptome Revealed the Effect ofInternational journal of molecular sciences · 2024Article
- The Structure of the Cardiac Mitochondria Respirasome Is Adapted for the β-Oxidation of Fatty Acids.International journal of molecular sciences · 2024Review
- SIRT3 deficiency decreases oxidative metabolism capacity but increases lifespan in male mice under caloric restriction.Aging cell · 2022Article
- Excessive gluconeogenesis causes the hepatic insulin resistance paradox and its sequelae.Heliyon · 2022Review
- Redox regulation of the immune response.Cellular & molecular immunology · 2022Review
- Cisplatin-Induced Kidney Toxicity: Potential Roles of Major NADBiomolecules · 2022Review
- The Combination of Niacinamide, Vitamin C, and PDRN Mitigates Melanogenesis by Modulating Nicotinamide Nucleotide Transhydrogenase.Molecules (Basel, Switzerland) · 2022Article
- Reduced nicotinamide adenine dinucleotide phosphate in redox balance and diseases: a friend or foe?Acta pharmacologica Sinica · 2022Review
- A maternal high-fat diet induces fetal origins of NASH-HCC in mice.Scientific reports · 2022Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The forward reaction of nicotinamide nucleotide transhydrogenase (NNT) reduces NADP(+) at the expense of NADH oxidation and H(+) movement down the electrochemical potential across the inner mitochondrial membrane, establishing an NADPH/NADP(+) ratio severalfold higher than the NADH/NAD(+) ratio in the matrix. In turn, NADPH drives processes, such as peroxide detoxification and reductive biosynthesis. In this study, we generated a congenic mouse model carrying a mutated Nnt(C57BL/6J) allele from the C57BL/6J substrain. Suspensions of isolated mitochondria from Nnt(+/+), Nnt(+/-), and Nnt(-/-) mouse liver were biochemically evaluated and challenged with exogenous peroxide under different respiratory states. The respiratory substrates were also varied, and the participation of concurrent NADPH sources (i.e. isocitrate dehydrogenase-2, malic enzymes, and glutamate dehydrogenase) was assessed. The principal findings include the following: Nnt(+/-) and Nnt(-/-) exhibit ∼50% and absent NNT activity, respectively, but the activities of concurrent NADPH sources are unchanged. The lack of NNT activity in Nnt(-/-) mice impairs peroxide metabolism in intact mitochondria. The contribution of NNT to peroxide metabolism is decreased during ADP phosphorylation compared with the non-phosphorylating state; however, it is accompanied by increased contributions of concurrent NADPH sources, especially glutamate dehydrogenase. NNT makes a major contribution to peroxide metabolism during the blockage of mitochondrial electron transport. Interestingly, peroxide metabolism in the Nnt(+/-) mitochondria matched that in the Nnt(+/+) mitochondria. Overall, this study demonstrates that the respiratory state and/or substrates that sustain energy metabolism markedly influence the relative contribution of NNT (i.e. varies between nearly 0 and 100%) to NADPH-dependent mitochondrial peroxide metabolism.
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