Can NAD(P)+ transhydrogenase (NNT) mediate a physiologically meaningful increase in energy expenditure by mitochondria during H2O2 removal?
Bibliographic record
Abstract
Smith et al. (1Smith C.D. Schmidt C.A. Lin C.-T. Fisher-Wellman K.H. Neufer P.D. Flux through mitochondrial redox circuits linked to nicotinamide nucleotide transhydrogenase generates counterbalance changes in energy expenditure.J. Biol. Chem. 2020; 295: 16207-16216Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar) studied skeletal muscle mitochondria (SMM) from different inbred mouse strains (C57BL/6NJ versus C57BL/6J; NNT function is absent in the latter) and concluded that NNT activity mediates meaningful increases in respiration when NADPH-dependent mitochondrial H2O2 removal is stimulated. To be valid, this contention requires the NNT reaction stoichiometry to be ∼200 H+ translocated per NAD(P) hydride transferred based on expected stoichiometries in mitochondrial respiration (at least 6H+:1O) and some of the authors’ reported values (1Smith C.D. Schmidt C.A. Lin C.-T. Fisher-Wellman K.H. Neufer P.D. Flux through mitochondrial redox circuits linked to nicotinamide nucleotide transhydrogenase generates counterbalance changes in energy expenditure.J. Biol. Chem. 2020; 295: 16207-16216Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). The authors argued that NNT’s stoichiometry may be altered when the enzyme is generating NADPH (1Smith C.D. Schmidt C.A. Lin C.-T. Fisher-Wellman K.H. Neufer P.D. Flux through mitochondrial redox circuits linked to nicotinamide nucleotide transhydrogenase generates counterbalance changes in energy expenditure.J. Biol. Chem. 2020; 295: 16207-16216Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar), but a ratio of 200 H+ per hydride transfer challenges recent advances on the structure of NNT (2Leung J.H. Schurig-Briccio L.A. Yamaguchi M. Moeller A. Speir J.A. Gennis R.B. Stout C.D. Structural biology. Division of labor in transhydrogenase by alternating proton translocation and hydride transfer.Science. 2015; 347: 178-181Crossref PubMed Scopus (29) Google Scholar, 3Kampjut D. Sazanov L.A. Structure and mechanism of mitochondrial proton-translocating transhydrogenase.Nature. 2019; 573: 291-295Crossref PubMed Scopus (32) Google Scholar), which provide strong evidence these two molecular events are tightly coupled with a ratio of 1:1. Smith et al. (1Smith C.D. Schmidt C.A. Lin C.-T. Fisher-Wellman K.H. Neufer P.D. Flux through mitochondrial redox circuits linked to nicotinamide nucleotide transhydrogenase generates counterbalance changes in energy expenditure.J. Biol. Chem. 2020; 295: 16207-16216Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar) assert NADPH-dependent H2O2 removal can be linked to respiration by adding auranofin plus bis-chloroethylnitrosourea to mitochondria. However, these compounds caused similar decreases (∼35%, see Fig. 4D (1Smith C.D. Schmidt C.A. Lin C.-T. Fisher-Wellman K.H. Neufer P.D. Flux through mitochondrial redox circuits linked to nicotinamide nucleotide transhydrogenase generates counterbalance changes in energy expenditure.J. Biol. Chem. 2020; 295: 16207-16216Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar)) in O2 consumption in both mouse strains, indicating suppression of respiration irrespective of NNT flux and making conclusions based on these inhibitors ambiguous. Finally, previous studies comparing mitochondria from mice with or without functional NNT (using genetically closer controls) found no evidence of NNT-mediated flux sufficient to be measured as increased respiration (4Parker N. Crichton P.G. Vidal-Puig A.J. Brand M.D. Uncoupling protein-1 (UCP1) contributes to the basal proton conductance of brown adipose tissue mitochondria.J. Bioenerg. Biomembr. 2009; 41: 335-342Crossref PubMed Scopus (47) Google Scholar, 5Ronchi J.A. Francisco A. Passos L.A.C. Figueira T.R. Castilho R.F. 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.J. Biol. Chem. 2016; 291: 20173-20187Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). While the findings of Smith et al. (1Smith C.D. Schmidt C.A. Lin C.-T. Fisher-Wellman K.H. Neufer P.D. Flux through mitochondrial redox circuits linked to nicotinamide nucleotide transhydrogenase generates counterbalance changes in energy expenditure.J. Biol. Chem. 2020; 295: 16207-16216Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar) are attractive, we contend more direct evidence is needed before the role of redox circuits through NNT can be definitively understood in the context of energy expenditure. The authors declare that they have no conflicts of interest with the contents of this article.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.002 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".