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Can NAD(P)+ transhydrogenase (NNT) mediate a physiologically meaningful increase in energy expenditure by mitochondria during H2O2 removal?

Open AccessPublished:March 08, 2021DOI:https://doi.org/10.1016/j.jbc.2021.100377
      Smith et al. (
      • Smith 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.
      ) 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 (
      • Smith 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.
      ). The authors argued that NNT’s stoichiometry may be altered when the enzyme is generating NADPH (
      • Smith 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.
      ), but a ratio of 200 H+ per hydride transfer challenges recent advances on the structure of NNT (
      • Leung 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.
      ,
      • Kampjut D.
      • Sazanov L.A.
      Structure and mechanism of mitochondrial proton-translocating transhydrogenase.
      ), which provide strong evidence these two molecular events are tightly coupled with a ratio of 1:1. Smith et al. (
      • Smith 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.
      ) 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 (
      • Smith 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.
      )) 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 (
      • Parker 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.
      ,
      • Ronchi 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.
      ). While the findings of Smith et al. (
      • Smith 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.
      ) 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.

      Conflict of interest

      The authors declare that they have no conflicts of interest with the contents of this article.

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