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Cited by 10Mitochondrial Function and PathologySirtuins and Resveratrol in MedicineRedox biology and oxidative stress

Undesirable Effects of Chemical Inhibitors of NAD(P)+ Transhydrogenase on Mitochondrial Respiratory Function

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Bicego, Rafaela, Francisco, Annelise, Ruas, Juliana S., Siqueira-Santos, Edilene S., Castilho, Roger F.·2020·Archives of Biochemistry and Biophysics
DOI 10.1016/j.abb.2020.108535
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Abstract

NAD(P)+ transhydrogenase (NNT) is located in the inner mitochondrial membrane and catalyzes a reversible hydride transfer between NAD(H) and NADP(H) that is coupled to proton translocation between the intermembrane space and mitochondrial matrix. NNT activity has an essential role in maintaining the NADPH supply for antioxidant defense and biosynthetic pathways. In the present report, we evaluated the effects of chemical compounds used as inhibitors of NNT over the last five decades, namely, 4-chloro-7-nitrobenzofurazan (NBD-Cl), N,N'-dicyclohexylcarbodiimide (DCC), palmitoyl-CoA, palmitoyl-l-carnitine, and rhein, on NNT activity and mitochondrial respiratory function. Concentrations of these compounds that partially inhibited the forward and reverse NNT reactions in detergent-solubilized mouse liver mitochondria significantly impaired mitochondrial respiratory function, as estimated by ADP-stimulated and nonphosphorylating respiration. Among the tested compounds, NBD-Cl showed the best relationship between NNT inhibition and low impact on respiratory function. Despite this, NBD-Cl concentrations that partially inhibited NNT activity impaired mitochondrial respiratory function and significantly decreased the viability of cultured Nnt-/- mouse astrocytes. We conclude that even though the tested compounds indeed presented inhibitory effects on NNT activity, at effective concentrations, they cause important undesirable effects on mitochondrial respiratory function and cell viability.

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Authors
Bicego, R., Francisco, A., Ruas, J. S., Siqueira-Santos, E. S., & Castilho, R. F.
Affiliations
Universidade Estadual de Campinas (UNICAMP) (BR)
Corresponding author
  • Francisco, Annelise
  • Castilho, Roger F.
ORCID
Venue
Archives of Biochemistry and Biophysics
Publisher
Elsevier BV
Published
2020-10
Volume
692
Pages
108535
ISSN
0003-9861 (ISSN-L)
DOI
10.1016/j.abb.2020.108535
OpenAlex
W3047986409
Cited by
10
References
0
Citations by year
2025: 1 · 2024: 3 · 2023: 3 · 2021: 3
FWCI
0.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Archives of Biochemistry and Biophysics (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (17/17728-8, 15/22063-0, 20/05202-4)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico
  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (PNPD 88887.473373/2020\u201300)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
mitochondrial respiration, NBD-Cl, DCC, palmitoyl-CoA, palmitoyl-L-carnitine, rhein, NADPH, cell viability, liver mitochondria, hydride transfer
MeSH terms
Animals, Enzyme Inhibitors, Female, Mitochondria, Liver, Oxygen Consumption, Mice, Knockout, Mitochondrial Proteins, Mice, NADP Transhydrogenase, AB-Specific

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