Arabidopsis thaliana alternative dehydrogenases: A potential therapy for mitochondrial complex i deficiency? Perspectives and pitfalls

Alessia Catania, Arcangela Iuso, Juliette Bouchereau, Laura S. Kremer, Marina Paviolo, Caterina Terrile, Paule Bénit, Allan G. Rasmusson, Thomas Schwarzmayr, Valeria Tiranti, Pierre Rustin, Malgorzata Rak, Holger Prokisch, Manuel Schiff

Research output: Contribution to journalArticle

Abstract

Background: Complex I (CI or NADH:ubiquinone oxidoreductase) deficiency is the most frequent cause of mitochondrial respiratory chain defect. Successful attempts to rescue CI function by introducing an exogenous NADH dehydrogenase, such as the NDI1 from Saccharomyces cerevisiae (ScNDI1), have been reported although with drawbacks related to competition with CI. In contrast to ScNDI1, which is permanently active in yeast naturally devoid of CI, plant alternative NADH dehydrogenases (NDH-2) support the oxidation of NADH only when the CI is metabolically inactive and conceivably when the concentration of matrix NADH exceeds a certain threshold. We therefore explored the feasibility of CI rescue by NDH-2 from Arabidopsis thaliana (At) in human CI defective fibroblasts. Results: We showed that, other than ScNDI1, two different NDH-2 (AtNDA2 and AtNDB4) targeted to the mitochondria were able to rescue CI deficiency and decrease oxidative stress as indicated by a normalization of SOD activity in human CI-defective fibroblasts. We further demonstrated that when expressed in human control fibroblasts, AtNDA2 shows an affinity for NADH oxidation similar to that of CI, thus competing with CI for the oxidation of NADH as opposed to our initial hypothesis. This competition reduced the amount of ATP produced per oxygen atom reduced to water by half in control cells. Conclusions: In conclusion, despite their promising potential to rescue CI defects, due to a possible competition with remaining CI activity, plant NDH-2 should be regarded with caution as potential therapeutic tools for human mitochondrial diseases.

Original languageEnglish
Article number236
JournalOrphanet Journal of Rare Diseases
Volume14
Issue number1
DOIs
Publication statusPublished - Oct 29 2019

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Keywords

  • Alternative dehydrogenases
  • Arabidopsis thaliana
  • AtNDA2
  • Complex I
  • Mitochondria
  • Mitochondrial diseases

ASJC Scopus subject areas

  • Genetics(clinical)
  • Pharmacology (medical)

Cite this

Catania, A., Iuso, A., Bouchereau, J., Kremer, L. S., Paviolo, M., Terrile, C., Bénit, P., Rasmusson, A. G., Schwarzmayr, T., Tiranti, V., Rustin, P., Rak, M., Prokisch, H., & Schiff, M. (2019). Arabidopsis thaliana alternative dehydrogenases: A potential therapy for mitochondrial complex i deficiency? Perspectives and pitfalls. Orphanet Journal of Rare Diseases, 14(1), [236]. https://doi.org/10.1186/s13023-019-1185-3