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Open Access 01-12-2019 | Research

Arabidopsis thaliana alternative dehydrogenases: a potential therapy for mitochondrial complex I deficiency? Perspectives and pitfalls

Authors: 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

Published in: Orphanet Journal of Rare Diseases | Issue 1/2019

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.

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Title: Arabidopsis thaliana alternative dehydrogenases: a potential therapy for mitochondrial complex I deficiency? Perspectives and pitfalls
Authors: 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
Publication date: 01-12-2019
Publisher: BioMed Central
Published in: Orphanet Journal of Rare Diseases / Issue 1/2019
Electronic ISSN: 1750-1172
DOI: https://doi.org/10.1186/s13023-019-1185-3

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Arabidopsis thaliana alternative dehydrogenases: a potential therapy for mitochondrial complex I deficiency? Perspectives and pitfalls

Abstract

Background

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Results

Conclusions

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