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

Author

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, and Manuel Schiff

Subjects
Mitochondria, Mitochondrial diseases, Complex I, Alternative dehydrogenases, Arabidopsis thaliana, AtNDA2, Medicine
Abstract

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.

Published
2019
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2. Arabidopsis thaliana alternative dehydrogenases: a potential therapy for mitochondrial complex I deficiency? Perspectives and pitfalls

Author

Caterina Terrile, Juliette Bouchereau, Valeria Tiranti, Marina Paviolo, Paule Bénit, Manuel Schiff, Malgorzata Rak, Allan G. Rasmusson, Holger Prokisch, Arcangela Iuso, Thomas Schwarzmayr, Pierre Rustin, Alessia Catania, Laura S. Kremer, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unit of Medical Genetics and Neurogenetics [Milan, Italy], Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Institute of Human Genetics [Neuherberg] (IHG), Helmholtz-Zentrum München (HZM), Institute of Human Genetics [Munich, Germany], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Centre de référence pour les erreurs innées du métabolisme [Hôpital Robert Debré - APHP], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Biology [Lund, Sweden] (Biology building A), Lund University [Lund, Sweden], Department of Pediatrics [Munich, Germany] (Dr. von Hauner Children’s Hospital), Ludwig-Maximilians-Universität München (LMU), This study was supported by the German BMBF and Horizon2020 through E-Rare project GENOMIT (01GM1603 and 01GM1906B to H.P.), Horizon2020 Project SOUND (633974 to H.P.), German Network for Mitochondrial Disorders (mitoNET 01GM1113C to H.P.), AMMi (Association contre les Maladies Mitochondriales) grants to M.P., P.R., P.B. and M.S., E-Rare project GENOMIT (ANR-15-RAR3–0012 to P.R., A.C. and M.S.), Italian Ministry of Health (RF-2016-02361495 to A.C.), Mitocon (Grant no. 2018–01 to V.T.), Mariani Foundation (V.T.)., ANR-15-RAR3-0012,GENOMIT,Mitochondrial Disorders- from a pan-European Registry to medical genetics, toward molecular mechanisms and new therapeutic options(2015), European Project: 633974,H2020,H2020-PHC-2014-two-stage,SOUND(2015), Helmholtz Zentrum München = German Research Center for Environmental Health, Lund University [Lund], Rak, Malgorzata, Mitochondrial Disorders- from a pan-European Registry to medical genetics, toward molecular mechanisms and new therapeutic options - - GENOMIT2015 - ANR-15-RAR3-0012 - E-Rare-3 - VALID, and Statistical multi-Omics UNDerstanding of Patient Samples - SOUND - - H20202015-09-01 - 2018-08-31 - 633974 - VALID

Subjects
0301 basic medicine, Arabidopsis thaliana, [SDV]Life Sciences [q-bio], Arabidopsis, lcsh:Medicine, Mitochondrion, medicine.disease_cause, 0302 clinical medicine, NADH, NADPH Oxidoreductases, Pharmacology (medical), [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Cells, Cultured, Genetics (clinical), chemistry.chemical_classification, biology, Chemistry, NADH dehydrogenase, Mitochondria, Mitochondrial Diseases, Complex I, Alternative Dehydrogenases, Arabidopsis Thaliana, Atnda2, General Medicine, AtNDA2, ddc, [SDV] Life Sciences [q-bio], Mitochondrial respiratory chain, Biochemistry, Saccharomyces cerevisiae Proteins, Saccharomyces cerevisiae, Mitochondrial diseases, Transfection, 03 medical and health sciences, Oxidoreductase, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Alternative dehydrogenases, Electron Transport Complex I, Arabidopsis Proteins, Superoxide Dismutase, Research, lcsh:R, NADPH Dehydrogenase, Fibroblasts, biology.organism_classification, Yeast, 030104 developmental biology, biology.protein, 030217 neurology & neurosurgery, Oxidative stress
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.

Published
2019
Full Text
View/download PDF

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