Arabidopsis thaliana alternative dehydrogenases: a potential therapy for mitochondrial complex I deficiency? Perspectives and pitfalls
In: ISSN: 1750-1172 ; Orphanet Journal of Rare Diseases ; https://hal.science/hal-02414326 ; Orphanet Journal of Rare Diseases, 2019, 2019
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International audience ; 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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Arabidopsis thaliana alternative dehydrogenases: a potential therapy for mitochondrial complex I deficiency? Perspectives and pitfalls
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Autor/in / Beteiligte Person: | Catania, Alessia ; Iuso, Arcangela ; Bouchereau, Juliette ; Kremer, Laura, S ; Paviolo, Marina ; Terrile, Caterina ; Bénit, Paule ; Rasmusson, Allan ; Schwarzmayr, Thomas ; Tiranti, Valeria ; Rustin, Pierre ; Rak, Malgorzata ; Prokisch, Holger ; Schiff, Manuel ; 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 = German Research Center for Environmental Health (HMGU) ; Institute of Human Genetics Munich, Germany ; Technische Universität Munchen - Technical University Munich - Université Technique de Munich (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) ; Skane University Hospital Lund ; Department of Pediatrics Munich, Germany (Dr. von Hauner Children’s Hospital) ; Ludwig Maximilian University Munich = 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) |
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Zeitschrift: | ISSN: 1750-1172 ; Orphanet Journal of Rare Diseases ; https://hal.science/hal-02414326 ; Orphanet Journal of Rare Diseases, 2019, 2019 |
Veröffentlichung: | HAL CCSD ; BioMed Central, 2019 |
Medientyp: | academicJournal |
DOI: | 10.1186/s13023-019-1185-3 |
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