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Arabidopsis thaliana alternative dehydrogenases: A potential therapy for mitochondrial complex I deficiency? Perspectives and pitfalls.
Orphanet J. Rare Dis. 14:236 (2019)
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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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Mitochondria ; Mitochondrial Diseases ; Complex I ; Alternative Dehydrogenases ; Arabidopsis Thaliana ; Atnda2; Nadh-quinone Oxidoreductase; Nad(p)h Dehydrogenases; Electron-transport; Skin Fibroblasts; Inner Surface; Chain; Mutation; Gene; Membrane; Kinetics
ISSN (print) / ISBN
1750-1172
e-ISSN
1750-1172
Zeitschrift
Orphanet Journal of Rare Diseases : OJRD
Quellenangaben
Band: 14,
Heft: 1,
Artikelnummer: 236
Verlag
BioMed Central
Verlagsort
London
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed