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

Catania, Alessia ; Iuso, Arcangela ; Bouchereau, Juliette ; Kremer, Laura S. ; Paviolo, Marina ; Terrile, Caterina ; Bénit, Paule ; Rasmusson, Allan G. LU ; Schwarzmayr, Thomas and Tiranti, Valeria , et al. (2019) In Orphanet Journal of Rare Diseases 14(1).
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... (More)

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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published
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keywords
Alternative dehydrogenases, Arabidopsis thaliana, AtNDA2, Complex I, Mitochondria, Mitochondrial diseases
in
Orphanet Journal of Rare Diseases
volume
14
issue
1
article number
236
publisher
BioMed Central
external identifiers
  • scopus:85074418928
  • pmid:31665043
ISSN
1750-1172
DOI
10.1186/s13023-019-1185-3
language
English
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yes
id
c5a26e8f-0393-49d4-b57f-0df5d4652e6e
date added to LUP
2019-11-20 12:52:45
date last changed
2019-11-25 09:35:48
@article{c5a26e8f-0393-49d4-b57f-0df5d4652e6e,
  abstract     = {<p>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.</p>},
  author       = {Catania, Alessia and Iuso, Arcangela and Bouchereau, Juliette and Kremer, Laura S. and Paviolo, Marina and Terrile, Caterina and Bénit, Paule and Rasmusson, Allan G. and Schwarzmayr, Thomas and Tiranti, Valeria and Rustin, Pierre and Rak, Malgorzata and Prokisch, Holger and Schiff, Manuel},
  issn         = {1750-1172},
  language     = {eng},
  month        = {10},
  number       = {1},
  publisher    = {BioMed Central},
  series       = {Orphanet Journal of Rare Diseases},
  title        = {Arabidopsis thaliana alternative dehydrogenases : A potential therapy for mitochondrial complex i deficiency? Perspectives and pitfalls},
  url          = {http://dx.doi.org/10.1186/s13023-019-1185-3},
  doi          = {10.1186/s13023-019-1185-3},
  volume       = {14},
  year         = {2019},
}