Alternative respiratory chain enzymes: Therapeutic potential and possible pitfalls

Saari, Sina; Garcia, Geovana S.; Bremer, Katharina; Chioda, Marina M.; Andjelković, Ana; Debes, Paul V.; Nikinmaa, Mikko; Szibor, Marten; Dufour, Éric; Rustin, Pierre; Oliveira, Marcos T.; Jacobs, Howard T.

doi:10.1016/j.bbadis.2018.10.012

Cited by 25 publications

(69 citation statements)

References 72 publications

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“…Considering (a) the role played by NDH-2/NDI-like proteins in bacterial/fungal respiration [7,25], (b) the direct interaction between a T. paradoxus flavoprotein oxidoreductase and a CytC-like protein [44], and (c) the recently proposed rotenone sensitive NADH:UQ oxidoreductase activity of AIF [11,12], it could be speculated that a direct interaction between AIF and CytC and other mitochondrial copper-binding proteins of the inner membrane [59][60][61] might also exist in Metazoan mitochondria, with several implications regarding AIF participation in mitochondrial respiration. These data are coherent with previous observations about alternative respiratory protein complexes [62][63][64][65].…”

Section: New Clues In Support Of Aif Participation In Mitochondrial Rsupporting

confidence: 92%

FAD/NADH Dependent Oxidoreductases: From Different Amino Acid Sequences to Similar Protein Shapes for Playing an Ancient Function

Trisolini

Gambacorta

Gorgoglione

et al. 2019

JCM

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Flavoprotein oxidoreductases are members of a large protein family of specialized dehydrogenases, which include type II NADH dehydrogenase, pyridine nucleotide-disulphide oxidoreductases, ferredoxin-NAD+ reductases, NADH oxidases, and NADH peroxidases, playing a crucial role in the metabolism of several prokaryotes and eukaryotes. Although several studies have been performed on single members or protein subgroups of flavoprotein oxidoreductases, a comprehensive analysis on structure–function relationships among the different members and subgroups of this great dehydrogenase family is still missing. Here, we present a structural comparative analysis showing that the investigated flavoprotein oxidoreductases have a highly similar overall structure, although the investigated dehydrogenases are quite different in functional annotations and global amino acid composition. The different functional annotation is ascribed to their participation in species-specific metabolic pathways based on the same biochemical reaction, i.e., the oxidation of specific cofactors, like NADH and FADH2. Notably, the performed comparative analysis sheds light on conserved sequence features that reflect very similar oxidation mechanisms, conserved among flavoprotein oxidoreductases belonging to phylogenetically distant species, as the bacterial type II NADH dehydrogenases and the mammalian apoptosis-inducing factor protein, until now retained as unique protein entities in Bacteria/Fungi or Animals, respectively. Furthermore, the presented computational analyses will allow consideration of FAD/NADH oxidoreductases as a possible target of new small molecules to be used as modulators of mitochondrial respiration for patients affected by rare diseases or cancer showing mitochondrial dysfunction, or antibiotics for treating bacterial/fungal/protista infections.

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Section: New Clues In Support Of Aif Participation In Mitochondrial Rsupporting

confidence: 92%

FAD/NADH Dependent Oxidoreductases: From Different Amino Acid Sequences to Similar Protein Shapes for Playing an Ancient Function

Trisolini

Gambacorta

Gorgoglione

et al. 2019

JCM

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“…In an earlier series of experiments, we found that flies expressing the alternative oxidase AOX from the tunicate Ciona intestinalis failed to complete development when reared on a low-nutrient agar medium containing only yeast and glucose (Saari et al, 2018). AOX branches the mitochondrial respiratory chain, bypassing complexes III and IV in a non-proton-motive reaction that oxidizes ubiquinol directly by molecular oxygen (Rogov, Sukhanova, Uralskaya, Aliverdieva, & Zvyagilskaya, 2014).…”

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confidence: 99%

Alternative oxidase confers nutritional limitation on Drosophila development

et al. 2019

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The mitochondrial alternative oxidase, AOX, present in most eukaryotes apart from vertebrates and insects, catalyzes the direct oxidation of ubiquinol by oxygen, by‐passing the terminal proton‐motive steps of the respiratory chain. Its physiological role is not fully understood, but it is proposed to buffer stresses in the respiratory chain similar to those encountered in mitochondrial diseases in humans. Previously, we found that the ubiquitous expression of AOX from Ciona intestinalis in Drosophila perturbs the development of flies cultured under low‐nutrient conditions (media containing only glucose and yeast). Here we tested the effects of a wide range of nutritional supplements on Drosophila development, to gain insight into the physiological mechanism underlying this developmental failure. On low‐nutrient medium, larvae contained decreased amounts of triglycerides, lactate, and pyruvate, irrespective of AOX expression. Complex food supplements, including treacle (molasses), restored normal development to AOX‐expressing flies, but many individual additives did not. Inhibition of AOX by treacle extract was excluded as a mechanism, since the supplement did not alter the enzymatic activity of AOX in vitro. Furthermore, antibiotics did not influence the organismal phenotype, indicating that commensal microbes were not involved. Fractionation of treacle identified a water‐soluble fraction with low solubility in ethanol, rich in lactate and tricarboxylic acid cycle intermediates, which contained the critical activity. We propose that the partial activation of AOX during metamorphosis impairs the efficient use of stored metabolites, resulting in developmental failure.

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“…NDH-2 can functionally replace NADH oxidizing activity of CI, transferring electrons from NADH directly to ubiquinone, while AOXs can be a functional substitute of complexes III and IV (AOXs being able to transfer electrons from a ubiquinol pool directly to oxygen, see Fig. 1) [5].…”

Section: Introductionmentioning

confidence: 99%

“…A very similar strategy based on the expression of the tunicate Ciona intestinalis alternative oxidase (AOX) has previously been shown to exert beneficial effects in counteracting the consequences of complexes III or IV respiratory chain deficiency in human cells and animal models [20], even though relevant constraints deriving from a profound influence on energy production and other biological processes have been recently reported after transfection in Drosophila [5].…”

Section: Introductionmentioning

confidence: 99%

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

Catania

Iuso

Bouchereau

et al. 2019

Orphanet J Rare Dis

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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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Alternative respiratory chain enzymes: Therapeutic potential and possible pitfalls

Cited by 25 publications

References 72 publications

FAD/NADH Dependent Oxidoreductases: From Different Amino Acid Sequences to Similar Protein Shapes for Playing an Ancient Function

FAD/NADH Dependent Oxidoreductases: From Different Amino Acid Sequences to Similar Protein Shapes for Playing an Ancient Function

Alternative oxidase confers nutritional limitation on Drosophila development

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

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