Alternative NAD(P)H dehydrogenase and alternative oxidase: Proposed physiological roles in animals

McDonald, Allison E.; Gospodaryov, Dmytro V.

doi:10.1016/j.mito.2018.01.009

Cited by 52 publications

(70 citation statements)

References 130 publications

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“…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, ). The gene for AOX is present in most groups of eukaryotes, including animals (McDonald & Gospodaryov, ), but has been lost from specific lineages during the course of evolution, notably from vertebrates and advanced insects. The reasons for its evolutionary loss or retention are unclear.…”

Section: Introductionmentioning

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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Section: Introductionmentioning

confidence: 99%

Alternative oxidase confers nutritional limitation on Drosophila development

et al. 2019

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“…We have shown that AOX is in the genomes of multiple species of copepods from around the world that inhabit a wide variety of ecological niches (Table 2.) The first reports of AOX from arthropods were in the brine shrimp Artemia franciscana and putative sequences from other members of the Chelicerata, Hexapoda, and Crustacea (Rodriguez-Armenta et al, 2018;McDonald and Gospodaryov, 2018). It was previously hypothesized that AOX was not present in arthropods due to a gene loss event (McDonald et al, 2009), however, the above data refute this hypothesis.…”

Section: Discovery Of Aox In Copepods and The Phylum Arthropodamentioning

confidence: 93%

“…AOX has been identified in several animal species due to the presence of AOX DNA or mRNA sequences in public molecular databases (McDonald and Vanlerberghe, 2004;McDonald et al, 2009). Recent database searches have revealed the presence of AOX DNA or mRNA in the phyla Ctenophora, Platyhelminthes, Arthropoda, Tardigrada, Scalidophora, Brachiopoda, and Rotifera for the first time (McDonald and Gospodaryov, 2018). Experimental evidence for the expression of AOX mRNA exists for the sponge Ephydatia muelleri, and the molluscs Anadara ovalis, Crassostrea gigas, Crassostrea virginica, and Mercenaria mercenaria (McDonald et al, 2009;Liu and Guo, 2017).…”

Section: Aox In Animalsmentioning

confidence: 99%

“…Many animals also contain additional enzymes capable of putting electrons into and/or removing electrons from the ETS (McDonald and Gospodaryov, 2018). One such enzyme is the alternative oxidase (AOX), a terminal quinol oxidase that catalyzes the oxidation of ubiquinol and the reduction of oxygen to water (McDonald and Vanlerberghe, 2004;McDonald, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Identification of the alternative oxidase gene and its expression in the copepod Tigriopus californicus

Tward

Singh

Cygelfarb

et al. 2019

Comparative Biochemistry and Physiology Part B: Biochemistry an

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In addition to the typical electron transport system (ETS) in animal mitochondria responsible for oxidative phosphorylation, in some species there exists an alternative oxidase (AOX) pathway capable of catalyzing the oxidation of ubiquinol and the reduction of oxygen to water. The discovery of AOX in animals is recent and further investigations into its expression, regulation, and physiological role have been hampered by the lack of a tractable experimental model organism. Our recent DNA database searches using bioinformatics revealed an AOX sequence in several marine copepods including Tigriopus californicus. This species lives in tidepools along the west coast of North America and is subject to a wide variety of daily environmental stresses. Here we verify the presence of the AOX gene in T. californicus and the expression of AOX mRNA and AOX protein in various life stages of the animal. We demonstrate that levels of the AOX protein increase in T. californicus in response to cold and heat stress compared to normal rearing temperature. We predict that a functional AOX pathway is present in T. californicus, propose that this species will be a useful model organism for the study of AOX in animals, and discuss future directions for animal AOX research.

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“…These alternative enzymes possess some key properties that distinguish them from other mitochondrial complexes: they are single or oligo subunit, non-proton pumping enzymes, as the energy they convey during their activation does not support mitochondrial potential; they are not inhibited by cytochrome pathway inhibitors (e.g. rotenone and cyanide) and, in contrast to other mitochondrial complexes, they are not transmembrane proteins but are associated to either the inner or the outer surface of the inner mitochondrial membrane [6,7].…”

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 NAD(P)H dehydrogenase and alternative oxidase: Proposed physiological roles in animals

Cited by 52 publications

References 130 publications

Alternative oxidase confers nutritional limitation on Drosophila development

Alternative oxidase confers nutritional limitation on Drosophila development

Identification of the alternative oxidase gene and its expression in the copepod Tigriopus californicus

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

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