Diiron centre mutations in Ciona intestinalis alternative oxidase abolish enzymatic activity and prevent rescue of cytochrome oxidase deficiency in flies

Andjelković, Ana; Oliveira, Marcos T.; Cannino, Giuseppe; Yalgin, Cagri; Dhandapani, Praveen K.; Dufour, Éric; Rustin, Pierre; Szibor, Marten; Jacobs, Howard T.

doi:10.1038/srep18295

Cited by 19 publications

(37 citation statements)

References 37 publications

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“…This could be verified by using an enzymatically incapacitated version of the enzyme expressed at the same high level as daGAL4-driven UAS-AOX. A previously generated control line transgenic for a mutated (inactive) AOX variant would not suffice, since the transgene was expressed at a much lower level (Andjelković et al, 2015). However, the expression of neither cytosolically expressed GFP (Saari et al, 2018) nor the GAL4 transcription factor caused developmental failure in low-nutrient medium, making it unlikely that a general proteotoxic effect is responsible.…”

Section: Mechanism Of Developmental Failure Of Aox-expressing Fliesmentioning

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: Mechanism Of Developmental Failure Of Aox-expressing Fliesmentioning

confidence: 99%

Alternative oxidase confers nutritional limitation on Drosophila development

et al. 2019

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“…Superoxide levels increased under hypoxic conditions in WT but not in AOX PASMC. To validate this finding, we expressed either native AOX or a catalytically inactive mutant AOX (20) in WT mouse PASMC. Only the inactive mutant AOX showed a hypoxia-dependent increase in superoxide ( Fig.…”

Section: Aox Inhibits Hypoxia-induced Mitochondrial Superoxide Releasmentioning

confidence: 96%

Bypassing mitochondrial complex III using alternative oxidase inhibits acute pulmonary oxygen sensing

et al. 2020

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Mitochondria play an important role in sensing both acute and chronic hypoxia in the pulmonary vasculature, but their primary oxygen-sensing mechanism and contribution to stabilization of the hypoxia-inducible factor (HIF) remains elusive. Alteration of the mitochondrial electron flux and increased superoxide release from complex III has been proposed as an essential trigger for hypoxic pulmonary vasoconstriction (HPV). We used mice expressing a tunicate alternative oxidase, AOX, which maintains electron flux when respiratory complexes III and/or IV are inhibited. Respiratory restoration by AOX prevented acute HPV and hypoxic responses of pulmonary arterial smooth muscle cells (PASMC), acute hypoxia-induced redox changes of NADH and cytochrome c, and superoxide production. In contrast, AOX did not affect the development of chronic hypoxia-induced pulmonary hypertension and HIF-1α stabilization. These results indicate that distal inhibition of the mitochondrial electron transport chain in PASMC is an essential initial step for acute but not chronic oxygen sensing.

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“…AOX was able to rescue completely or at least substantially these phenotypes, depending on their severity or tissue‐specificity. Later, we showed that a catalytically inactive form of this alternative enzyme was unable to rescue the deleterious effects of complex IV knockdown (Andjelković et al, ). A replica of the developmental assays demonstrating AOX rescue of complex IV depletion is shown in Figure for illustration purposes.…”

Section: Effects Of Alternative Oxidase Expression In Model Organismsmentioning

confidence: 99%

“…A catalytically inactive form of AOX (indicated as mut ) is unable to provide such developmental rescue. More details about the fly lines used here and other complex IV defects rescued by AOX are shown in Kemppainen et al () and Andjelković et al ().…”

Section: Effects Of Alternative Oxidase Expression In Model Organismsmentioning

confidence: 99%

Xenotopic expression of alternative electron transport enzymes in animal mitochondria and their impact in health and disease

Camargo

Chioda

Rodrigues

et al. 2018

Cell Biology International

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The mitochondrial respiratory chain in vertebrates and arthropods is different from that of most other eukaryotes because they lack alternative enzymes that provide electron transfer pathways additional to the oxidative phosphorylation (OXPHOS) system. However, the use of diverse experimental models, such as human cells in culture, Drosophila melanogaster and the mouse, has demonstrated that the transgenic expression of these alternative enzymes can impact positively many phenotypes associated with human mitochondrial and other cellular dysfunction, including those typically presented in complex IV deficiencies, Parkinson's, and Alzheimer's. In addition, these enzymes have recently provided extremely valuable data on how, when, and where reactive oxygen species, considered by many as “by‐products” of OXPHOS, can contribute to animal longevity. It has also been shown that the expression of the alternative enzymes is thermogenic in cultured cells, causes reproductive defects in flies, and enhances the deleterious phenotype of some mitochondrial disease models. Therefore, all the reported beneficial effects must be considered with caution, as these enzymes have been proposed to be deployed in putative gene therapies to treat human diseases. Here, we present a brief review of the scientific data accumulated over the past decade that show the benefits and the risks of introducing alternative branches of the electron transport into mammalian and insect mitochondria, and we provide a perspective on the future of this research field.

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Diiron centre mutations in Ciona intestinalis alternative oxidase abolish enzymatic activity and prevent rescue of cytochrome oxidase deficiency in flies

Cited by 19 publications

References 37 publications

Alternative oxidase confers nutritional limitation on Drosophila development

Alternative oxidase confers nutritional limitation on Drosophila development

Bypassing mitochondrial complex III using alternative oxidase inhibits acute pulmonary oxygen sensing

Xenotopic expression of alternative electron transport enzymes in animal mitochondria and their impact in health and disease

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