Sea squirt alternative oxidase bypasses fatal mitochondrial heart disease

Saada, Ann

doi:10.15252/emmm.201809962

Cited by 6 publications

(4 citation statements)

References 10 publications

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“…So far two other animal models, both obtained due to heterologous expression of the tunicate C. intestinalis AOX in fruit ies and mice, have been used in research on AOX impact on animal physiology and the enzyme possible application in therapy of human mitochondrial diseases (e.g. [1,3,[9][10][11][12]. The data obtained for H. exemplaris could supplement the models due to the presence of native AOX as well as simplicity of the tardigrade culture and AOX research in intact specimens.…”

Section: Discussionmentioning

confidence: 99%

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The Tardigrade Hypsibius Exemplaris as an Emerging Model to Study the Mitochondrial Alternative Oxidase at Animal Organismal Level

Grobys

Roszkowska

Kaczmarek

et al. 2020

Preprint

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Background: Mitochondrial alternative oxidase (AOX) is suggested to be present in mitochondria of most invertebrates but not vertebrates. Independently of the reason concerning the enzyme occurrence in animal mitochondria, expression of AOX in human mitochondria is regarded as a potential therapeutic strategy in treatment of mitochondrial diseases caused by the mitochondrial respiratory chain (MRC) deficiency or blockage. Undoubtedly, development of AOX expression-based therapy requires explanation of AOX contribution to animal physiology. Till now the relevant data has been obtained mainly due to heterologous AOX expression in cells and animals that do not have natively expressed AOX. We think that application of animals natively expressing AOX could importantly contribute to the research and therapy development. Because the available genomic and transcriptomic data suggests the presence of functional AOX protein in mitochondria of the tardigrade Hypsibius exemplaris, we decided to investigate the possibility of the animal application as a model for AOX activity analysis at organismal level.Results: We observed that H. exemplaris tolerance to the blockage of the MRC complexes III and/or IV was diminished in the presence of AOX inhibitor and the inhibitor-sensitive respiration enabled the tardigrade respiration under condition of the blockage. Furthermore, although detection of H. exemplaris AOX at protein level and pronounced oxygraphic registration of its activity required the MRC complex III and/or IV blockage, the obtained data indicated that AOX clearly contributed to the animal functioning, also in the absence of the blockage. Conclusions: According to our best knowledge we demonstrated, for the first time, that AOX activity of small aquatic invertebrates, represented by the studied tardigrade species, can be monitored by measurement of intact specimen whole-body respiration. Furthermore, it was also possible to monitor the impact of the MRC complex IV blockage on AOX expression level and AOX inhibition in the absence of the blockage on animal functioning. Thus, H. exemplaris could be applied as a whole-animal model suitable to study activity and expression regulation of natively expressed animal AOX.

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Section: Discussionmentioning

confidence: 99%

“…Moreover, it is suggested that AOX can bypass blockade or de ciency of the MRC complexes III and IV by restoring electron ow upstream of the MRC complex III. Consequently, AOX is considered to be an important element of a therapeutic strategy against impairment of these complexes [1,3,[9][10][11][12].…”

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confidence: 99%

The Tardigrade Hypsibius Exemplaris as an Emerging Model to Study the Mitochondrial Alternative Oxidase at Animal Organismal Level

Grobys

Roszkowska

Kaczmarek

et al. 2020

Preprint

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“…A previous study [ 14 ] showed that niclosamide can damage the liver and gonad (liver-gonad), ganglion, and muscle tissues of O. hupensis , with systems such as those of the mitochondrion, endoplasmic reticulum, and nucleus being the most affected. The mitochondrion is an organelle central to the production of chemical energy; it is involved in carbohydrate, amino acid and fatty acid metabolism, redox homeostasis, and cell signal transduction pathways, and is responsible for more than 90% of the adenosine triphosphate (ATP) produced in the cells of animals [ 15 , 16 ]. Our previous studies on the enzymatic histochemistry and metabolic changes of O. hupensis in response to niclosamide revealed that the activities of cytochrome c oxidase (CCO), succinic dehydrogenase (SDH), and glucose-6-phosphatase in the respiratory chain of mitochondrial oxidative phosphorylation decreased after niclosamide treatment.…”

Section: Introductionmentioning

confidence: 99%

The identification of alternative oxidase in intermediate host snails of Schistosoma and its potential role in protecting Oncomelania hupensis against niclosamide-induced stress

Zhang

et al. 2022

Parasites Vectors

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Background Snail intermediate hosts are mandatory for the transmission of schistosomiasis, which has to date infected more than 200 million people worldwide. Our previous studies showed that niclosamide treatment caused the inhibition of aerobic respiration and oxidative phosphorylation, and the disruption of energy supply, in one of the intermediate hosts of schistosomiasis, Oncomelania hupensis, which eventually led to the death of the snails. Meanwhile, the terminal oxidase in the mitochondrial respiratory chain, alternative oxidase (AOX), was significantly up-regulated, which was thought to counterbalance the oxidative stress and maintain metabolic homeostasis in the snails. The aims of the present study are to identify the AOXs in several species of snails and investigate the potential activation of O. hupensis AOX (OhAOX) under niclosamide-induced stress, leading to enhanced survival of the snail when exposed to this molluscicide. Methods The complete complementary DNA was amplified from the AOXs of O. hupensis and three species of Biomphalaria; the sequence characteristics were analysed and the phylogenetics investigated. The dynamic expression and localisation of the AOX gene and protein in O. hupensis under niclosamide-induced stress were examined. In addition, the expression pattern of genes in the mitochondrial respiratory complex was determined and the production of reactive oxygen species (ROS) calculated. Finally, the molluscicidal effect of niclosamide was compared between snails with and without inhibition of AOX activity. Results AOXs containing the invertebrate AOX-specific motif NP-[YF]-XPG-[KQE] were identified from four species of snail, which phylogenetically clustered together into Gastropoda AOXs and further into Mollusca AOXs. After niclosamide treatment, the levels of OhAOX messenger RNA (mRNA) and OhAOX protein in the whole snail were 14.8 and 2.6 times those in untreated snails, respectively, but varied widely among tissues. Meanwhile, the level of cytochrome C reductase mRNA showed a significant decrease in the whole snail, and ROS production showed a significant decrease in the liver plus gonad (liver-gonad) of the snails. At 24 h post-treatment, the mortality of snails treated with 0.06–0.1 mg/L niclosamide and AOX inhibitor was 56.31–76.12% higher than that of snails treated with 0.1 mg/L niclosamide alone. Conclusions AOX was found in all the snail intermediate hosts of Schistosoma examined here. AOX was significantly activated in O. hupensis under niclosamide-induced stress, which led to a reduction in oxidative stress in the snail. The inhibition of AOX activity in snails can dramatically enhance the molluscicidal effect of niclosamide. A potential target for the development of an environmentally safe snail control method, which acts by inhibiting the activity of AOX, was identified in this study. Graphical abstract

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“…Moreover, it is suggested that AOX can bypass blockade or deficiency of the MRC complexes III and IV by restoring electron flow upstream of the MRC complex III. Consequently, AOX is considered to be an important element of a therapeutic strategy against impairment of these complexes [1,3,[9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

The tardigradeHypsibius exemplarisas an emerging model to study the mitochondrial alternative oxidase at animal organismal level

Grobys

Roszkowska

Kaczmarek

et al. 2020

Preprint

View full text Add to dashboard Cite

Mitochondrial alternative oxidase (AOX) is present in mitochondria of many invertebrates. Independently of the reason concerning the enzyme occurrence in animal mitochondria, expression of AOX in human mitochondria is regarded as a potential therapeutic strategy. Till now, relevant data were obtained due to heterologous AOX expression in cells and animals without natively expressed AOX. Application of animals natively expressing AOX importantly contribute the research. Thus, we investigated Hypsibius exemplaris as a model for AOX activity analysis. We observed that H. exemplaris tolerance to the blockage of the MRC complexes was diminished in the presence of AOX inhibitor and the inhibitor-sensitive respiration enabled the tardigrade respiration under condition of the blockage. Furthermore, although detection of AOX at protein level and pronounced oxygraphic registration of its activity required the MRC complex blockage, the obtained data indicated that AOX clearly contributed animal functioning. We demonstrated that AOX activity in tardigrades, can be monitored by measurement of intact specimen whole-body respiration. Furthermore, it was also possible to monitor the impact of the MRC complex IV blockage on AOX expression and AOX inhibition in the absence of the blockage on animal functioning. Thus, H. exemplaris is applied as a whole-animal model suitable to study AOX.

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Sea squirt alternative oxidase bypasses fatal mitochondrial heart disease

Cited by 6 publications

References 10 publications

The Tardigrade Hypsibius Exemplaris as an Emerging Model to Study the Mitochondrial Alternative Oxidase at Animal Organismal Level

The Tardigrade Hypsibius Exemplaris as an Emerging Model to Study the Mitochondrial Alternative Oxidase at Animal Organismal Level

The identification of alternative oxidase in intermediate host snails of Schistosoma and its potential role in protecting Oncomelania hupensis against niclosamide-induced stress

The tardigradeHypsibius exemplarisas an emerging model to study the mitochondrial alternative oxidase at animal organismal level

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