Mutations in Cytochrome c Oxidase Subunit VIa Cause Neurodegeneration and Motor Dysfunction in Drosophila

Liu, Wensheng; Gnanasambandam, Radhakrishnan; Benjamin, J. L.; Kaur, Gunisha; Getman, Patricia B.; Siegel, Alan J.; Shortridge, Randall D.; Singh, Satpal

doi:10.1534/genetics.107.071688

Cited by 46 publications

(38 citation statements)

References 78 publications

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“…Interestingly, these mutants also displayed two phenotypes that are hallmarks of mitochondrial dysfunction, bang sensitivity and erect wings (Figure 5B, 5C, S5A, and S5B; Greene et al, 2003; Fergestad et al, 2006). In addition, dSdhaf4 mutant retinas displayed a marked disorganization of retinal architecture (Figure 5D, asterisks), consistent with the known association between bang sensitivity and neurodegeneration (Celotto et al, 2006a; Gnerer et al, 2006; Liu et al, 2007). The photoreceptors were also highly vesicularized (Figure 5D, arrows; Kiselev et al, 2000), with aberrant mitochondrial morphology (Figure 5D, arrowheads).…”

Section: Resultssupporting

confidence: 81%

SDHAF4 Promotes Mitochondrial Succinate Dehydrogenase Activity and Prevents Neurodegeneration

et al. 2014

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SUMMARY Succinate dehydrogenase (SDH) occupies a central place in cellular energy production, linking the tricarboxylic cycle with the electron transport chain. As a result, a subset of cancers and neuromuscular disorders result from mutations affecting any of the four SDH structural subunits or either of two known SDH assembly factors. Herein we characterize a novel evolutionarily conserved SDH assembly factor designated Sdh8/SDHAF4, using yeast, Drosophila, and mammalian cells. Sdh8 interacts specifically with the catalytic Sdh1 subunit in the mitochondrial matrix, facilitating its association with Sdh2 and the subsequent assembly of the SDH holocomplex. These roles for Sdh8 are critical for preventing motility defects and neurodegeneration in Drosophila as well as the excess ROS generated by free Sdh1. These studies provide insights into the mechanisms by which SDH is assembled and raise the possibility that some forms of neuromuscular disease may be associated with mutations that affect this SDH assembly factor.

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Section: Resultssupporting

confidence: 81%

SDHAF4 Promotes Mitochondrial Succinate Dehydrogenase Activity and Prevents Neurodegeneration

et al. 2014

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“…We examined this first in Drosophila, as Drosophila serves as an important model for human cardiac pharmacology and cardiomyopathies (10,(15)(16)(17)(18) as well as other human disorders (19,20). Heart rate in Drosophila was significantly reduced by exposure to 3 M celecoxib (Fig.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Delayed Rectifier Potassium Channels and Induction of Arrhythmia

Frolov

Berim

Singh

2008

Journal of Biological Chemistry

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Selective inhibitors of cyclooxygenase-2 (COX-2), such as rofecoxib (Vioxx), celecoxib (Celebrex), and valdecoxib (Bextra), have been developed for treating arthritis and other musculoskeletal complaints. Selective inhibition of COX-2 over COX-1 results in preferential decrease in prostacyclin production over thromboxane A2 production, thus leading to less gastric effects than those seen with nonselective COX inhibitors such as acetylsalicylic acid (aspirin). Here we show a novel effect of celecoxib via a mechanism that is independent of COX-2 inhibition. The drug inhibited the delayed rectifier (Kv2) potassium channels from Drosophila, rats, and humans and led to pronounced arrhythmia in Drosophila heart and arrhythmic beating of rat heart cells in culture. These effects occurred despite the genomic absence of cyclooxygenases in Drosophila and the failure of acetylsalicylic acid, a potent inhibitor of both COX-1 and COX-2, to inhibit rat Kv2.1 channels. A genetically null mutant of Drosophila Shab (Kv2) channels reproduced the cardiac effect of celecoxib, and the drug was unable to further enhance the effect of the mutation. These observations reveal an unanticipated effect of celecoxib on Drosophila hearts and on heart cells from rats, implicating the inhibition of Kv2 channels as the mechanism underlying this effect.Selective COX-2 2 inhibitors, or coxibs, were developed for use as nonsteroidal anti-inflammatory drugs without adverse gastric effects (1, 2). Gastric effects of nonselective cyclooxygenase inhibitors, such as acetylsalicylic acid (aspirin), arise in main part from inhibition of cyclooxygenase-1. A selective inhibition of COX-2 by coxibs helps avoid these effects (3, 4); however, adverse cardiovascular effects complicate the use of coxibs (5-7). These effects of coxibs have been attributed to a reduction in antithrombotic, COX-2-derived prostacyclin without a reduction in prothrombotic, COX-1-derived platelet thromboxane. This shifts the balance toward a prothrombotic state resulting in clot formation (7).The adverse effects of drugs like celecoxib arising from their selective inhibition of COX-2 is currently the topic of intense discussion (7,8). We now show that celecoxib can have additional, heretofore unanticipated effects on Drosophila hearts and rat heart cells via a pathway independent of cyclooxygenase inhibition. At low micromolar concentrations, celecoxib reduced heart rate and induced pronounced arrhythmia in Drosophila hearts. A similar effect was observed in rat cardiomyocytes in culture in which the drug reduced the beating rate in clusters of cells and made the beating arrhythmic. These effects were not mediated via cyclooxygenase inhibition but involved inhibition of the voltage-activated delayed rectifier K ϩ channels (Kv2) by the drug. These observations reveal a new molecular mechanism underlying the effects of celecoxib that may operate in addition to its prothrombotic influence. The data also raise the possibility of effects on other tissues that express Kv2 channels. EXPERIM...

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“…Mitochondrial function may be interrupted during development to efficiently extend lifespan in C. elegans [131], thus both mutations and gene knock-down extend lifespan to a similar extent but not through the same mechanisms [23]. In flies, mutations in or strong depletion of ETC components using RNAi dramatically shortens fly lifespan [24,[132][133][134], whilst mild knock-down of ETC subunits has a positive effect on longevity [24,92]. However, and in contrast to what occurs in worms, knock-down must be induced both during development and adulthood in order to extend fly lifespan [92,135].…”

Section: Is Where Ros Are Produced Important?mentioning

confidence: 99%

Mitochondrial reactive oxygen species: Do they extend or shorten animal lifespan?

Sanz

2016

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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Testing the predictions of the Mitochondrial Free Radical Theory of Ageing (MFRTA) has provided a deep understanding of the role of reactive oxygen species (ROS) and mitochondria in the aging process. However those data, which support MFRTA are in the majority correlative (e.g. increasing oxidative damage with age). In contrast the majority of direct experimental data contradict MFRTA (e.g. changes in ROS levels do not alter longevity as expected). Unfortunately, in the past, ROS measurements have mainly been performed using isolated mitochondria, a method which is prone to experimental artifacts and does not reflect the complexity of the in vivo process. New technology to study different ROS (e.g. superoxide or hydrogen peroxide) in vivo is now available; these new methods combined with state-of-the-art genetic engineering technology will allow a deeper interrogation of, where, when and how free radicals affect aging and pathological processes. In fact data that combine these new approaches, indicate that boosting mitochondrial ROS in lower animals is a way to extend both healthy and maximum lifespan. In this review, I discuss the latest literature focused on the role of mitochondrial ROS in aging, and how these new discoveries are helping to better understand the role of mitochondria in health and disease. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.

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Mutations in Cytochrome c Oxidase Subunit VIa Cause Neurodegeneration and Motor Dysfunction in Drosophila

Cited by 46 publications

References 78 publications

SDHAF4 Promotes Mitochondrial Succinate Dehydrogenase Activity and Prevents Neurodegeneration

SDHAF4 Promotes Mitochondrial Succinate Dehydrogenase Activity and Prevents Neurodegeneration

Inhibition of Delayed Rectifier Potassium Channels and Induction of Arrhythmia

Mitochondrial reactive oxygen species: Do they extend or shorten animal lifespan?

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