Effects of menadione and its derivative on cultured cardiomyocytes with mitochondrial disorders

Shneyvays, Vladimir; Leshem, Dorit; Shmist, Yelena A.; Zinman, Tova; Shainberg, Asher

doi:10.1016/j.yjmcc.2005.03.017

Cited by 23 publications

(12 citation statements)

References 41 publications

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“…Our data complements studies from other labs showing that MB and VK potentiate mitochondrial energy production by acting as alternative electron carriers (Wen et al, 2011, Vos et al, 2012, Shneyvays et al, 2005). VK3, MB and NQN1 did not increase ECAR (Figure 4D), suggesting that the elevated ATP levels we measured (Figure 5) are indeed due to increased mitochondrial oxidative phosphorylation, and not glycolysis.…”

Section: Discussionsupporting

confidence: 90%

Novel Vitamin K analogs suppress seizures in zebrafish and mouse models of epilepsy

et al. 2014

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Epilepsy is a debilitating disease affecting 1-2% of the world’s population. Despite this high prevalence, 30% of patients suffering from epilepsy are not successfully managed by current medication suggesting a critical need for new anti-epileptic drugs (AEDs). In an effort to discover new therapeutics for the management of epilepsy, we began our study by screening drugs that, like some currently used AEDs, inhibit HDACs using a well-established larval zebrafish model. In this model, 7-day post fertilization (dpf) larvae are treated with the widely used seizure-inducing compound pentylenetetrazol (PTZ) which stimulates a rapid increase in swimming behavior previously determined to be a measurable manifestation of seizures. In our first screen, we tested a number of different HDAC inhibitors and found that one, NQN1, significantly decreased swim activity to levels equal to that of VPA. We continued to screen structurally related compounds including Vitamin K3 (VK3) and a number of novel Vitamin K (VK) analogues. We found that VK3 was a robust inhibitor of the PTZ-induced swim activity, as were several of our novel compounds. Three of these compounds were subsequently tested on mouse seizure models at the National Institute of Neurological Disorders and Stroke (NINDS) Anticonvulsant Screening Program. Compound 2h reduced seizures particularly well in the minimal clonic seizure (6 Hz) and corneal kindled mouse models of epilepsy, with no observable toxicity. As VK3 affects mitochondrial function, we tested the effects of our compounds on mitochondrial respiration and ATP production in a mouse hippocampal cell line. We demonstrate that these compounds affect ATP metabolism and increase total cellular ATP. Our data indicate the potential utility of these and other VK analogues for prevention of seizures and suggest the potential mechanism for this protection may lie in the ability of these compounds to affect energy production.

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Section: Discussionsupporting

confidence: 90%

Novel Vitamin K analogs suppress seizures in zebrafish and mouse models of epilepsy

et al. 2014

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“…Accordingly, in yeast except of menadione no other quinone was able to bridge the electron transfer of NADH oxidation when complex III was inhibited (Nosoh et al ., ; Brivet‐Chevillotte and di Rago, ). Likewise, menadione restored the electron flow and ATP formation in cardiomyocytes after the inhibition of complex I with rotenone (Shneyvays et al ., ).…”

Section: Discussionmentioning

confidence: 97%

The hypoxia‐induced dehydrogenase HorA is required for coenzyme Q10 biosynthesis, azole sensitivity and virulence of Aspergillus fumigatus

Kroll

Shekhova

Mattern

et al. 2016

Molecular Microbiology

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Aspergillus fumigatus is the predominant airborne pathogenic fungus causing invasive aspergillosis in immunocompromised patients. During infection A. fumigatus has to adapt to oxygen-limiting conditions in inflammatory or necrotic tissue. Previously, we identified a mitochondrial protein to be highly up-regulated during hypoxic adaptation. Here, this protein was found to represent the novel oxidoreductase HorA. In Saccharomyces cerevisiae a homologue was shown to play a role in biosynthesis of coenzyme Q. Consistently, reduced coenzyme Q content in the generated ΔhorA mutant indicated a respective function in A. fumigatus. Since coenzyme Q is involved in cellular respiration and maintaining cellular redox homeostasis, the strain ΔhorA displayed an impaired response to both oxidative and reductive stress, a delay in germination and an accumulation of NADH. Moreover, an increased resistance against antifungal drugs was observed. All phenotypes were completely reversed by the addition of the synthetic electron carrier menadione. The deletion strain ΔhorA showed significantly attenuated virulence in two murine infection models of invasive pulmonary aspergillosis. Therefore, the biosynthesis of coenzyme Q and, particularly, the fungal-specific protein HorA play a crucial role in virulence of A. fumigatus. Due to its absence in mammals, HorA might represent a novel therapeutic target against fungal infections.

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“…Addition of menadione (MEN, Vitamin K 3 ), can stimulate electron transfer within the inner membranes of the mitochondria, 42 which can produce a significant and rapid increase in Fp and decrease in NAD(P)H fluorescence intensity respectively (Figs. 4 and 5).…”

Section: Resultsmentioning

confidence: 99%

Probing the Impact of Gamma-Irradiation on the Metabolic State of Neural Stem and Precursor Cells Using Dual-Wavelength Intrinsic Signal Two-Photon Excited Fluorescence

Krasieva

Giedzinski

Tran

et al. 2011

J. Innov. Opt. Health Sci.

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Two-photon excited fluorescence (TPEF) spectroscopy and imaging were used to investigate the effects of gamma-irradiation on neural stem and precursor cells (NSPCs). While the observed signal from reduced nicotinamide adenine dinucleotide (NADH) was localized to the mitochondria, the signal typically associated with oxidized flavoproteins (Fp) was distributed diffusely throughout the cell. The measured TPEF emission and excitation spectra were similar to the established spectra of NAD(P)H and Fp. Fp fluorescence intensity was markedly increased by addition of the electron transport chain (ETC) modulator menadione to the medium, along with a concomitant decrease in the NAD(P)H signal. Three-dimensional (3D) neurospheres were imaged to obtain the cellular metabolic index (CMI), calculated as the ratio of Fp to NAD(P)H fluorescence intensity. Radiation effects were found to differ between low-dose (≤ 50 cGy) and high-dose (≥ 50 cGy) exposures. Low-dose irradiation caused a marked drop in CMI values accompanied by increased cellular proliferation. At higher doses, both NAD(P)H and Fp signals increased, leading to an overall elevation in CMI values. These findings underscore the complex relationship between radiation dose, metabolic state, and proliferation status in NSPCs and highlight the ability of TPEF spectroscopy and imaging to characterize metabolism in 3D spheroids.

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Effects of menadione and its derivative on cultured cardiomyocytes with mitochondrial disorders

Cited by 23 publications

References 41 publications

Novel Vitamin K analogs suppress seizures in zebrafish and mouse models of epilepsy

Novel Vitamin K analogs suppress seizures in zebrafish and mouse models of epilepsy

The hypoxia‐induced dehydrogenase HorA is required for coenzyme Q10 biosynthesis, azole sensitivity and virulence of Aspergillus fumigatus

Probing the Impact of Gamma-Irradiation on the Metabolic State of Neural Stem and Precursor Cells Using Dual-Wavelength Intrinsic Signal Two-Photon Excited Fluorescence

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