Primary Coenzyme Q deficiency Due to Novel ADCK3 Variants, Studies in Fibroblasts and Review of Literature

Shalata, Adel; Edery, Michael; Habib, Clair; Genizi, Jacob; Mahroum, Mohammad; Khalaily, Lama; Assaf, Nurit; Segal, Idan; Rahim, Hoda Abed El; Shapira, Hana; Urian, Danielle; Tzur, Shay; Douiev, Liza; Saada, Ann

doi:10.1007/s11064-019-02786-5

Cited by 18 publications

(25 citation statements)

References 22 publications

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“…This can be demonstrated by the ADP-dependent stimulation of state 3 respiration, which occurs in both 2OHOA-treated and untreated cells, but is more prominent in the treated ones, and by the increased sensitivity of OCR in 2OHOA-treated cells to the ATPase inhibitor oligomycin. Apparently, the inhibition of complex II + III activity by 2OHOA (Figure 4A), measured using supraphysiological concentrations of the electron acceptor oxidized cytochrome c and limited only by intra/inter-complex electron transfer rate [34,35,39], does not reflect physiological complexes II + III activities within proton gradient-limiting conditions. We suggest that, under these physiological conditions, the 2OHOA-stimulated complex IV activity (Figures 4A and 6) serves as an energetic sink, especially given that its reduction potential is the highest in the ETC.…”

Section: Discussionmentioning

confidence: 94%

Multifaceted Analyses of Isolated Mitochondria Establish the Anticancer Drug 2-Hydroxyoleic Acid as an Inhibitor of Substrate Oxidation and an Activator of Complex IV-Dependent State 3 Respiration

Mishra

Péter

Nardiello

et al. 2022

Cells

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The synthetic fatty acid 2-hydroxyoleic acid (2OHOA) has been extensively investigated as a cancer therapy mainly based on its regulation of membrane lipid composition and structure, activating various cell fate pathways. We discovered, additionally, that 2OHOA can uncouple oxidative phosphorylation, but this has never been demonstrated mechanistically. Here, we explored the effect of 2OHOA on mitochondria isolated by ultracentrifugation from U118MG glioblastoma cells. Mitochondria were analyzed by shotgun lipidomics, molecular dynamic simulations, spectrophotometric assays for determining respiratory complex activity, mass spectrometry for assessing beta oxidation and Seahorse technology for bioenergetic profiling. We showed that the main impact of 2OHOA on mitochondrial lipids is their hydroxylation, demonstrated by simulations to decrease co-enzyme Q diffusion in the liquid disordered membranes embedding respiratory complexes. This decreased co-enzyme Q diffusion can explain the inhibition of disjointly measured complexes I-III activity. However, it doesn’t explain how 2OHOA increases complex IV and state 3 respiration in intact mitochondria. This increased respiration probably allows mitochondrial oxidative phosphorylation to maintain ATP production against the 2OHOA-mediated inhibition of glycolytic ATP production. This work correlates 2OHOA function with its modulation of mitochondrial lipid composition, reflecting both 2OHOA anticancer activity and adaptation to it by enhancement of state 3 respiration.

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Section: Discussionmentioning

confidence: 94%

Multifaceted Analyses of Isolated Mitochondria Establish the Anticancer Drug 2-Hydroxyoleic Acid as an Inhibitor of Substrate Oxidation and an Activator of Complex IV-Dependent State 3 Respiration

Mishra

Péter

Nardiello

et al. 2022

Cells

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“…More than 70 patients suffering from primary CoQ 10 deficiency were described in the literature, and novel cases appear every year [ 66 , 67 , 68 ]. However, up to 123,789 patients were predicted according to the prevalence of homozygous and compound heterozygous afflicted individuals worldwide (27,321 patients carrying a mutation in COQ8A ) [ 69 ].…”

Section: Discussionmentioning

confidence: 99%

Microarray and qPCR Analysis of Mitochondrial Metabolism Activation during Prenatal and Early Postnatal Development in Rats and Humans with Emphasis on CoQ10 Biosynthesis

Křížová

Hůlková

Čapek

et al. 2021

Biology

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At the end of the mammalian intra-uterine foetal development, a rapid switch from glycolytic to oxidative metabolism must proceed. Using microarray techniques, qPCR, enzyme activities and coenzyme Q content measurements, we describe perinatal mitochondrial metabolism acceleration in rat liver and skeletal muscle during the perinatal period and correlate the results with those in humans. Out of 1546 mitochondrial genes, we found significant changes in expression in 1119 and 827 genes in rat liver and skeletal muscle, respectively. The most remarkable expression shift occurred in the rat liver at least two days before birth. Coenzyme Q-based evaluation in both the rat model and human tissues showed the same trend: the total CoQ content is low prenatally, significantly increasing after birth in both the liver and skeletal muscle. We propose that an important regulator of rat coenzyme Q biosynthesis might be COQ8A, an atypical kinase involved in the biosynthesis of coenzyme Q. Our microarray data, a total of 16,557 RefSeq (Entrez) genes, have been deposited in NCBI’s Gene Expression Omnibus and are freely available to the broad scientific community. Our microarray data could serve as a suitable background for finding key factors regulating mitochondrial metabolism and the preparation of the foetus for the transition to extra-uterine conditions.

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“…In the largest cohort of patients with COQ10D4, 44 different likely pathogenic variants of the COQ8A gene were found [ 2 ]. The most frequent subgroup of COQ8A mutation consists of missense variants [ 2 , 11 ]. Nonsense mutations, splicing, deletions, insertions and duplications, and complex rearrangement mutations were also reported [ 11 ].…”

Section: Primary Coenzyme Q10 Deficiency-4mentioning

confidence: 99%

“…Cerebellar ataxia is the most common feature of this condition [ 4 ]. The prevalence of COQ8A -ataxia is unknown; so far, 123 patients from 24 different countries have been described [ 2 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ]. In this group, only one patient from Poland has been reported [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

COQ8A-Ataxia as a Manifestation of Primary Coenzyme Q Deficiency

et al. 2022

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COQ8A-ataxia is a mitochondrial disease in which a defect in coenzyme Q10 synthesis leads to dysfunction of the respiratory chain. The disease is usually present as childhood-onset progressive ataxia with developmental regression and cerebellar atrophy. However, due to variable phenotype, it may be hard to distinguish from other mitochondrial diseases and a wide spectrum of childhood-onset cerebellar ataxia. COQ8A-ataxia is a potentially treatable condition with the supplementation of coenzyme Q10 as a main therapy; however, even 50% may not respond to the treatment. In this study we review the clinical manifestation and management of COQ8A-ataxia, focusing on current knowledge of coenzyme Q10 supplementation and approach to further therapies. Moreover, the case of a 22-month-old girl with cerebellar ataxia and developmental regression will be presented.

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Primary Coenzyme Q deficiency Due to Novel ADCK3 Variants, Studies in Fibroblasts and Review of Literature

Cited by 18 publications

References 22 publications

Multifaceted Analyses of Isolated Mitochondria Establish the Anticancer Drug 2-Hydroxyoleic Acid as an Inhibitor of Substrate Oxidation and an Activator of Complex IV-Dependent State 3 Respiration

Multifaceted Analyses of Isolated Mitochondria Establish the Anticancer Drug 2-Hydroxyoleic Acid as an Inhibitor of Substrate Oxidation and an Activator of Complex IV-Dependent State 3 Respiration

Microarray and qPCR Analysis of Mitochondrial Metabolism Activation during Prenatal and Early Postnatal Development in Rats and Humans with Emphasis on CoQ10 Biosynthesis

COQ8A-Ataxia as a Manifestation of Primary Coenzyme Q Deficiency

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