RESUMO
How does a single amino acid mutation occurring in the blinding disease, Leber's hereditary optic neuropathy (LHON), impair electron shuttling in mitochondria? We investigated changes induced by the m.3460 G>A mutation in mitochondrial protein ND1 using the tools of Molecular Dynamics and Free Energy Perturbation simulations, with the goal of determining the mechanism by which this mutation affects mitochondrial function. A recent analysis suggested that the mutation's replacement of alanine A52 with a threonine perturbs the stability of a region where binding of the electron shuttling protein, Coenzyme Q10, occurs. We found two functionally opposing changes involving the role of Coenzyme Q10. The first showed that quantum electron transfer from the terminal Fe/S complex, N2, to the Coenzyme Q10 headgroup, docked in its binding pocket, is enhanced. However, this positive adjustment is overshadowed by our finding that the mobility of Coenzyme Q10 in its oxidized and reduced states, entering and exiting its binding pocket, is disrupted by the mutation in a manner that leads to conditions promoting the generation of reactive oxygen species. An increase in reactive oxygen species caused by the LHON mutation has been proposed to be responsible for this optic neuropathy.
Assuntos
Atrofia Óptica Hereditária de Leber , Humanos , Atrofia Óptica Hereditária de Leber/genética , Espécies Reativas de Oxigênio , Complexo I de Transporte de Elétrons/genética , AlaninaRESUMO
Coenzyme Q10 (CoQ10) is an important cofactor and antioxidant for numerous cellular processes, and its deficiency has been linked to human disorders including mitochondrial disease, heart failure, Parkinson's disease, and hypertension. Unfortunately, treatment with exogenous CoQ10 is often ineffective, likely due to its extreme hydrophobicity and high molecular weight. Here, we show that less hydrophobic CoQ species with shorter isoprenoid tails can serve as viable substitutes for CoQ10 in human cells. We demonstrate that CoQ4 can perform multiple functions of CoQ10 in CoQ-deficient cells at markedly lower treatment concentrations, motivating further investigation of CoQ4 as a supplement for CoQ10 deficiencies. In addition, we describe the synthesis and evaluation of an initial set of compounds designed to target CoQ4 selectively to mitochondria using triphenylphosphonium. Our results indicate that select versions of these compounds can successfully be delivered to mitochondria in a cell model and be cleaved to produce CoQ4, laying the groundwork for further development.
Assuntos
Ataxia , Mitocôndrias , Doenças Mitocondriais , Debilidade Muscular , Ubiquinona , Humanos , Mitocôndrias/enzimologia , Doenças Mitocondriais/enzimologia , Doenças Mitocondriais/genética , Debilidade Muscular/enzimologia , Debilidade Muscular/genética , Ubiquinona/análogos & derivados , Ubiquinona/deficiência , Células Hep G2RESUMO
Coenzyme Q (CoQ) is an essential component of the electron transport system in aerobic organisms. CoQ10 has ten isoprene units in its quinone structure and is especially valuable as a food supplement. However, the CoQ biosynthetic pathway has not been fully elucidated, including synthesis of the p-hydroxybenzoic acid (PHB) precursor to form a quinone backbone. To identify the novel components of CoQ10 synthesis, we investigated CoQ10 production in 400 Schizosaccharomyces pombe gene-deleted strains in which individual mitochondrial proteins were lost. We found that deletion of coq11 (an S. cerevisiae COQ11 homolog) and a novel gene designated coq12 lowered CoQ levels to â¼4% of that of the WT strain. Addition of PHB or p-hydroxybenzaldehyde restored the CoQ content and growth and lowered hydrogen sulfide production of the Δcoq12 strain, but these compounds did not affect the Δcoq11 strain. The primary structure of Coq12 has a flavin reductase motif coupled with an NAD+ reductase domain. We determined that purified Coq12 protein from S. pombe displayed NAD+ reductase activity when incubated with ethanol-extracted substrate of S. pombe. Because purified Coq12 from Escherichia coli did not exhibit reductase activity under the same conditions, an extra protein is thought to be necessary for its activity. Analysis of Coq12-interacting proteins by LC-MS/MS revealed interactions with other Coq proteins, suggesting formation of a complex. Thus, our analysis indicates that Coq12 is required for PHB synthesis, and it has diverged among species.
Assuntos
NADH NADPH Oxirredutases , Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Cromatografia Líquida , NAD/metabolismo , NADH NADPH Oxirredutases/química , NADH NADPH Oxirredutases/genética , NADH NADPH Oxirredutases/isolamento & purificação , NADH NADPH Oxirredutases/metabolismo , Schizosaccharomyces/enzimologia , Schizosaccharomyces/genética , Schizosaccharomyces/metabolismo , Proteínas de Schizosaccharomyces pombe/química , Proteínas de Schizosaccharomyces pombe/genética , Proteínas de Schizosaccharomyces pombe/isolamento & purificação , Proteínas de Schizosaccharomyces pombe/metabolismo , Espectrometria de Massas em Tandem , Ubiquinona/análogos & derivados , Ubiquinona/metabolismoRESUMO
Maintenance of stable mitochondrial respiratory chains could enhance adaptability to high temperature, but the potential mechanism was not elucidated clearly in plants. In this study, we identified and isolated a TrFQR1 gene encoding the flavodoxin-like quinone reductase 1 (TrFQR1) located in mitochondria of leguminous white clover (Trifolium repens). Phylogenetic analysis indicated that amino acid sequences of FQR1 in various plant species showed a high degree of similarities. Ectopic expression of TrFQR1 protected yeast (Saccharomyces cerevisiae) from heat damage and toxic levels of benzoquinone, phenanthraquinone and hydroquinone. Transgenic Arabidopsis thaliana and white clover overexpressing TrFQR1 exhibited significantly lower oxidative damage and better photosynthetic capacity and growth than wild-type in response to high-temperature stress, whereas AtFQR1-RNAi A. thaliana showed more severe oxidative damage and growth retardation under heat stress. TrFQR1-transgenic white clover also maintained better respiratory electron transport chain than wild-type plants, as manifested by significantly higher mitochondrial complex II and III activities, alternative oxidase activity, NAD(P)H content, and coenzyme Q10 content in response to heat stress. In addition, overexpression of TrFQR1 enhanced the accumulation of lipids including phosphatidylglycerol, monogalactosyl diacylglycerol, sulfoquinovosyl diacylglycerol and cardiolipin as important compositions of bilayers involved in dynamic membrane assembly in mitochondria or chloroplasts positively associated with heat tolerance. TrFQR1-transgenic white clover also exhibited higher lipids saturation level and phosphatidylcholine:phosphatidylethanolamine ratio, which could be beneficial to membrane stability and integrity during a prolonged period of heat stress. The current study proves that TrFQR1 is essential for heat tolerance associated with mitochondrial respiratory chain, cellular reactive oxygen species homeostasis, and lipids remodeling in plants. TrFQR1 could be selected as a key candidate marker gene to screen heat-tolerant genotypes or develop heat-tolerant crops via molecular-based breeding.
Assuntos
Arabidopsis , Trifolium , Trifolium/genética , Trifolium/metabolismo , Flavodoxina/genética , Flavodoxina/metabolismo , Diglicerídeos/metabolismo , Filogenia , Temperatura , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Estresse Oxidativo , Arabidopsis/genética , Arabidopsis/metabolismo , Homeostase , Regulação da Expressão Gênica de Plantas , Plantas Geneticamente Modificadas/metabolismoRESUMO
Complementary and alternative medicines (CAM) are commonly used across the world by diverse populations and ethnicities but remain largely unregulated. Although many CAM agents are purported to be efficacious and safe by the public, clinical evidence supporting the use of CAM in heart failure remains limited and controversial. Furthermore, health care professionals rarely inquire or document use of CAM as part of the medical record, and patients infrequently disclose their use without further prompting. The goal of this scientific statement is to summarize published efficacy and safety data for CAM and adjunctive interventional wellness approaches in heart failure. Furthermore, other important considerations such as adverse effects and drug interactions that could influence the safety of patients with heart failure are reviewed and discussed.
Assuntos
Terapias Complementares , Insuficiência Cardíaca , Estados Unidos , Humanos , American Heart Association , Insuficiência Cardíaca/terapiaRESUMO
Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombotic events and/or pregnancy complications in the presence of persistently positive antiphospholipid antibodies (aPL). Although long-term anticoagulation with vitamin K antagonists is considered standard of care, there is an unmet need for safe therapeutics as primary thromboprophylaxis or adjuncts to standard of care in APS. APS is driven by oxidative stress, procoagulant, proinflammatory and angiogenic pathways. For these reasons there has been an increased interest into the investigation of antithrombotic, anti-inflammatory and anti-oxidant properties of natural supplements in APS. The objective of this review is to summarize the mechanistic, epidemiologic and clinical evidence behind the use of natural supplements in APS, with a specific focus on vitamin D, omega-3 fatty acids, coenzyme Q10, gingerol, and isoquercetin. This review should serve as a compelling argument for the future study of natural supplements in APS.
Assuntos
Síndrome Antifosfolipídica , Complicações na Gravidez , Tromboembolia Venosa , Feminino , Gravidez , Humanos , Anticoagulantes/uso terapêutico , Tromboembolia Venosa/complicações , Tromboembolia Venosa/tratamento farmacológico , Anticorpos Antifosfolipídeos , Complicações na Gravidez/tratamento farmacológicoRESUMO
BACKGROUND: Selenium-dependent deiodinases play a central role in thyroid hormone regulation and metabolism. In many European countries, insufficient selenium intake may consequently lead to adverse effects on thyroid function. In this randomised placebo-controlled double-blind study, we examined the effect of supplementation with selenium and coenzyme Q10 on thyroid hormonal status, cardiovascular (CV) mortality and health-related quality of life (Hr-QoL). METHODS: Free T3, free T4, reverse T3, and TSH were determined in 414 individuals at baseline, and the effect of selenium yeast (200 µg/day) and coenzyme Q10 (200 mg/day) supplementation on hormone concentrations, CV mortality and Hr-QoL was evaluated after 48 months using Short Form 36 (SF-36). Pre-intervention plasma selenium was low, mean 67 µg/L, corresponding to an estimated intake of 35 µg/day. Changes in concentrations of thyroid hormones following the intervention were assessed using T-tests, repeated measures of variance, and ANCOVA analyses. RESULTS: In the total population, the group with the lowest selenium concentration at baseline presented with significantly higher levels of TSH and lower levels of fT3 as compared to subjects with the highest selenium concentration. Supplementation with selenium and coenzyme Q10 for 4 years significantly increased fT3 and rT3, decreased fT4, and diminished the increase in TSH levels compared with placebo treatment (p = 0.03, all). In the placebo group, TSH and fT4 values above the median were associated with an increase in 10-year CV mortality, as compared with the mortality rate among those with TSH and fT4 below the median (p < 0.04, both), with no difference in mortality rate according to TSH and fT4 levels in the active intervention group. Similarly, TSH > median and fT3 < median were associated with a decline in mental Hr-QoL measures vs. TSH < and fT3 > median in the placebo group during 4 years of follow-up, but this was wiped out in the active group. CONCLUSIONS: Supplementation with selenium and coenzyme Q10 had a beneficial effect on thyroid hormones with respect to CV mortality and Hr-QoL outcomes. The initial deficient selenium status was associated with an impaired thyroid function and the changes in thyroid hormone levels can be explained by increased activity of deiodinases. We conclude that a substantial part of the elderly study population might suffer from suboptimal thyroidal function with adverse clinical implications due to selenium deficiency. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov and has the identifier NCT01443780. Since it was not mandatory to register at the time the study began, the study has been registered retrospectively.
Assuntos
Doenças Cardiovasculares , Suplementos Nutricionais , Qualidade de Vida , Selênio , Hormônios Tireóideos , Ubiquinona , Humanos , Ubiquinona/análogos & derivados , Ubiquinona/administração & dosagem , Ubiquinona/sangue , Selênio/administração & dosagem , Selênio/sangue , Masculino , Idoso , Feminino , Hormônios Tireóideos/sangue , Método Duplo-Cego , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/sangue , Suécia/epidemiologia , Idoso de 80 Anos ou mais , Pessoa de Meia-Idade , Placebos/administração & dosagemRESUMO
Status epilepticus (SE), the most severe form of epilepsy, leads to brain damage. Uncertainty persists about the mechanisms that lead to the pathophysiology of epilepsy and the death of neurons. Overloading of intracellular iron ions has recently been identified as the cause of a newly recognized form of controlled cell death called ferroptosis. Inhibiting ferroptosis has shown promise as a treatment for epilepsy, according to recent studies. So, the current study aimed to assess the possible antiepileptic impact of CoQ10 either alone or with the standard antiepileptic drug sodium valproate (SVP) and to evaluate the targeted effect of COQ10 on hippocampal oxidative stress and ferroptosis in a SE rat model. Using a lithium-pilocarpine rat model of epilepsy, we evaluated the effect of SVP, CoQ10, or both on seizure severity, histological, and immunohistochemical of the hippocampus. Furthermore, due to the essential role of oxidative stress and lipid peroxidation in inducing ferroptosis, we evaluated malonaldehyde (MDA), reduced glutathione (GSH), glutathione peroxidase 4 (GPX4), and ferritin in tissue homogenate. Our work illustrated that ferroptosis occurs in murine models of lithium-pilocarpine-induced seizures (epileptic group). Nissl staining revealed significant neurodegeneration. A significant increase in the number of astrocytes stained with an astrocyte-specific marker was observed in the hippocampus. Effective seizure relief can be achieved in the seizure model by administering CoQ10 alone compared to SVP. This was accomplished by lowering ferritin levels and increasing GPX4, reducing MDA, and increasing GSH in the hippocampus tissue homogenate. In addition, the benefits of SVP therapy for regulating iron stores, GPX4, and oxidative stress markers were amplified by incorporating CoQ10 as compared to SVP alone. It was concluded that CoQ10 alone has a more beneficial effect than SVP alone in restoring histological structures and has a targeted effect on hippocampal oxidative stress and ferroptosis. In addition, COQ10 could be useful as an adjuvant to SVP in protecting against oxidative damage and ferroptosis-related damage that result from epileptic seizures.
Assuntos
Modelos Animais de Doenças , Ferroptose , Hipocampo , Estado Epiléptico , Ubiquinona , Animais , Ferroptose/efeitos dos fármacos , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/patologia , Estado Epiléptico/induzido quimicamente , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Ubiquinona/uso terapêutico , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/metabolismo , Ratos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Pilocarpina , Ratos Sprague-Dawley , Ácido Valproico/farmacologia , Ácido Valproico/uso terapêutico , Peroxidação de Lipídeos/efeitos dos fármacosRESUMO
BACKROUND: Metabolic-dysfunction Associated Steatotic Liver Disease (MASLD) has been associated with increased cardiovascular risk. The aim of this Randomized Double-blind clinical Trial was to evaluate the effects of coenzyme-Q10 supplementation in patients with MASLD in terms of endothelial, vascular and myocardial function. METHODS: Sixty patients with MASLD were randomized to receive daily 240 mg of coenzyme-Q10 or placebo. At baseline and at 6-months, the a)Perfused boundary region of sublingual vessels using the Sideview Darkfield imaging technique, b)pulse-wave-velocity, c)flow-mediated dilation of the brachial artery, d)left ventricular global longitudinal strain, e)coronary flow reserve of the left anterior descending coronary artery and f)controlled attenuation parameter for the quantification of liver steatosis were evaluated. RESULTS: Six months post-treatment, patients under coenzyme-Q10 showed reduced Perfused boundary region (2.18 ± 0.23vs.2.29 ± 0.18 µm), pulse-wave-velocity (9.5 ± 2vs.10.2 ± 2.3 m/s), controlled attenuation parameter (280.9 ± 33.4vs.304.8 ± 37.4dB/m), and increased flow-mediated dilation (6.1 ± 3.8vs.4.3 ± 2.8%), global longitudinal strain (-19.6 ± 1.6vs.-18.8 ± 1.9%) and coronary flow reserve (3.1 ± 0.4vs.2.8 ± 0.4) compared to baseline (p < 0.05). The placebo group exhibited no improvement during the 6-month follow-up period (p > 0.05). In patients under coenzyme-Q10, the reduction in controlled attenuation parameter score was positively related to the reduction in Perfused boundary region and pulse wave velocity and reversely related to the increase in coronary flow reserve and flow-mediated dilation (p < 0.05 for all relations). CONCLUSIONS: Six-month treatment with high-dose coenzyme-Q10 reduces liver steatosis and improves endothelial, vascular and left ventricle myocardial function in patients with MASLD, demonstrating significant improvements in micro- and macro-vasculature function. TRIAL REGISTRATION: NCT05941910.
Assuntos
Endotélio Vascular , Ubiquinona , Função Ventricular Esquerda , Humanos , Método Duplo-Cego , Ubiquinona/análogos & derivados , Ubiquinona/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Resultado do Tratamento , Função Ventricular Esquerda/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Endotélio Vascular/efeitos dos fármacos , Fatores de Tempo , Suplementos Nutricionais , Idoso , Vasodilatação/efeitos dos fármacos , Adulto , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Circulação Coronária/efeitos dos fármacos , Análise de Onda de Pulso , Fígado Gorduroso/fisiopatologia , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/diagnósticoRESUMO
One of the major hitches for statins' utilization is the development of myotoxicity. Versatile studies reported that the underlining molecular mechanisms including coenzyme Q10 (CoQ10)/ubiquinone depletion, as well as the disturbance in the cytoplasmic Ca2+ homeostasis. Therefore, we investigated the consequences of supplementing CoQ10 and dantrolene, a cytoplasmic Ca2+ reducing agent, in combination with simvastatin. This adjuvant therapy normalized the simvastatin-mediated elevation in serum ALT, AST, CK-MM, as well as tissue Ca2+ content, in addition to suppressing the simvastatin-mediated oxidative stress in simvastatin-treated rats, while having no effect upon statin-induced antihyperlipidemic effect. Additionally, the combination inhibited the simvastatin-induced TGF-ß/ Smad4 pathway activation. Collectively, the current study emphasizes on the potential utilization of dantrolene and CoQ10 as an adjuvant therapy to statins treatment for improving their side effect profile.
Assuntos
Dantroleno , Dieta Hiperlipídica , Inibidores de Hidroximetilglutaril-CoA Redutases , Espécies Reativas de Oxigênio , Transdução de Sinais , Sinvastatina , Proteína Smad4 , Fator de Crescimento Transformador beta , Ubiquinona , Ubiquinona/análogos & derivados , Animais , Dantroleno/farmacologia , Dantroleno/uso terapêutico , Ubiquinona/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Masculino , Espécies Reativas de Oxigênio/metabolismo , Sinvastatina/farmacologia , Proteína Smad4/metabolismo , Ratos , Fator de Crescimento Transformador beta/metabolismo , Dieta Hiperlipídica/efeitos adversos , Doenças Musculares/induzido quimicamente , Doenças Musculares/metabolismo , Doenças Musculares/prevenção & controle , Quimioterapia Combinada , Estresse Oxidativo/efeitos dos fármacos , Ratos WistarRESUMO
We report on measurements and control of proton gradient across interfaces of water and dichloroethane. Such interfaces are interesting as mimics of biological membranes. We use impedance spectroscopy to quantify interfacial proton gradient and identify proton transfer modes. We quantify proton movement using reciprocal of time constant (τ-1 ) acquired from electrochemical impedance modeling. We show that proton gradient across interfaces of water/dichloroethane and τ-1 correlate with the aqueous phase pH, changing from ca. 1â s-1 at pHâ 1 to 0.2â s-1 at pHâ 7. τ-1 changes in the presence of proton shuttling fat-soluble molecules. Dinitrophenol acts as a pH activated proton coupler which is active at around neutral pH and inert at pH <4. However, quinone type cofactors change the interfacial proton transport when activated by redox reactions with ferrocene type molecules, such as decamethyl ferrocence (DMFc). Quinone type cofactors show distinct features in their impedance response assigned to a proton coupled electron transfer (PCET) process, different from the uncoupled proton transfer activity of dinitrophenol. The observed PCET reaction significantly changes τ-1 . We use τ-1 as a proton transport descriptor. In particular, CoQ10 -DMFc shows a τ-1 of 3.5â s-1 at pHâ 7, indicating how small-molecule assemblies change proton availability.
RESUMO
Ischaemic heart diseases (IHD) are among the major causes of mortality in the elderly population. Although timely reperfusion is a common treatment for IHD, it causes additional damage to the ischaemic myocardium known as ischaemia-reperfusion (IR) injury. Considering the importance of preventing reperfusion injuries, we aimed to examine the combination effect of mitochondrial transplantation (MT) and coenzyme Q10 (CoQ10 ) in myocardial IR injury of aged male rats. Seventy-two aged male Wistar rats were randomly divided into six groups: Sham, IR, CoQ10 , MT, combination therapy (MT + CoQ10 ) and vehicle. Myocardial IR injury was established by occlusion of the left anterior descending coronary artery followed by reopening. Young male Wistar rats were used as mitochondria donors. Isolated mitochondria were injected intraventricularly (500 µL of a respiration buffer containing 6 × 106 ± 5 × 105 mitochondria/mL) in MT-receiving groups at the onset of reperfusion. CoQ10 (10 mg/kg/day) was injected intraperitoneally for 2 weeks before IR induction. Twenty-four hours after reperfusion, haemodynamic parameters, myocardial infarct size (IS), lactate dehydrogenase (LDH) release and cardiac mitochondrial function (mitochondrial reactive oxygen species (ROS) generation and membrane potential) were measured. The combination of MT and CoQ10 improved haemodynamic index changes and reduced IS and LDH release (P < 0.05). It also decreased mitochondrial ROS generation and increased membrane potential (P < 0.05). CoQ10 also showed a significant cardioprotective effect. Combination therapy displayed greater cardioprotective effects than single treatments. This study revealed that MT and CoQ10 combination treatment can be considered as a promising cardioprotective strategy to reduce myocardial IR injury in ageing, in part by restoring mitochondrial function.
RESUMO
BACKGROUND: Among the three most used anticancer drugs, cyclophosphamide, Adriamycin, and 5-Fluorouracil (CAF), the most significant outcome is chemobrain, caused by increased oxidative stress, inflammatory insult, and mitochondrial dysfunction. OBJECTIVE: In this study, endogenous antioxidant coenzyme Q10 (CoQ10) was evaluated for its neuroprotective effects in CICI. MATERIALS AND METHODS: The chemobrain was induced in Swiss albino female mice by administering CAF (40 + 4 + 25 mg/kg) intraperitoneal (i.p.) in three cycles (single injection per week) followed by treatment with CoQ10 (40 mg/kg; p.o.) for up to 3 weeks followed by behavioral, biochemical, molecular and histopathological analysis. RESULTS: Treatment with CoQ10 significantly improved cognition by improving exploring time in novel objects recognition test followed by increasing the time spent in the target quadrant in MWM test as compared to CAF-treated animals. Moreover, CoQ10 demonstrated antioxidant properties by reducing the expression of LPO while increasing levels of GSH, SOD, and catalase as compared to CAF-treated animals. While the levels of AChEs were significantly reduced after CoQ10 treatment in CAF-treated animals. In terms of its mechanism, it effectively counteracted the pro-inflammatory substances (TNF-α and IL-1ß) triggered by CAF while also enhancing the levels of anti-inflammatory markers (IL-10 and Nrf2). Moreover, CoQ10 showed mitochondrial enhancers and it improved the level of Complex (I, II, and IV). Besides that, mitochondrial morphological analysis was done by TEM, and neuronal morphology along with quantification analysis was performed by H&E staining using Image J software to confirm the neuroprotective effect of CoQ10 over CAF-induced cognitive impairment. CONCLUSION: This study suggests CoQ10 can protect the mitochondria by imposing antioxidant, and anti-inflammatory properties, which could be a potential therapy for CICI.
Assuntos
Antioxidantes , Estresse Oxidativo , Ubiquinona , Animais , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Ubiquinona/uso terapêutico , Camundongos , Feminino , Antioxidantes/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Comprometimento Cognitivo Relacionado à Quimioterapia/tratamento farmacológico , Comprometimento Cognitivo Relacionado à Quimioterapia/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Doxorrubicina/efeitos adversos , Fluoruracila/efeitos adversos , Fluoruracila/farmacologia , Modelos Animais de Doenças , Antineoplásicos/farmacologia , Antineoplásicos/efeitos adversos , Ciclofosfamida/efeitos adversos , Ciclofosfamida/farmacologiaRESUMO
Fragile X syndrome (FXS) is a genetic disorder characterized by mutation in the FMR1 gene, leading to the absence or reduced levels of fragile X Messenger Ribonucleoprotein 1 (FMRP). This results in neurodevelopmental deficits, including autistic spectrum conditions. On the other hand, Fragile X-associated tremor/ataxia syndrome (FXTAS) is a distinct disorder caused by the premutation in the FMR1 gene. FXTAS is associated with elevated levels of FMR1 mRNA, leading to neurodegenerative manifestations such as tremors and ataxia.Mounting evidence suggests a link between both syndromes and mitochondrial dysfunction (MDF). In this minireview, we critically examine the intricate relationship between FXS, FXTAS, and MDF, focusing on potential therapeutic avenues to counteract or mitigate their adverse effects. Specifically, we explore the role of mitochondrial cofactors and antioxidants, with a particular emphasis on alpha-lipoic acid (ALA), carnitine (CARN) and Coenzyme Q10 (CoQ10). Findings from this review will contribute to a deeper understanding of these disorders and foster novel therapeutic strategies to enhance patient outcomes.
Assuntos
Síndrome do Cromossomo X Frágil , Doenças Mitocondriais , Humanos , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Síndrome do Cromossomo X Frágil/genética , Tremor/tratamento farmacológico , Tremor/genética , Antioxidantes/uso terapêutico , Ataxia/tratamento farmacológico , Ataxia/genética , Proteína do X Frágil da Deficiência Intelectual/genéticaRESUMO
Distal hereditary motor neuropathy represents a group of motor inherited neuropathies leading to distal weakness. We report a family of two brothers and a sister affected by distal hereditary motor neuropathy in whom a homozygous variant c.3G>T (p.1Met?) was identified in the COQ7 gene. This gene encodes a protein required for coenzyme Q10 biosynthesis, a component of the respiratory chain in mitochondria. Mutations of COQ7 were previously associated with severe multi-organ disorders characterized by early childhood onset and developmental delay. Using patient blood samples and fibroblasts derived from a skin biopsy, we investigated the pathogenicity of the variant of unknown significance c.3G>T (p.1Met?) in the COQ7 gene and the effect of coenzyme Q10 supplementation in vitro. We showed that this variation leads to a severe decrease in COQ7 protein levels in the patient's fibroblasts, resulting in a decrease in coenzyme Q10 production and in the accumulation of 6-demethoxycoenzyme Q10, the COQ7 substrate. Interestingly, such accumulation was also found in the patient's plasma. Normal coenzyme Q10 and 6-demethoxycoenzyme Q10 levels were restored in vitro by using the coenzyme Q10 precursor 2,4-dihydroxybenzoic acid, thus bypassing the COQ7 requirement. Coenzyme Q10 biosynthesis deficiency is known to impair the mitochondrial respiratory chain. Seahorse experiments showed that the patient's cells mainly rely on glycolysis to maintain sufficient ATP production. Consistently, the replacement of glucose by galactose in the culture medium of these cells reduced their proliferation rate. Interestingly, normal proliferation was restored by coenzyme Q10 supplementation of the culture medium, suggesting a therapeutic avenue for these patients. Altogether, we have identified the first example of recessive distal hereditary motor neuropathy caused by a homozygous variation in the COQ7 gene, which should thus be included in the gene panels used to diagnose peripheral inherited neuropathies. Furthermore, 6-demethoxycoenzyme Q10 accumulation in the blood can be used to confirm the pathogenic nature of the mutation. Finally, supplementation with coenzyme Q10 or derivatives should be considered to prevent the progression of COQ7-related peripheral inherited neuropathy in diagnosed patients.
Assuntos
Doenças Mitocondriais , Ubiquinona , Masculino , Humanos , Pré-Escolar , Ubiquinona/uso terapêutico , Mutação/genética , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/genética , Ataxia/genéticaRESUMO
COQ8A-ataxia is a rare form of neurodegenerative disorder due to mutations in the COQ8A gene. The encoded mitochondrial protein is involved in the regulation of coenzyme Q10 biosynthesis. Previous studies on the constitutive Coq8a-/- mice indicated specific alterations of cerebellar Purkinje neurons involving altered electrophysiological function and dark cell degeneration. In the present manuscript, we extend our understanding of the contribution of Purkinje neuron dysfunction to the pathology. By generating a Purkinje-specific conditional COQ8A knockout, we demonstrate that loss of COQ8A in Purkinje neurons is the main cause of cerebellar ataxia. Furthermore, through in vivo and in vitro approaches, we show that COQ8A-depleted Purkinje neurons have abnormal dendritic arborizations, altered mitochondria function and intracellular calcium dysregulation. Furthermore, we demonstrate that oxidative phosphorylation, in particular Complex IV, is primarily altered at presymptomatic stages of the disease. Finally, the morphology of primary Purkinje neurons as well as the mitochondrial dysfunction and calcium dysregulation could be rescued by CoQ10 treatment, suggesting that CoQ10 could be a beneficial treatment for COQ8A-ataxia.
Assuntos
Ataxia Cerebelar , Camundongos , Animais , Ataxia Cerebelar/tratamento farmacológico , Ataxia Cerebelar/genética , Ataxia Cerebelar/metabolismo , Células de Purkinje/patologia , Cálcio/metabolismo , Ataxia/tratamento farmacológico , Ataxia/genética , Ataxia/metabolismo , Mitocôndrias/metabolismoRESUMO
Heavy metal contamination is an alarming concern on a global scale, as drinking tainted water significantly increases human susceptibility to heavy metals. In a realistic scenario, humans are often exposed to a combination of harmful chemicals rather than a single toxicant. Phloretin (PHL), biochanin-A (BCA), and coenzyme Q10 (CoQ10) are bioactive compounds owning plentiful pharmacological properties. Henceforth, the current research explored the putative energizing effects of selected nutraceuticals in combined chromium (Cr) and arsenic (As) intoxicated Swiss albino mice. Potassium dichromate (75 ppm) and sodium meta-arsenite (100 ppm) were given in the drinking water to induce hepatotoxicity, conjugated with PHL and BCA (50 mg/kg each), and CoQ10 (10 mg/kg) intraperitoneally for 2 weeks. After the statistical evaluation, it was observed that the hepato-somatic index, metal load, and antioxidant activity (lipid peroxidation and protein carbonyl content) increased along with the concomitant decrease in the antioxidants (catalase, glutathione-S-transferase, superoxide dismutase, reduced glutathione, and total thiol) in the Cr and As intoxicated mice. Additionally, light microscopy observations, DNA breakages, decreased silent information regulator 1 (SIRT1), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase (HO-1), and NAD(P)H quinone dehydrogenase 1 (NQO1) gene expressions, together with stimulated apoptotic cell death manifested by the increased expressions of caspase 8 and caspase 3, thus, proved consistency with the aforementioned outcomes. Importantly, the treatment with nutraceuticals not only restored the antioxidant activity but also favorably altered the expressions of SIRT1, Nrf2, HO-1, and NQO1 signaling and apoptosis markers. These findings highlight the crucial role of the PHL, BCA, and CoQ10 combination in reducing Cr and As-induced hepatotoxicity in mice. By averting the triggered apoptosis in conjunction with oxidative stress, this combination increases the SIRT1, Nrf2, HO-1, and NQO1 signaling, thereby reassuringly maintaining the cellular equilibrium.
Assuntos
Apoptose , Cromo , Genisteína , Fígado , NAD(P)H Desidrogenase (Quinona) , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Floretina , Transdução de Sinais , Sirtuína 1 , Ubiquinona , Animais , Sirtuína 1/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Camundongos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Genisteína/farmacologia , Apoptose/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Cromo/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Floretina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Masculino , Arsênio/toxicidade , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase-1/metabolismo , Proteínas de MembranaRESUMO
BACKGROUND: The protective effect of Coenzyme Q10 (CoQ10) on the cardiovascular system has been reported, however, whether it can promote early recovery of cardiac function and alleviate cardiac remodeling after myocardial infarction (MI) remains to be elucidated. Whether CoQ10 may regulate the macrophage-mediated pro-inflammatory response after MI and its potential mechanism are worth further exploration. METHODS: To determine the baseline plasma levels of CoQ10 by LC-MS/MS, healthy controls and MI patients (n = 11 each) with age- and gender-matched were randomly enrolled. Additional MI patients were consecutively enrolled and randomized into the blank control (n = 59) or CoQ10 group (n = 61). Follow-ups were performed at 1- and 3-month to assess cardiac function after percutaneous coronary intervention (PCI). In the animal study, mice were orally administered CoQ10/vehicle daily and were subjected to left anterior descending coronary artery (LAD) ligation or sham operation. Echocardiography and serum BNP measured by ELISA were analyzed to evaluate cardiac function. Masson staining and WGA staining were performed to analyze the myocardial fibrosis and cardiomyocyte hypertrophy, respectively. Immunofluorescence staining was performed to assess the infiltration of IL1ß/ROS-positive macrophages into the ischemic myocardium. Flow cytometry was employed to analyze the recruitment of myeloid immune cells to the ischemic myocardium post-MI. The expression of inflammatory indicators was assessed through RNA-seq, qPCR, and western blotting (WB). RESULTS: Compared to controls, MI patients showed a plasma deficiency of CoQ10 (0.76 ± 0.31 vs. 0.46 ± 0.10 µg/ml). CoQ10 supplementation significantly promoted the recovery of cardiac function in MI patients at 1 and 3 months after PCI. In mice study, compared to vehicle-treated MI mice, CoQ10-treated MI mice showed a favorable trend in survival rate (42.85% vs. 61.90%), as well as significantly alleviated cardiac dysfunction, myocardial fibrosis, and cardiac hypertrophy. Notably, CoQ10 administration significantly suppressed the recruitment of pro-inflammatory CCR2+ macrophages into infarct myocardium and their mediated inflammatory response, partially by attenuating the activation of the NLR family pyrin domain containing 3 (NLRP3)/Interleukin-1 beta (IL1ß) signaling pathway. CONCLUSIONS: These findings suggest that CoQ10 can significantly promote early recovery of cardiac function after MI. CoQ10 may function by inhibiting the recruitment of CCR2+ macrophages and suppressing the activation of the NLRP3/IL1ß pathway in macrophages. TRIAL REGISTRATION: Date of registration 09/04/2021 (number: ChiCTR2100045256).
Assuntos
Infarto do Miocárdio , Intervenção Coronária Percutânea , Ubiquinona , Animais , Humanos , Camundongos , Cromatografia Líquida , Modelos Animais de Doenças , Fibrose , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espectrometria de Massas em Tandem , Ubiquinona/análogos & derivados , Ubiquinona/sangue , Remodelação VentricularRESUMO
The efficacy of mesenchymal stem cell (MSC) transplantation has been reported for various diseases. We previously developed a drug delivery system targeting mitochondria (MITO-Porter) by using a microfluidic device to encapsulate Coenzyme Q10 (CoQ10) on a large scale. The current study aimed to confirm if treatment with CoQ10 encapsulated by MITO-Porter enhanced mitochondrial functions in MSCs, with the potential to improve MSC transplantation therapy. We used highly purified human bone marrow-derived MSCs, described as rapidly expanding clones (RECs), and attempted to control and increase the amount of CoQ10 encapsulated in the MITO-Porter using microfluidic device system. We treated these RECs with CoQ10 encapsulated MITO-Porter, and evaluated its cellular uptake, co-localization with mitochondria, changes in mitochondrial respiratory capacity, and cellular toxicity. There was no significant change in mitochondrial respiratory capacity following treatment with the previous CoQ10 encapsulated MITO-Porter; however, mitochondrial respiratory capacity in RECs was significantly increased by treatment with CoQ10-rich MITO-Porter. Utilization of a microfluidic device enabled the amount of CoQ10 encapsulated in MITO-Porter to be controlled, and treatment with CoQ10-rich MITO-Porter successfully activated mitochondrial functions in MSCs. The MITO-Porter system thus provides a promising tool to improve MSC cell transplantation therapy.
Assuntos
Células-Tronco Mesenquimais , Mitocôndrias , Ubiquinona , Ubiquinona/análogos & derivados , Ubiquinona/administração & dosagem , Ubiquinona/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Células Cultivadas , Dispositivos Lab-On-A-ChipRESUMO
Principles and problems in the development of simultaneous liquid chromatography (LC) analytical methods for potent antioxidative molecules resveratrol, tocopherol, and coenzyme Q10 in capsules, have been investigated and systematically compared and summarized. For these purposes, experiments within the full polarity spectrum of LC techniques. were tested and recorded. The whole range of polarities included: Alkyl C18 bonded reversed phase, phenyl, cyanopropyl, diol, and the most polar base silica-filled column matrixes have been used. The summarized results concluded that all mentioned LC techniques could be used for the determination of the mentioned group of the three analytes with different run characteristics and efficiency. These successes could be achieved after careful analyses of molecular physicochemical data of analytes. They are especially organic solubilities. The ultraviolet spectral absorption characteristics of each analyte and the mobile phase constituents for appropriate separation were very important to be known. The ultimate targets were the development method with the isocratic mode of separation yielding symmetrical peak shapes for the best sensitivity and accuracy, with the shortest run time and best reproducibility. From an analytical point of view important for LC, the three analytes have quite distinct characteristics that contribute to successful method development. These features are their organic solvent and water solubility, molecular polarities, and ultraviolet-absorption characteristics, like spectra and absorptivities. All these mentioned parameters were taken into account for solving complications appearing in the development of rapid LC methods for the simultaneous determination of three antioxidant molecules.