RESUMO
Obesity represents a significant health challenge, intricately linked to conditions such as type II diabetes, metabolic syndrome, and hepatic steatosis. Several existing obesity treatments exhibit limited efficacy, undesirable side effects or a limited capability to maintain therapeutics effects in the long-term. Recently, modulation Coenzyme Q (CoQ) metabolism has emerged as a promising target for treatment of metabolic syndrome. This potential intervention could involve the modulation of endogenous CoQ biosynthesis by the use of analogs of the precursor of its biosynthesis, such as ß-resorcylic acid (ß-RA). Here, we show that oral supplementation with ß-RA, incorporated into the diet of diet-induced obese (DIO) mice, leads to substantial weight loss. The anti-obesity effects of ß-RA are partially elucidated through the normalization of mitochondrial CoQ metabolism in white adipose tissue (WAT). Additionally, we identify an HFN4α/LXR-dependent transcriptomic activation of the hepatic lipid metabolism that contributes to the anti-obesity effects of ß-RA. Consequently, ß-RA mitigates WAT hypertrophy, prevents hepatic steatosis, counteracts metabolic abnormalities in WAT and liver, and enhances glucose homeostasis by reducing the insulin/glucagon ratio and plasma levels of gastric inhibitory peptide (GIP). Moreover, pharmacokinetic evaluation of ß-RA supports its translational potential. Thus, ß-RA emerges as an efficient, safe, and translatable therapeutic option for the treatment and/or prevention of obesity, metabolic dysfunction-associated steatotic liver disease (MASLD).
Assuntos
Camundongos Endogâmicos C57BL , Obesidade , Animais , Obesidade/metabolismo , Obesidade/tratamento farmacológico , Camundongos , Masculino , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Ubiquinona/metabolismo , Ubiquinona/administração & dosagem , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/patologia , Fígado/metabolismo , Fígado/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Administração Oral , Dieta Hiperlipídica/efeitos adversos , HumanosRESUMO
Coenzyme Q (CoQ) deficiency syndrome is conventionally treated with limited efficacy using exogenous CoQ10. Poor outcomes result from low absorption and bioavailability of CoQ10 and the clinical heterogenicity of the disease. Here, we demonstrate that supplementation with 4-hydroxybenzoic acid (4HB), the precursor of the benzoquinone ring in the CoQ biosynthetic pathway, completely rescues multisystemic disease and perinatal lethality in a mouse model of CoQ deficiency. 4HB stimulates endogenous CoQ biosynthesis in tissues of Coq2 mutant mice, normalizing mitochondrial function and rescuing cardiac insufficiency, edema, and neurodevelopmental delay. In contrast, exogenous CoQ10 supplementation falls short in fully restoring the phenotype. The treatment is translatable to human use, as proven by in vitro studies in skin fibroblasts from patients with pathogenic variants in COQ2. The therapeutic approach extends to other disorders characterized by deficiencies in the production of 4HB and early steps of CoQ biosynthesis and instances of secondary CoQ deficiency.
Assuntos
Modelos Animais de Doenças , Doenças Mitocondriais , Parabenos , Ubiquinona , Animais , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/patologia , Doenças Mitocondriais/metabolismo , Parabenos/farmacologia , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Ubiquinona/metabolismo , Ubiquinona/deficiência , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Humanos , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Debilidade Muscular/tratamento farmacológico , Debilidade Muscular/metabolismo , Debilidade Muscular/patologia , Ataxia/tratamento farmacológico , Ataxia/patologia , Ataxia/metabolismoRESUMO
The purpose of this short essay is to describe the data management processes utilized in the Long Term Career Outcome Study at the Center for Health Professions Education and the Postgraduate Dental College of the Uniformed Services University. It includes descriptions of our workflow, how we obtain the data, challenges, and recommendations based on our experience for data managers and institutions to follow. This descriptive writing may help guide practice for other institutions looking to streamline their data management plan.
Assuntos
Redação , Humanos , UniversidadesRESUMO
The oncostatic effects of melatonin correlate with increased reactive oxygen species (ROS) levels, but how melatonin induces this ROS generation is unknown. In the present study, we aimed to elucidate the two seemingly opposing actions of melatonin regarding its relationship with free radicals. We analyzed the effects of melatonin on head and neck squamous cell carcinoma cell lines (Cal-27 and SCC-9), which were treated with 0.5 or 1 mM melatonin. We further examined the potential effects of melatonin to induce ROS and apoptosis in Cal-27 xenograft mice. Here we report that melatonin mediates apoptosis in head and neck cancer by driving mitochondrial reverse electron transport (RET) to induce ROS production. Melatonin-induced changes in tumoral metabolism led to increased mitochondrial activity, which, in turn, induced ROS-dependent mitochondrial uncoupling. Interestingly, mitochondrial complex inhibitors, including rotenone, abolished the ROS elevation indicating that melatonin increased ROS generation via RET. Melatonin also increased membrane potential and CoQ10 H2 /CoQ10 ratio to elevate mitochondrial ROS production, which are essential conditions for RET. We found that genetic manipulation of cancer cells with alternative oxidase, which transfers electrons from QH2 to oxygen, inhibited melatonin-induced ROS generation, and apoptosis. RET restored the melatonin-induced oncostatic effect, highlighting the importance of RET as the site of ROS production. These results illustrate that RET and ROS production are crucial factors in melatonin's effects in cancer cells and establish the dual effect of melatonin in protecting normal cells and inducing apoptosis in cancer cells.
Assuntos
Neoplasias de Cabeça e Pescoço , Melatonina , Animais , Apoptose , Transporte de Elétrons , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Melatonina/farmacologia , Camundongos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Defects in Coenzyme Q (CoQ) metabolism have been associated with primary mitochondrial disorders, neurodegenerative diseases and metabolic conditions. The consequences of CoQ deficiency have not been fully addressed, and effective treatment remains challenging. Here, we use mice with primary CoQ deficiency (Coq9R239X), and we demonstrate that CoQ deficiency profoundly alters the Q-junction, leading to extensive changes in the mitochondrial proteome and metabolism in the kidneys and, to a lesser extent, in the brain. CoQ deficiency also induces reactive gliosis, which mediates a neuroinflammatory response, both of which lead to an encephalopathic phenotype. Importantly, treatment with either vanillic acid (VA) or ß-resorcylic acid (ß-RA), two analogs of the natural precursor for CoQ biosynthesis, partially restores CoQ metabolism, particularly in the kidneys, and induces profound normalization of the mitochondrial proteome and metabolism, ultimately leading to reductions in gliosis, neuroinflammation and spongiosis and, consequently, reversing the phenotype. Together, these results provide key mechanistic insights into defects in CoQ metabolism and identify potential disease biomarkers. Furthermore, our findings clearly indicate that the use of analogs of the CoQ biosynthetic precursor is a promising alternative therapy for primary CoQ deficiency and has potential for use in the treatment of more common neurodegenerative and metabolic diseases that are associated with secondary CoQ deficiency.
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BACKGROUND: Numerous contemporary non-persistent pesticides may elicit neurodevelopmental impairments. Brain-derived neurotrophic factor (BDNF) has been proposed as a novel effect biomarker of neurological function that could help to understand the biological responses of some environmental exposures. OBJECTIVES: To investigate the relationship between exposure to various non-persistent pesticides, BDNF, and behavioral functioning among adolescents. METHODS: The concentrations of organophosphate (OP) insecticide metabolites 3,5,6-trichloro-2-pyridinol (TCPy), 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMPy), malathion diacid (MDA), and diethyl thiophosphate (DETP); metabolites of pyrethroids 3-phenoxybenzoic acid (3-PBA) and dimethylcyclopropane carboxylic acid (DCCA), the metabolite of insecticide carbaryl 1-naphthol (1-N), and the metabolite of ethylene-bis-dithiocarbamate fungicides ethylene thiourea (ETU) were measured in spot urine samples, as well as serum BDNF protein levels and blood DNA methylation of Exon IV of BDNF gene in 15-17-year-old boys from the INMA-Granada cohort in Spain. Adolescents' behavior was reported by parents using the Child Behavior Check List (CBCL/6-18). This study included 140 adolescents of whom 118 had data on BDNF gene DNA methylation. Multivariable linear regression, weighted quantile sum (WQS) for mixture effects, and mediation models were fit. RESULTS: IMPy, MDA, DCCA, and ETU were detected in more than 70% of urine samples, DETP in 53%, and TCPy, 3-PBA, and 1-N in less than 50% of samples. Higher levels of IMPy, TCPy, and ETU were significantly associated with more behavioral problems as social, thought problems, and rule-breaking symptoms. IMPy, MDA, DETP, and 1-N were significantly associated with decreased serum BDNF levels, while MDA, 3-PBA, and ETU were associated with higher DNA methylation percentages at several CpGs. WQS models suggest a mixture effect on more behavioral problems and BDNF DNA methylation at several CpGs. A mediated effect of serum BDNF within IMPy-thought and IMPy-rule breaking associations was suggested. CONCLUSION: BDNF biomarkers measured at different levels of biological complexity provided novel information regarding the potential disruption of behavioral function due to contemporary pesticides, highlighting exposure to diazinon (IMPy) and the combined effect of IMPy, MDA, DCCA, and ETU. However, further research is warranted.
Assuntos
Comportamento do Adolescente , Fator Neurotrófico Derivado do Encéfalo , Praguicidas , Adolescente , Comportamento do Adolescente/efeitos dos fármacos , Biomarcadores , Fator Neurotrófico Derivado do Encéfalo/genética , Exposição Ambiental/efeitos adversos , Etilenos , Humanos , Masculino , Compostos Organofosforados/urina , Praguicidas/toxicidade , Praguicidas/urina , Piretrinas/urinaRESUMO
Coenzyme Q (CoQ) is a vital lipophilic molecule that is endogenously synthesized in the mitochondria of each cell. The CoQ biosynthetic pathway is complex and not completely characterized, and it involves at least thirteen catalytic and regulatory proteins. Once it is synthesized, CoQ exerts a wide variety of mitochondrial and extramitochondrial functions thank to its redox capacity and its lipophilicity. Thus, low levels of CoQ cause diseases with heterogeneous clinical symptoms, which are not always understood. The decreased levels of CoQ may be primary caused by defects in the CoQ biosynthetic pathway or secondarily associated with other diseases. In both cases, the pathomechanisms are related to the CoQ functions, although further experimental evidence is required to establish this association. The conventional treatment for CoQ deficiencies is the high doses of oral CoQ10 supplementation, but this therapy is not effective for some specific clinical presentations, especially in those involving the nervous system. To better understand the CoQ biosynthetic pathway, the biological functions linked to CoQ and the pathomechanisms of CoQ deficiencies, and to improve the therapeutic outcomes of this syndrome, a variety of animal models have been generated and characterized in the last decade. In this review, we show all the animal models available, remarking on the most important outcomes that each model has provided. Finally, we also comment some gaps and future research directions related to CoQ metabolism and how the current and novel animal models may help in the development of future research studies.
RESUMO
Coenzyme Q10 (CoQ10) is classically viewed as an important endogenous antioxidant and key component of the mitochondrial respiratory chain. For this second function, CoQ molecules seem to be dynamically segmented in a pool attached and engulfed by the super-complexes I + III, and a free pool available for complex II or any other mitochondrial enzyme that uses CoQ as a cofactor. This CoQ-free pool is, therefore, used by enzymes that link the mitochondrial respiratory chain to other pathways, such as the pyrimidine de novo biosynthesis, fatty acid ß-oxidation and amino acid catabolism, glycine metabolism, proline, glyoxylate and arginine metabolism, and sulfide oxidation metabolism. Some of these mitochondrial pathways are also connected to metabolic pathways in other compartments of the cell and, consequently, CoQ could indirectly modulate metabolic pathways located outside the mitochondria. Thus, we review the most relevant findings in all these metabolic functions of CoQ and their relations with the pathomechanisms of some metabolic diseases, highlighting some future perspectives and potential therapeutic implications.
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BACKGROUND: Mitochondrial disorders are genetic diseases for which therapy remains woefully inadequate. Therapy of these disorders is particularly challenging partially due to the heterogeneity and tissue-specificity of pathomechanisms involved in these disorders. Abnormalities in hydrogen sulfide (H2S) metabolism are emerging as novel mechanism in mitochondrial dysfunction. However, further studies are necessary to understand the effects, protective or detrimental, of these abnormalities, and their relevance, in mitochondrial diseases. AIM OF REVIEW: To review the recent evidences of derangement of the metabolism of H2S, at biosynthesis or oxidation levels, in mitochondrial dysfunction, focusing specifically on the alterations of H2S oxidation caused by primary Coenzyme Q (CoQ) deficiency. KEY SCIENTIFIC CONCEPTS OF REVIEW: Mitochondria play a key role in the regulation of H2S and GSH metabolism pathways. However, further studies are needed to understand the consequences of abnormalities of H2S and GSH synthesis on the oxidation pathway, and vice versa; and on the levels of H2S and GSH, their tissue-specific detrimental effects, and their role the role in mitochondrial diseases. Beside the known H2S pathways, additional, tissue-specific, enzymatic systems, involved in H2S production and elimination, might exist.
RESUMO
Abnormalities of one carbon, glutathione and sulfide metabolisms have recently emerged as novel pathomechanisms in diseases with mitochondrial dysfunction. However, the mechanisms underlying these abnormalities are not clear. Also, we recently showed that sulfide oxidation is impaired in Coenzyme Q10 (CoQ10) deficiency. This finding leads us to hypothesize that the therapeutic effects of CoQ10, frequently administered to patients with primary or secondary mitochondrial dysfunction, might be due to its function as cofactor for sulfide:quinone oxidoreductase (SQOR), the first enzyme in the sulfide oxidation pathway. Here, using biased and unbiased approaches, we show that supraphysiological levels of CoQ10 induces an increase in the expression of SQOR in skin fibroblasts from control subjects and patients with mutations in Complex I subunits genes or CoQ biosynthetic genes. This increase of SQOR induces the downregulation of the cystathionine ß-synthase and cystathionine γ-lyase, two enzymes of the transsulfuration pathway, the subsequent downregulation of serine biosynthesis and the adaptation of other sulfide linked pathways, such as folate cycle, nucleotides metabolism and glutathione system. These metabolic changes are independent of the presence of sulfur aminoacids, are confirmed in mouse models, and are recapitulated by overexpression of SQOR, further proving that the metabolic effects of CoQ10 supplementation are mediated by the overexpression of SQOR. Our results contribute to a better understanding of how sulfide metabolism is integrated in one carbon metabolism and may explain some of the benefits of CoQ10 supplementation observed in mitochondrial diseases.
Assuntos
Ataxia/patologia , Carbono/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Mitocôndrias/patologia , Doenças Mitocondriais/patologia , Debilidade Muscular/patologia , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/metabolismo , Sulfetos/metabolismo , Ubiquinona/análogos & derivados , Ubiquinona/deficiência , Animais , Ataxia/genética , Ataxia/metabolismo , Transporte de Elétrons , Complexo I de Transporte de Elétrons/genética , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Glutationa/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Debilidade Muscular/genética , Debilidade Muscular/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/genética , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Transcriptoma , Ubiquinona/genética , Ubiquinona/metabolismo , Ubiquinona/farmacologia , Vitaminas/farmacologiaRESUMO
Coenzyme Q (CoQ) is an essential endogenously synthesized molecule that links different metabolic pathways to mitochondrial energy production thanks to its location in the mitochondrial inner membrane and its redox capacity, which also provide it with the capability to work as an antioxidant. Although defects in CoQ biosynthesis in human and mouse models cause CoQ deficiency syndrome, some animals models with particular defects in the CoQ biosynthetic pathway have shown an increase in life span, a fact that has been attributed to the concept of mitohormesis. Paradoxically, CoQ levels decline in some tissues in human and rodents during aging and coenzyme Q10 (CoQ10) supplementation has shown benefits as an anti-aging agent, especially under certain conditions associated with increased oxidative stress. Also, CoQ10 has shown therapeutic benefits in aging-related disorders, particularly in cardiovascular and metabolic diseases. Thus, we discuss the paradox of health benefits due to a defect in the CoQ biosynthetic pathway or exogenous supplementation of CoQ10.
Assuntos
Envelhecimento , Ataxia , Doenças Mitocondriais , Debilidade Muscular , Ubiquinona/análogos & derivados , Ubiquinona/deficiência , Adulto , Animais , Antioxidantes , Caenorhabditis elegans , Dieta , Feminino , Hormese/fisiologia , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Mitocôndrias/fisiologia , Ratos , Adulto JovemRESUMO
Head and neck cancer is the sixth leading cancer by incidence worldwide. Unfortunately, drug resistance and relapse are the principal limitations of clinical oncology for many patients, and the failure of conventional treatments is an extremely demoralizing experience. It is therefore crucial to find new therapeutic targets and drugs to enhance the cytotoxic effects of conventional treatments without potentiating or offsetting the adverse effects. Melatonin has oncostatic effects, although the mechanisms involved and doses required remain unclear. The purpose of this study is to determine the precise underlying mitochondrial mechanisms of melatonin, which increase the cytotoxicity of oncological treatments, and also to propose new melatonin treatments in order to alleviate and reverse radio- and chemoresistant processes. We analyzed the effects of melatonin on head and neck squamous cell carcinoma (HNSCC) cell lines (Cal-27 and SCC-9), which were treated with 0.1, 0.5, 1, and 1.5 mM melatonin combined with 8 Gy irradiation or 10 µM cisplatin. Clonogenic and MTT assays, as well as autophagy and apoptosis, involving flow cytometry and western blot, were performed in order to determine the cytotoxic effects of the treatments. Mitochondrial function was evaluated by measuring mitochondrial respiration, mtDNA content (RT-PCR), and mitochondrial mass (NAO). ROS production, antioxidant enzyme activity, and GSH/GSSG levels were analyzed using a fluorometric method. We show that high concentrations of melatonin potentiate the cytotoxic effects of radiotherapy and CDDP in HNSCC, which are associated with increased mitochondrial function in these cells. In HNSCC, melatonin induces intracellular ROS, whose accumulation plays an upstream role in mitochondria-mediated apoptosis and autophagy. Our findings indicate that melatonin, at high concentrations, combined with cisplatin and radiotherapy to improve its effectiveness, is a potential adjuvant agent.
Assuntos
Antineoplásicos/uso terapêutico , Antioxidantes/uso terapêutico , Cisplatino/uso terapêutico , Melatonina/uso terapêutico , Mitocôndrias/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Apoptose , Autofagia , Cisplatino/farmacologia , Humanos , Melatonina/farmacologia , Espécies Reativas de Oxigênio , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologiaRESUMO
To investigate the role of NLRP3 inflammasome in muscular aging, we evaluated here the morphological and functional markers of sarcopenia in the NLRP3-knockout mice, as well as the beneficial effect of melatonin supplementation. The gastrocnemius muscles of young (3 months), early-aged (12 months), and old-aged (24 months) NLRP3-knockout female mice were examined. Moreover, locomotor activity and apoptosis were assessed. The results revealed early markers of sarcopenia at the age of 12 months, including reduction of lactate, ratio of muscle weight to body weight, muscle fibers number, and mitochondrial number. Increased interstitial tissues, apoptosis, and muscle fibers area, as well as mitochondrial damage were detected, with little muscular activity effects. In the old-aged, these alterations progressed with a reduction in locomotor activity, mitochondrial cristae destruction, nuclear fragmentation, tubular aggregates (TAs) formation, and increased frailty index. Oral melatonin supplementation preserved the normal muscular structure, muscle fibers number, and muscular activity in old age. Melatonin enhanced lactate production, recovered mitochondria, inhibited TAs formation, reduced apoptosis, and normalized frailty index. The fewer sarcopenic changes as well as the highly detectable prophylactic effects of melatonin treatment reported here in the muscle of NLRP3-knockout mice comparing with that previously detected in wild-type mice, confirming NLRP3 inflammasome implication in muscular aging and sarcopenia onset and progression.
Assuntos
Envelhecimento/genética , Inflamassomos/genética , Melatonina/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Sarcopenia/genética , Envelhecimento/fisiologia , Animais , Biópsia por Agulha , Feminino , Regulação da Expressão Gênica , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Força Muscular/genética , Força Muscular/fisiologia , Sarcopenia/patologia , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: The vast majority of mitochondrial disorders have limited the clinical management to palliative care. Rapamycin has emerged as a potential therapeutic drug for mitochondrial diseases since it has shown therapeutic benefits in a few mouse models of mitochondrial disorders. However, the underlying therapeutic mechanism is unclear, the minimal effective dose needs to be defined and whether this therapy can be generally used is unknown. METHODS: We have evaluated whether low and high doses of rapamycin administration may result in therapeutic effects in a mouse model (Coq9R239X) of mitochondrial encephalopathy due to CoQ deficiency. The evaluation involved phenotypic, molecular, image (histopathology and MRI), metabolomics, transcriptomics and bioenergetics analyses. FINDINGS: Low dose of rapamycin induces metabolic changes in liver and transcriptomics modifications in midbrain. The high dose of rapamycin induces further changes in the transcriptomics profile in midbrain due to the general inhibition of mTORC1. However, neither low nor high dose of rapamycin were able to improve the mitochondrial bioenergetics, the brain injuries and the phenotypic characteristics of Coq9R239X mice, resulting in the lack of efficacy for increasing the survival. INTERPRETATION: These results may be due to the lack of microgliosis-derived neuroinflammation, the limitation to induce autophagy, or the need of a functional CoQ-junction. Therefore, the translation of rapamycin therapy into the clinic for patients with mitochondrial disorders requires, at least, the consideration of the particularities of each mitochondrial disease. FUND: Supported by the grants from "Fundación Isabel Gemio - Federación Española de Enfermedades Neuromusculares - Federación FEDER" (TSR-1), the NIH (P01HD080642) and the ERC (Stg-337327).
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Doenças Mitocondriais/tratamento farmacológico , Sirolimo/uso terapêutico , Animais , Autofagia , Respiração Celular/efeitos dos fármacos , Respiração Celular/genética , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Metabolômica/métodos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/etiologia , Encefalomiopatias Mitocondriais/tratamento farmacológico , Encefalomiopatias Mitocondriais/genética , Encefalomiopatias Mitocondriais/metabolismo , Fenótipo , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Sirolimo/farmacocinética , Resultado do Tratamento , Ubiquinona/análogos & derivados , Ubiquinona/genética , Ubiquinona/metabolismoRESUMO
Coenzyme Q (CoQ) deficiency has been associated with primary defects in the CoQ biosynthetic pathway or to secondary events. In some cases, the exogenous CoQ supplementation has limited efficacy. In the Coq9R239X mouse model with fatal mitochondrial encephalopathy due to CoQ deficiency, we have tested the therapeutic potential of ß-resorcylic acid (ß-RA), a structural analog of the CoQ precursor 4-hydroxybenzoic acid and the anti-inflammatory salicylic acid. ß-RA noticeably rescued the phenotypic, morphological, and histopathological signs of the encephalopathy, leading to a significant increase in the survival. Those effects were due to the decrease of the levels of demethoxyubiquinone-9 (DMQ9) and the increase of mitochondrial bioenergetics in peripheral tissues. However, neither CoQ biosynthesis nor mitochondrial function changed in the brain after the therapy, suggesting that some endocrine interactions may induce the reduction of the astrogliosis, spongiosis, and the secondary down-regulation of astrocytes-related neuroinflammatory genes. Because the therapeutic outcomes of ß-RA administration were superior to those after CoQ10 supplementation, its use in the clinic should be considered in CoQ deficiencies.
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Hidroxibenzoatos/administração & dosagem , Encefalomiopatias Mitocondriais/tratamento farmacológico , Encefalomiopatias Mitocondriais/patologia , Fármacos Neuroprotetores/administração & dosagem , Ubiquinona/análogos & derivados , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Metabolismo Energético , Histocitoquímica , Camundongos , Ácido Salicílico/administração & dosagem , Análise de Sobrevida , Resultado do Tratamento , Ubiquinona/análise , Ubiquinona/deficiência , Ubiquinona/genética , Ubiquinona/metabolismoRESUMO
Nephrotic syndrome (NS), a frequent chronic kidney disease in children and young adults, is the most common phenotype associated with primary coenzyme Q10 (CoQ10) deficiency and is very responsive to CoQ10 supplementation, although the pathomechanism is not clear. Here, using a mouse model of CoQ deficiency-associated NS, we show that long-term oral CoQ10 supplementation prevents kidney failure by rescuing defects of sulfides oxidation and ameliorating oxidative stress, despite only incomplete normalization of kidney CoQ levels and lack of rescue of CoQ-dependent respiratory enzymes activities. Liver and kidney lipidomics, and urine metabolomics analyses, did not show CoQ metabolites. To further demonstrate that sulfides metabolism defects cause oxidative stress in CoQ deficiency, we show that silencing of sulfide quinone oxido-reductase (SQOR) in wild-type HeLa cells leads to similar increases of reactive oxygen species (ROS) observed in HeLa cells depleted of the CoQ biosynthesis regulatory protein COQ8A. While CoQ10 supplementation of COQ8A depleted cells decreases ROS and increases SQOR protein levels, knock-down of SQOR prevents CoQ10 antioxidant effects. We conclude that kidney failure in CoQ deficiency-associated NS is caused by oxidative stress mediated by impaired sulfides oxidation and propose that CoQ supplementation does not significantly increase the kidney pool of CoQ bound to the respiratory supercomplexes, but rather enhances the free pool of CoQ, which stabilizes SQOR protein levels rescuing oxidative stress.
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Antioxidantes/farmacologia , Ataxia/tratamento farmacológico , Sulfeto de Hidrogênio/metabolismo , Doenças Mitocondriais/tratamento farmacológico , Debilidade Muscular/tratamento farmacológico , Síndrome Nefrótica/tratamento farmacológico , Ubiquinona/análogos & derivados , Ubiquinona/deficiência , Alquil e Aril Transferases/genética , Animais , Antioxidantes/uso terapêutico , Ataxia/complicações , Ataxia/metabolismo , Modelos Animais de Doenças , Células HeLa , Humanos , Rim/metabolismo , Rim/patologia , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Doenças Mitocondriais/complicações , Doenças Mitocondriais/metabolismo , Debilidade Muscular/complicações , Debilidade Muscular/metabolismo , Síndrome Nefrótica/etiologia , Síndrome Nefrótica/metabolismo , Síndrome Nefrótica/patologia , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/genética , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ubiquinona/metabolismo , Ubiquinona/farmacologia , Ubiquinona/uso terapêuticoRESUMO
Mitohormesis is an adaptive response induced by a mild mitochondrial stress that promotes longevity and metabolic health in different organisms. This mechanism has been proposed as the cause of the increase in the survival in Coq7+/- (Mclk1+/-) mice, which show hepatic reduction of COQ7, early mitochondrial dysfunction and increased oxidative stress. Our study shows that the lack of COQ9 in Coq9Q95X mice triggers the reduction of COQ7, COQ6 and COQ5, which results in an increase in life expectancy. However, our results reveal that the hepatic CoQ levels are not decreased and, therefore, neither mitochondrial dysfunction or increased oxidative stress are observed in liver of Coq9Q95X mice. These data point out the tissue specific differences in CoQ biosynthesis. Moreover, our results suggest that the effect of reduced levels of COQ7 on the increased survival in Coq9Q95X mice may be due to mitochondrial mechanisms in non-liver tissues or to other unknown mechanisms.
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Longevidade , Mitocôndrias Hepáticas/metabolismo , Ubiquinona/biossíntese , Animais , Antioxidantes/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias Hepáticas/patologia , Ubiquinona/fisiologiaRESUMO
To gain insight into the mechanism of sarcopenia and the protective effect of melatonin, the gastrocnemius muscles of young (3-4 months), early-aged (12 months), and old-aged (24 months) wild-type C57BL/6J female mice were examined by magnetic resonance and microscopy. Locomotor activity, lactate production, and nuclear apoptosis were also assessed. The results support the early onset of sarcopenia at 12 months of age, with reduction of muscle fiber number, muscle weight/body weight ratio, lactate, and locomotor activity. Lipid droplet infiltration and autophagosomes were also detected. These changes driven little effects on the early-aged muscle, but they got worse in old-aged animals by the progressive damage of the muscle. Old-aged muscle showed a reduction of the mitochondrial number, a destruction of the mitochondrial cristae, and swelling. Tubular aggregates and nucleic acid fragmentation were the most striking findings in old-aged muscle, reflecting a broad damage with loss of autophagy efficacy. Oral melatonin administration conserved the normal muscular architecture, weight, muscle fiber number, and activity in the old age; it stimulated lactate production, prevented mitochondrial damage and tubular aggregates, and reduced the percentage of apoptotic nuclei in aged muscles. Altogether, gastrocnemius muscle showed age-mediated signs of sarcopenia that were reduced by melatonin treatment.
Assuntos
Melatonina/uso terapêutico , Sarcopenia/tratamento farmacológico , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Feminino , Ácido Láctico/metabolismo , Imageamento por Ressonância Magnética , Melatonina/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/patologia , Atividade Motora/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/ultraestrutura , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/uso terapêutico , Sarcopenia/metabolismo , Sarcopenia/patologiaRESUMO
Primary disorders of the human coenzyme Q10 (CoQ10) biosynthesis pathway are a known cause of severe pediatric diseases. So far, oral administration of CoQ10 is the only treatment strategy for affected individuals. However, the real benefit of CoQ10 supplementation remains questionable and clinical studies regarding efficiency are lacking. Here we provide an outlook on novel treatment approaches using CoQ precursor compounds. These metabolic bypass strategies might be a promising alternative for oral CoQ10 supplementation regimens.
Assuntos
Ataxia/tratamento farmacológico , Hidroxibenzoatos/uso terapêutico , Doenças Mitocondriais/tratamento farmacológico , Debilidade Muscular/tratamento farmacológico , Ubiquinona/análogos & derivados , Ubiquinona/deficiência , Animais , Apoptose/efeitos dos fármacos , Ataxia/genética , Ataxia/patologia , Vias Biossintéticas/efeitos dos fármacos , Vias Biossintéticas/genética , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Modelos Animais de Doenças , Humanos , Hidroxibenzoatos/farmacologia , Camundongos , Mitocôndrias/metabolismo , Doenças Mitocondriais/genética , Doenças Mitocondriais/patologia , Debilidade Muscular/genética , Debilidade Muscular/patologia , Pirimidinas/metabolismo , Solubilidade , Resultado do Tratamento , Ubiquinona/biossíntese , Ubiquinona/genética , Ubiquinona/metabolismo , Ubiquinona/uso terapêutico , Vitaminas/uso terapêuticoRESUMO
Head and neck squamous cell carcinoma (HNSCC) clearly involves activation of the Akt mammalian target of rapamycin (mTOR) signalling pathway. However, the effectiveness of treatment with the mTOR inhibitor rapamycin is often limited by chemoresistance. Melatonin suppresses neoplastic growth via different mechanisms in a variety of tumours. In this study, we aimed to elucidate the effects of melatonin on rapamycin-induced HNSCC cell death and to identify potential cross-talk pathways. We analysed the dose-dependent effects of melatonin in rapamycin-treated HNSCC cell lines (Cal-27 and SCC-9). These cells were treated with 0.1, 0.5 or 1 mmol/L melatonin combined with 20 nM rapamycin. We further examined the potential synergistic effects of melatonin with rapamycin in Cal-27 xenograft mice. Relationships between inhibition of the mTOR pathway, reactive oxygen species (ROS), and apoptosis and mitophagy reportedly increased the cytotoxic effects of rapamycin in HNSCC. Our results demonstrated that combined treatment with rapamycin and melatonin blocked the negative feedback loop from the specific downstream effector of mTOR activation S6K1 to Akt signalling, which decreased cell viability, proliferation and clonogenic capacity. Interestingly, combined treatment with rapamycin and melatonin-induced changes in mitochondrial function, which were associated with increased ROS production, increasing apoptosis and mitophagy. This led to increase cell death and cellular differentiation. Our data further indicated that melatonin administration reduced rapamycin-associated toxicity to healthy cells. Overall, our findings suggested that melatonin could be used as an adjuvant agent with rapamycin, improving effectiveness while minimizing its side effects.