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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).
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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
In eukaryotic cells, aerobic energy is produced by mitochondria through oxygen uptake. However, little is known about the early mitochondrial responses to moderate hypobaric hypoxia (MHH) in highly metabolic active tissues. Here, we describe the mitochondrial responses to acute MHH in the heart and skeletal muscle. Rats were randomly allocated into a normoxia control group (n = 10) and a hypoxia group (n = 30), divided into three groups (0, 6, and 24 h post-MHH). The normoxia situation was recapitulated at the University of Granada, at 662 m above sea level. The MHH situation was performed at the High-Performance Altitude Training Centre of Sierra Nevada located in Granada at 2320 m above sea level. We found a significant increase in mitochondrial supercomplex assembly in the heart as soon as the animals reached 2320 m above sea level and their levels are maintained 24 h post-exposure, but not in skeletal muscle. Furthermore, in skeletal muscle, at 0 and 6 h, there was increased dynamin-related protein 1 (Drp1) expression and a significant reduction in Mitofusin 2. In conclusion, mitochondria from the muscle and heart respond differently to MHH: mitochondrial supercomplexes increase in the heart, whereas, in skeletal muscle, the mitochondrial pro-fission response is trigged. Considering that skeletal muscle was not actively involved in the ascent when the heart was beating faster to compensate for the hypobaric, hypoxic conditions, we speculate that the different responses to MHH are a result of the different energetic requirements of the tissues upon MHH. KEY POINTS: The heart and the skeletal muscle showed different mitochondrial responses to moderate hypobaric hypoxia. Moderate hypobaric hypoxia increases the assembly of the electron transport chain complexes into supercomplexes in the heart. Skeletal muscle shows an early mitochondrial pro-fission response following exposure to moderate hypobaric hypoxia.
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OBJECTIVE: To evaluate the impact of a curricular intervention to promote health-related fitness (HRF) among medical students in Bogota, Colombia. METHOD: The study was conducted between May 2014 and December 2015 as part of the medical physiology course, in which 208 medical students were enrolled.The curricular intervention included two lectures on physical activity (PA) and student-led group presentations on the physiological effects of exercise on human physiology. An academic incentive (10% of final grade) was given to students who reported and documented regular PA practice during the semester. This study assessed students' HRF variables, perceptions of the curriculum intervention, and PA practices using quantitative and qualitative approaches. RESULTS: 55% of the students were female, with a mean age of 19.5 years. Body fat, estimated maximum oxygen consumption (VO2max), handgrip, and sit-up strength showed statistically significant improvements at the end of the intervention. Students reported that PA practice was positively influenced by the curriculum intervention, particularly the academic incentive and the HRF tests. Students reported a wide variety of PA practices, which were mainly done with friends, classmates, or family members. Lack of time was the main reported barrier to PA practice. CONCLUSION: The curricular intervention was effective in improving HRF and promoting PA. It remains to be investigated whether these gains are sustained over time.
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Estudantes de Medicina , Humanos , Feminino , Adulto Jovem , Adulto , Masculino , Colômbia , Promoção da Saúde , Força da Mão , Exercício Físico/fisiologia , Currículo , Aptidão Física/fisiologiaRESUMO
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.
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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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Coenzyme Q (CoQ) is a conserved polyprenylated lipid composed of a redox-active benzoquinone ring and a long polyisoprenyl tail that serves as a membrane anchor. CoQ biosynthesis involves multiple steps, including multiple modifications of the precursor ring 4-hydroxybenzoic acid. Mutations in the enzymes involved in CoQ biosynthesis pathway result in primary coenzyme Q deficiencies, mitochondrial disorders whose clinical heterogenicity reflects the multiple biological function of CoQ. Patients with these disorders do not always respond to CoQ supplementation, and CoQ analogs have not been successful as alternative approaches. Progress made in understanding the CoQ biosynthesis pathway and studies of supplementation with 4-hydroxybenzoic acid ring analogs have opened a new area in the field of primary CoQ deficiencies treatment. Here, we will review these studies, focusing on efficacy of the different 4-hydroxybenzoic acid ring analogs, models in which they have been tested, and their mechanisms of action. Understanding how these compounds ameliorate biochemical, molecular, and/or clinical phenotypes of CoQ deficiencies is important to develop the most rational treatment for CoQ deficient patients, depending on their molecular defects.
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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.
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Primary mitochondrial diseases are caused by mutations in mitochondrial or nuclear genes, leading to the abnormal function of specific mitochondrial pathways. Mitochondrial dysfunction is also a secondary event in more common pathophysiological conditions, such as obesity and metabolic syndrome. In both cases, the improvement and management of mitochondrial homeostasis remain challenging. Here, we show that beta-resorcylic acid (ß-RA), which is a natural phenolic compound, competed in vivo with 4-hydroxybenzoic acid, which is the natural precursor of coenzyme Q biosynthesis. This led to a decrease in demethoxyubiquinone, which is an intermediate metabolite of CoQ biosynthesis that is abnormally accumulated in Coq9R239X mice. As a consequence, ß-RA rescued the phenotype of Coq9R239X mice, which is a model of primary mitochondrial encephalopathy. Moreover, we observed that long-term treatment with ß-RA also reduced the size and content of the white adipose tissue (WAT) that is normally accumulated during aging in wild-type mice, leading to the prevention of hepatic steatosis and an increase in survival at the elderly stage of life. The reduction in WAT content was due to a decrease in adipogenesis, an adaptation of the mitochondrial proteome in the kidneys, and stimulation of glycolysis and acetyl-CoA metabolism. Therefore, our results demonstrate that ß-RA acted through different cellular mechanisms, with effects on mitochondrial metabolism; as such, it may be used for the treatment of primary coenzyme Q deficiency, overweight, and hepatic steatosis.
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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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This paper presents an efficient cyberphysical platform for the smart management of smart territories. It is efficient because it facilitates the implementation of data acquisition and data management methods, as well as data representation and dashboard configuration. The platform allows for the use of any type of data source, ranging from the measurements of a multi-functional IoT sensing devices to relational and non-relational databases. It is also smart because it incorporates a complete artificial intelligence suit for data analysis; it includes techniques for data classification, clustering, forecasting, optimization, visualization, etc. It is also compatible with the edge computing concept, allowing for the distribution of intelligence and the use of intelligent sensors. The concept of smart cities is evolving and adapting to new applications; the trend to create intelligent neighbourhoods, districts or territories is becoming increasingly popular, as opposed to the previous approach of managing an entire megacity. In this paper, the platform is presented, and its architecture and functionalities are described. Moreover, its operation has been validated in a case study where the bike renting service of Paris-Vélib' Métropole has been managed. This platform could enable smart territories to develop adapted knowledge management systems, adapt them to new requirements and to use multiple types of data, and execute efficient computational and artificial intelligence algorithms. The platform optimizes the decisions taken by human experts through explainable artificial intelligence models that obtain data from IoT sensors, databases, the Internet, etc. The global intelligence of the platform could potentially coordinate its decision-making processes with intelligent nodes installed in the edge, which would use the most advanced data processing techniques.
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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
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
Hydroxytyrosol (HT) has been demonstrated to improve mitochondrial function, both in sedentary and in exercised animals. Herein, we assessed the effects of two different doses of HT on exercise-induced mitochondrial respiratory complex (C) assembly into supercomplexes (SCs) and the relation of the potential results to OPA1 levels and oxidative stress. Wistar rats were allocated into six groups: sedentary (SED), sedentary consuming 20â¯mg/kg/d of HT (SED-20), sedentary consuming 300â¯mg/kg/d of HT (SED-300); exercised (EXE), exercised consuming 20â¯mg/kg/d of HT (EXE-20) and exercised consuming 300â¯mg/kg/d of HT (EXE-300). Animals were exercised and/or supplemented for 10 weeks, and assembly of SCs, mitochondrial oxidative status and expression of OPA1 were quantified in the gastrocnemius muscle. Both EXE and EXE-20 animals exhibited increased assembly of CI into SCs, but this effect was absent in EXE-300 animals. Levels of CIII2 assembled into SCs were only increased in EXE-20 animals. Notably EXE-300 animals showed a decreased relative expression of s-OPA1 isoforms. Therefore, HT exerted dose-dependent effects on SC assembly in exercised animals. Although the mechanisms leading to SCs assembly in response to exercise and HT are unclear, it seems that a high HT dose can prevent SCs assembly during exercise by decreasing the expression of the s-OPA1 isoforms.
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Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Complexos Multiproteicos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Álcool Feniletílico/análogos & derivados , Condicionamento Físico Animal , Animais , Antioxidantes/farmacologia , Masculino , Mitocôndrias/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Oxirredução , Álcool Feniletílico/farmacologia , Ratos , Ratos WistarRESUMO
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
A methodology to calculate analytical figures of merit is not well established for detection systems that are based on sensor arrays with low sensor selectivity. In this work, we present a practical approach to estimate the Resolving Power of a sensory system, considering non-linear sensors and heteroscedastic sensor noise. We use the definition introduced by Shannon in the field of communication theory to quantify the number of symbols in a noisy environment, and its version adapted by Gardner and Barlett for chemical sensor systems. Our method combines dimensionality reduction and the use of algorithms to compute the convex hull of the empirical data to estimate the data volume in the sensor response space. We validate our methodology with synthetic data and with actual data captured with temperature-modulated MOX gas sensors. Unlike other methodologies, our method does not require the intrinsic dimensionality of the sensor response to be smaller than the dimensionality of the input space. Moreover, our method circumvents the problem to obtain the sensitivity matrix, which usually is not known. Hence, our method is able to successfully compute the Resolving Power of actual chemical sensor arrays. We provide a relevant figure of merit, and a methodology to calculate it, that was missing in the literature to benchmark broad-response gas sensor arrays.
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Although mitochondria dysfunction is related to multiple diseases, no in vivo studies are available on mitochondrial respiration in animal parkinsonian models. Our aim is to analyze in vivo mitochondrial respiration, which reflects changes in mitochondrial bioenergetics more precisely than in vitro mitochondrial preparations. These experiments can be carried out in zebrafish embryos, which were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) from 24 to 72 hours postfertilization (hpf). A reduction in electron transfer system capacity, ATP turnover, and increased proton leak were observed at 72 hpf in MPTP-treated embryos. These changes were followed by a significant oxidative stress due to inhibition in antioxidative defense and autophagy impairment. After removing MPTP from the treatment at 72 hpf, these bioenergetic deficiencies persisted up to 120 hpf. The administration of melatonin to zebrafish embryos at 72 hpf, when mitochondrial dysfunction is already present, restored the respiratory capacity and ATP production, reduced oxidative stress, and normalized autophagy after 48 h. Melatonin also counteracted mortality and embryonic malformations due to MPTP. Our results confirm for the first time the efficacy of melatonin in restoring parkinsonian phenotypes in animals.
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1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/efeitos adversos , Embrião não Mamífero/efeitos dos fármacos , Metabolismo Energético , Intoxicação por MPTP/tratamento farmacológico , Melatonina/farmacologia , Mitocôndrias/fisiologia , Peixe-Zebra/fisiologia , Animais , Embrião não Mamífero/metabolismo , Embrião não Mamífero/patologia , Intoxicação por MPTP/metabolismo , Intoxicação por MPTP/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Neurotoxinas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Peixe-Zebra/embriologiaRESUMO
Coenzyme Q (CoQ) is a lipid present in all cell membranes. One of the multiple metabolic functions of CoQ is to transport electrons in the reaction catalyzed by sulfide:quinone oxidoreductase (SQOR), the first enzyme of the oxidation pathway of sulfides (hydrogen sulfide, H2S). Early evidence of a defect in the metabolism of H2S in primary CoQ deficiency came from yeast studies in Schizosaccharomyces pombe strains defective for dps1 and ppt1 (homologs of PDSS1 and COQ2, respectively), which have H2S accumulation. Our recent studies in human skin fibroblasts and in murine models of primary CoQ deficiency show that, also in mammals, decreased CoQ levels cause impairment of H2S oxidation. Patient fibroblasts carrying different mutations in genes encoding proteins involved in CoQ biosynthesis show reduced SQOR activity and protein levels proportional to the levels of CoQ. In Pdss2kd/kd mice, kidney, the only organ clinically affected, shows reduced SQOR levels and downstream enzymes, accumulation of H2S, and glutathione depletion. Pdss2kd/kd mice have also low levels of thiosulfate in plasma and urine, and increased C4-C6 acylcarnitines in blood, due to inhibition of short-chain acyl-CoA dehydrogenase. Also in Coq9R239X mice, the symptomatic organ, cerebrum, shows accumulation of H2S, reduced SQOR, increase in thiosulfate sulfurtransferase and sulfite oxidase, and reduction in the levels of glutathione and glutathione enzymes, leading to alteration of the biosynthetic pathways of glutamate, serotonin, and catecholamines. Coq9R239X mice have also reduced blood pressure, possible consequence of H2S-induced vasorelaxation. Since liver is not clinically affected in Pdss2 and Coq9 mutant mice, the effects of the impairment of H2S oxidation in this organ were not investigated, despite its critical role in metabolism. In conclusion, in vitro and in vivo studies of CoQ deficient models provide evidence of tissue-specific H2S oxidation impairment, an additional pathomechanism that should be considered in the understanding and treatment of primary CoQ deficiency.
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Resumen Los estudios sobre felicidad incluyen diversas perpectivas, conceptualizaciones y factores asociados a este concepto; sin embargo, las investigaciones sobre felicidad con frecuencia se concentran en la dimensión individual de la misma. El presente trabajo hace énfasis en la concepción de la felicidad como un constructo multidimensional conformado por aspectos individuales y por aspectos colectivos. De manera que el propósito central del artículo es presentar un análisis sobre la dimensión colectiva de la felicidad, la cual ha sido poco estudiada en el contexto latinoamericano. En particular este artículo busca enfatizar el papel de las relaciones afectivas, la conducta prosocial y la inversión en los demás, en la comprensión de la felicidad. En las conclusiones se identifican temáticas relevantes asociadas a la dimensión colectiva que permitirán ampliar la investigación sobre la felicidad.
Abstract Studies of happiness include diverse perspectives, concepts and factors; however, research on happiness often focuses on its individual dimension. This work emphasizes the concept of happiness as a multidimensional construct of individual and collective aspects. The main purpose of the article is to present an analysis of the collective dimension of happiness, which has been little studied in the Latin American context. In particular, this article seeks to emphasize the role of relationships, prosocial behavior and investment in others in the understanding of happiness. The conclusions identify issues associated with the collective dimension that permit a broadening of the research on happiness.
Resumo Os estudos sobre felicidade incluem diversas perspectivas, conceituações e fatores associados a esse conceito; contu do, as pesquisas sobre felicidade com frequência concentram-se na dimensão individual dela. Este trabalho enfatiza a concepção da felicidade como um constructo multidimensional conformado por aspectos individuais e por aspectos coletivos. Assim, o propósito central deste artigo é apresentar uma análise sobre a dimensão coletiva da felicidade, a qual tem sido pouco estudada no contexto latino-americano. Em particular, neste texto, busca-se salientar o papel dos relacionamentos afetivos, do comportamento pró-social e do investimento nos demais, na compreensão da felicidade. Nas conclusões, identificam-se temáticas relevantes associadas à dimensão coletiva que permitirão ampliar a pesquisa sobre a felicidade.