Oral ß-RA induces metabolic rewiring leading to the rescue of diet-induced obesity.

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).

4-Hydroxybenzoic acid rescues multisystemic disease and perinatal lethality in a mouse model of mitochondrial disease.

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.

Intratumoral injection of melatonin enhances tumor regression in cell line-derived and patient-derived xenografts of head and neck cancer by increasing mitochondrial oxidative stress.

Head and neck squamous cell carcinoma present a high mortality rate. Melatonin has been shown to have oncostatic effects in different types of cancers. However, inconsistent results have been reported for in vivo applications. Consequently, an alternative administration route is needed to improve bioavailability and establish the optimal dosage of melatonin for cancer treatment. On the other hand, the use of patient-derived tumor models has transformed the field of drug research because they reflect the heterogeneity of patient tumor tissues. In the present study, we explore mechanisms for increasing melatonin bioavailability in tumors and investigate its potential as an adjuvant to improve the therapeutic efficacy of cisplatin in the setting of both xenotransplanted cell lines and primary human HNSCC. We analyzed the effect of two different formulations of melatonin administered subcutaneously or intratumorally in Cal-27 and SCC-9 xenografts and in patient-derived xenografts. Melatonin effects on tumor mitochondrial metabolism was also evaluated as well as melatonin actions on tumor cell migration. In contrast to the results obtained with the subcutaneous melatonin, intratumoral injection of melatonin drastically inhibited tumor progression in HNSCC-derived xenografts, as well as in patient-derived xenografts. Interestingly, intratumoral injection of melatonin potentiated CDDP effects, decreasing Cal-27 tumor growth. We demonstrated that melatonin increases ROS production and apoptosis in tumors, targeting mitochondria. Melatonin also reduces migration capacities and metastasis markers. These results illustrate the great clinical potential of intratumoral melatonin treatment and encourage a future clinical trial in cancer patients to establish a proper clinical melatonin treatment.

The Q-junction and the inflammatory response are critical pathological and therapeutic factors in CoQ deficiency.

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.

Animal Models of Coenzyme Q Deficiency: Mechanistic and Translational Learnings.

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.

ß-RA Targets Mitochondrial Metabolism and Adipogenesis, Leading to Therapeutic Benefits against CoQ Deficiency and Age-Related Overweight.

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.

Metabolic Targets of Coenzyme Q10 in Mitochondria.

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.

Coenzyme Q10 modulates sulfide metabolism and links the mitochondrial respiratory chain to pathways associated to one carbon metabolism.

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.

The Paradox of Coenzyme Q10 in Aging.

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.

Rapamycin administration is not a valid therapeutic strategy for every case of mitochondrial disease.

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).

Intervención promocional sobre lactancia materna en gestantes / Promotional intervention about breast feeding in pregnancies

Se realiza un estudio de intervención promocional para modificar criterios sobre la lactancia materna exclusiva en gestantes del segundo y tercer trimestre del Grupo Básico de Trabajo No4 del Policlínico Universitario Asdrúbal López Vázquez de Guantánamo, en el período julio 2002–2003. Del universo de 68 gestantes se selecciona una muestra de 30, en forma aleatoria simple (n=30), previo consentimiento de las mismas. Se aplica un formulario y una encuesta, antes y después de la intervención, que identificó las necesidades de aprendizaje y valoró la modificación de criterios erróneos. Los principales resultados son: La edad materna entre 20–34 años (80por ciento), predominó la secundaria terminada (43.3 por ciento), las trabajadoras (43.3 por ciento), la unión consensual (60 por ciento), los criterios erróneos sobre las ventajas y creencias (40,3 por ciento) y las técnicas de la lactancia (92.3 por ciento), los cuales fueron modificados después de la intervención. La labor de promoción debe perfeccionarse en cuanto a ventajas, creencias y técnicas de lactancia materna exclusiva.(AU)

Afecciones mamarias en mujeres de 30 a 65 años / Mammary affections in women of 30 to 65 years

Se realiza el pesquisaje de algunas afecciones mamarias (enfermedad fibroquística, neoplasias benignas y malignas) en 75 pacientes entre 30 y 65 años de edad, a través de examen clínico en el consultorio médico No 56 del Policlínico Universitario Asdrúbal López Vázquez, desde febrero a julio de 2004. Se detectan 35 pacientes, lo que permitió determinar las posibles relaciones existentes entre éstas y algunas variables como: edad, factores de riesgo, autoexamen de mamas y enfermedades asociadas más frecuentes. Se pemiten conclusiones y recomendaciones. Se anexan tablas(AU)

Mortalidad por tumores malignos / Mortality for malignant tumors

Se realiza un estudio descriptivo transversal de los fallecidos por tumores malignos seleccionados, pertenecientes al Policlínico Universitario Mártires del 4 de Agosto de la ciudad de Guantánamo en el quinquenio 2000-2004, con el objetivo de determinar la magnitud de los mismos, los años de vida potencial y laboralmente perdidos, así como su comportamiento. El universo lo conforman los 236 fallecidos por cáncer en este período, de los cuales se tomó una muestra de 196 (n=96). Para cumplir con los objetivos propuestos y representar los resultados se utilizan tablas. Los tumores pulmonares, hepatobiliares y linfomas muestran una alta letalidad. L a bronconeumonía como causa directa ocasiona casi la mitad de las defunciones. Existe una baja correlación clínico-necrópsica. Las neoplasias pulmonares provocan mayor pérdida de años de vida potencial y laboralmente, con tendencia ascendente los de pulmón, mama, cervicouterino y hepatobiliar(AU)

Prevalencia de hábitos tóxicos / Prevalence of toxic habits

Se realiza estudio descriptivo de corte transversal con el objetivo de determinar la prevalencia de los hábitos tóxicos en el área sur, municipio Guantánamo, durante el año 2005. El universo lo constituye la población de 15 y más años (58 600). De la muestra representativa, 750 habitantes, escogidos al azar (n=750), con proporción de hombres y mujeres, 616 personas consumían alcohol (82,13 por ciento) y, 607, tabaco, (80,93 por ciento), ambos en el sexo masculino en las edades entre 15 y 30 años. Mientras que 308 consumían café (41,07 por ciento) y, 146, psicofármacos (19.47 por ciento), en el sexo femenino entre 31 y 45 años. Se encuentra las tensiones y dificultades, el ausentismo, las riñas y los escándalos públicos como las principales repercusiones en la esfera familiar, laboral y social(AU)

Intervención comunitaria del riesgo reproductivo preconcepcional / Community intervention of the reproductive preconcepcional risk

Se realiza un estudio de intervención comunitaria en el consultorio No 55 del Policlínico Universitario Mártires del 4 de Agosto en el período enero-diciembre 2004, con la finalidad de dar a conocer los resultados obtenidos en el pesquizaje y control del riesgo reproductivo preconcepcional. El universo de estudio está conformado por 41 mujeres de riesgo, las cuales recibieron actividades educativas durante seis semanas. La hipertensión arterial es la afección más frecuente durante la investigación. Predominan las menores de 18 años y las malnutridas por defecto. Los problemas biopsicosociales y de funcionamiento familiar inadecuado predominan en nuestro estudio. Al concluir la investigación se comprobó mayor nivel de conocimientos acerca de los aspectos más importantes de la temática, y por ende, quedó protegido el total de pacientes de riesgo(AU)

Intervención promocional sobre lactancia materna en gestantes / Promotional intervention about breast feeding in pregnancies

Se realiza un estudio de intervención promocional para modificar criterios sobre la lactancia materna exclusiva en gestantes del segundo y tercer trimestre del Grupo Básico de Trabajo No4 del Policlínico Universitario Asdrúbal López Vázquez de Guantánamo, en el período julio 2002–2003. Del universo de 68 gestantes se selecciona una muestra de 30, en forma aleatoria simple (n=30), previo consentimiento de las mismas. Se aplica un formulario y una encuesta, antes y después de la intervención, que identificó las necesidades de aprendizaje y valoró la modificación de criterios erróneos. Los principales resultados son: La edad materna entre 20–34 años (80 por ciento), predominó la secundaria terminada (43,3 por ciento), las trabajadoras (43,3 por ciento), la unión consensual (60 por ciento), los criterios erróneos sobre las ventajas y creencias (40,3por ciento) y las técnicas de la lactancia (92,3 por ciento), los cuales fueron modificados después de la intervención. La labor de promoción debe perfeccionarse en cuanto a ventajas, creencias y técnicas de lactancia materna exclusiva(AU)