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1.
Neuropathol Appl Neurobiol ; 48(1): e12747, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34237158

RESUMEN

AIMS: Mitochondrial dysfunction and inflammation are at the core of axonal degeneration in several multifactorial neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, and Parkinson's disease. The transcriptional coregulator RIP140/NRIP1 (receptor-interacting protein 140) modulates these functions in liver and adipose tissue, but its role in the nervous system remains unexplored. Here, we investigated the impact of RIP140 in the Abcd1- mouse model of X-linked adrenoleukodystrophy (X-ALD), a genetic model of chronic axonopathy involving the convergence of redox imbalance, bioenergetic failure, and chronic inflammation. METHODS AND RESULTS: We provide evidence that RIP140 is modulated through a redox-dependent mechanism driven by very long-chain fatty acids (VLCFAs), the levels of which are increased in X-ALD. Genetic inactivation of RIP140 prevented mitochondrial depletion and dysfunction, bioenergetic failure, inflammatory dysregulation, axonal degeneration and associated locomotor disabilities in vivo in X-ALD mouse models. CONCLUSIONS: Together, these findings show that aberrant overactivation of RIP140 promotes neurodegeneration in X-ALD, underscoring its potential as a therapeutic target for X-ALD and other neurodegenerative disorders that present with metabolic and inflammatory dyshomeostasis.


Asunto(s)
Adrenoleucodistrofia , Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP/metabolismo , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Transportadoras de Casetes de Unión a ATP/uso terapéutico , Adrenoleucodistrofia/genética , Adrenoleucodistrofia/metabolismo , Animales , Modelos Animales de Enfermedad , Homeostasis , Ratones , Mitocondrias/metabolismo , Proteína de Interacción con Receptores Nucleares 1
2.
PLoS Genet ; 15(10): e1008410, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31584940

RESUMEN

Mitochondria have been increasingly recognized as a central regulatory nexus for multiple metabolic pathways, in addition to ATP production via oxidative phosphorylation (OXPHOS). Here we show that inducing mitochondrial DNA (mtDNA) stress in Drosophila using a mitochondrially-targeted Type I restriction endonuclease (mtEcoBI) results in unexpected metabolic reprogramming in adult flies, distinct from effects on OXPHOS. Carbohydrate utilization was repressed, with catabolism shifted towards lipid oxidation, accompanied by elevated serine synthesis. Cleavage and translocation, the two modes of mtEcoBI action, repressed carbohydrate rmetabolism via two different mechanisms. DNA cleavage activity induced a type II diabetes-like phenotype involving deactivation of Akt kinase and inhibition of pyruvate dehydrogenase, whilst translocation decreased post-translational protein acetylation by cytonuclear depletion of acetyl-CoA (AcCoA). The associated decrease in the concentrations of ketogenic amino acids also produced downstream effects on physiology and behavior, attributable to decreased neurotransmitter levels. We thus provide evidence for novel signaling pathways connecting mtDNA to metabolism, distinct from its role in supporting OXPHOS.


Asunto(s)
Reprogramación Celular/genética , ADN Mitocondrial/genética , Diabetes Mellitus Tipo 2/genética , Mitocondrias/genética , Adenosina Trifosfato/genética , Animales , Metabolismo de los Hidratos de Carbono/genética , Carbohidratos/genética , Enzimas de Restricción del ADN/genética , Diabetes Mellitus Tipo 2/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Humanos , Redes y Vías Metabólicas/genética , Mitocondrias/metabolismo , Fosforilación Oxidativa , Estrés Oxidativo/genética
3.
Cardiovasc Drugs Ther ; 34(6): 823-834, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32979176

RESUMEN

PURPOSE: HFpEF (heart failure with preserved ejection fraction) is a major consequence of diabetic cardiomyopathy with no effective treatments. Here, we have characterized Akita mice as a preclinical model of HFpEF and used it to confirm the therapeutic efficacy of the mitochondria-targeted dicarbonyl scavenger, MitoGamide. METHODS AND RESULTS: A longitudinal echocardiographic analysis confirmed that Akita mice develop diastolic dysfunction with reduced E peak velocity, E/A ratio and extended isovolumetric relaxation time (IVRT), while the systolic function remains comparable with wild-type mice. The myocardium of Akita mice had a decreased ATP/ADP ratio, elevated mitochondrial oxidative stress and increased organelle density, compared with that of wild-type mice. MitoGamide, a mitochondria-targeted 1,2-dicarbonyl scavenger, exhibited good stability in vivo, uptake into cells and mitochondria and reactivity with dicarbonyls. Treatment of Akita mice with MitoGamide for 12 weeks significantly improved the E/A ratio compared with the vehicle-treated group. CONCLUSION: Our work confirms that the Akita mouse model of diabetes replicates key clinical features of diabetic HFpEF, including cardiac and mitochondrial dysfunction. Furthermore, in this independent study, MitoGamide treatment improved diastolic function in Akita mice.


Asunto(s)
Benzamidas/farmacología , Fármacos Cardiovasculares/farmacología , Cardiomiopatías Diabéticas/prevención & control , Insuficiencia Cardíaca/prevención & control , Volumen Sistólico/efectos de los fármacos , Disfunción Ventricular Izquierda/prevención & control , Función Ventricular Izquierda/efectos de los fármacos , Animales , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/fisiopatología , Modelos Animales de Enfermedad , Productos Finales de Glicación Avanzada/metabolismo , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Masculino , Ratones Endogámicos C57BL , Ratones Mutantes , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/fisiopatología
4.
Hum Mol Genet ; 24(24): 6861-76, 2015 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-26370417

RESUMEN

X-linked adrenomyeloneuropathy (AMN) is an inherited neurometabolic disorder caused by malfunction of the ABCD1 gene, characterized by slowly progressing spastic paraplegia affecting corticospinal tracts, and adrenal insufficiency. AMN is the most common phenotypic manifestation of adrenoleukodystrophy (X-ALD). In some cases, an inflammatory cerebral demyelination occurs associated to poor prognosis in cerebral AMN (cAMN). Though ABCD1 codes for a peroxisomal transporter of very long-chain fatty acids, the molecular mechanisms that govern disease onset and progression, or its transformation to a cerebral, inflammatory demyelinating form, remain largely unknown. Here we used an integrated -omics approach to identify novel biomarkers and altered network dynamic characteristic of, and possibly driving, the disease. We combined an untargeted metabolome assay of plasma and peripheral blood mononuclear cells (PBMC) of AMN patients, which used liquid chromatography coupled to quadrupole-time-of-flight mass spectrometry (LC-Q-TOF), with a functional genomics analysis of spinal cords of Abcd1(-) mouse. The results uncovered altered nodes in lipid-driven proinflammatory cascades, such as glycosphingolipid and glycerophospholipid synthesis, governed by the ß-1,4-galactosyltransferase (B4GALT6), the phospholipase 2γ (PLA2G4C) and the choline/ethanolamine phosphotransferase (CEPT1) enzymes. Confirmatory investigations revealed a non-classic, inflammatory profile, consisting on the one hand of raised plasma levels of several eicosanoids derived from arachidonic acid through PLA2G4C activity, together with also the proinflammatory cytokines IL6, IL8, MCP-1 and tumor necrosis factor-α. In contrast, we detected a more protective, Th2-shifted response in PBMC. Thus, our findings illustrate a previously unreported connection between ABCD1 dysfunction, glyco- and glycerolipid-driven inflammatory signaling and a fine-tuned inflammatory response underlying a disease considered non-inflammatory.


Asunto(s)
Adrenoleucodistrofia/sangre , Glicerofosfolípidos/sangre , Glucolípidos/sangre , Mediadores de Inflamación/metabolismo , Transducción de Señal , Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP , Transportadoras de Casetes de Unión a ATP/genética , Adrenoleucodistrofia/genética , Adulto , Animales , Humanos , Leucocitos Mononucleares/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Adulto Joven
5.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1862(5): 485-495, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28185952

RESUMEN

Lipids played a determinant role in the evolution of the brain. It is postulated that the morphological and functional diversity among neural cells of the human central nervous system (CNS) is projected and achieved through the expression of particular lipid profiles. The present study was designed to evaluate the differential vulnerability to oxidative stress mediated by lipids through a cross-regional comparative approach. To this end, we compared 12 different regions of CNS of healthy adult subjects, and the fatty acid profile and vulnerability to lipid peroxidation, were determined by gas chromatography (GC) and gas chromatography/mass spectrometry (GC/MS), respectively. In addition, different components involved in PUFA biosynthesis, as well as adaptive defense mechanisms against lipid peroxidation, were also measured by western blot and immunohistochemistry, respectively. We found that: i) four fatty acids (18.1n-9, 22:6n-3, 20:1n-9, and 18:0) are significant discriminators among CNS regions; ii) these differential fatty acid profiles generate a differential selective neural vulnerability (expressed by the peroxidizability index); iii) the cross-regional differences for the fatty acid profiles follow a caudal-cranial gradient which is directly related to changes in the biosynthesis pathways which can be ascribed to neuronal cells; and iv) the higher the peroxidizability index for a given human brain region, the lower concentration of the protein damage markers, likely supported by the presence of adaptive antioxidant mechanisms. In conclusion, our results suggest that there is a region-specific vulnerability to lipid peroxidation and offer evidence of neuronal mechanisms for polyunsaturated fatty acid biosynthesis in the human central nervous system.


Asunto(s)
Encéfalo/metabolismo , Sistema Nervioso Central/metabolismo , Ácidos Grasos Insaturados/biosíntesis , Lípidos/aislamiento & purificación , Estrés Oxidativo , Adipogénesis/genética , Adulto , Autopsia , Encéfalo/patología , Sistema Nervioso Central/química , Sistema Nervioso Central/patología , Cromatografía de Gases y Espectrometría de Masas , Humanos , Peroxidación de Lípido , Lípidos/efectos adversos , Lipogénesis/genética , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Neuronas/metabolismo , Neuronas/patología
6.
FASEB J ; 28(12): 5163-71, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25169057

RESUMEN

Lipidomics reveals a remarkable diversity of lipids in human plasma. In this study, we have performed an in-depth lipidomic analysis of human plasma from healthy individuals and subjects with metabolic syndrome (MetS) in order to determine the lipidomic profile that allows prognosis of a pathological subpopulation with altered high-density lipoprotein (HDL) metabolism. The MetS population was categorized as having pathological or nonpathological HDL. Anthropometric parameters, cardiovascular risk markers, and lipoprotein subclasses of HDL and low-density lipoproteins were also evaluated. Lipidomic analysis revealed 357 differential molecules that were clustered (k means) in the two groups. The molecules identified in the whole lipidome showed that MetS subjects presented lower levels of glycerolipids and higher levels of glycerophospholipids with respect to control subjects. In contrast, when only statistically differential lipids were taken into account, differences were found between the two groups in almost cases. Furthermore, levels of saturated fatty acids were higher in patients with pathological HDL levels than in controls, whereas levels of unsaturated fatty acids were lower. These results highlight the potential of lipidomics as a clinical tool for risk assessment and monitoring of disease.


Asunto(s)
Lípidos/sangre , Lipoproteínas HDL/clasificación , Síndrome Metabólico/sangre , Adulto , Anciano , Antropometría , Femenino , Humanos , Lipoproteínas HDL/sangre , Masculino , Síndrome Metabólico/complicaciones , Persona de Mediana Edad , Obesidad/sangre , Obesidad/complicaciones
7.
J Bioenerg Biomembr ; 46(3): 159-72, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24318105

RESUMEN

A low rate of mitochondrial ROS production (mitROSp) and a low degree of fatty acid unsaturation are characteristic traits of long-lived animals and can be obtained in a single species by methionine restriction (MetR) or atenolol (AT) treatments. However, simultaneous application of both treatments has never been performed. In the present investigation it is shown that MetR lowers mitROSp and complex I content. Both the MetR and the AT treatments lower protein oxidative modification and oxidative damage to mtDNA and the fatty acid unsaturation degree in rat heart mitochondria. The decrease in fatty acid unsaturation seems to be due, at least in part, to decreases in desaturase and elongase activities or peroxisomal ß-oxidation. Furthermore, the phosphorylation of extracellular signal-regulated kinase (ERK) was stimulated by MetR and AT. The decrease in membrane fatty acid unsaturation and protein oxidation, and the changes in fatty acids and p-ERK showed additive effects of both treatments. In addition, the increase in mitROSp induced by AT observed in the present investigation was totally avoided with the combined MetR + AT treatment. It is concluded that the simultaneous treatment with MetR plus atenolol is more beneficial than either single treatment alone to lower oxidative stress in rat heart mitochondria, analogously to what has been reported in long-lived animal species.


Asunto(s)
Atenolol/administración & dosificación , Ácidos Grasos/metabolismo , Metionina/metabolismo , Mitocondrias Cardíacas/fisiología , Membranas Mitocondriales/metabolismo , Estrés Oxidativo/fisiología , Especies Reactivas de Oxígeno/metabolismo , Administración Oral , Antagonistas de Receptores Adrenérgicos beta 1/administración & dosificación , Animales , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Sinergismo Farmacológico , Masculino , Metionina/administración & dosificación , Mitocondrias Cardíacas/efectos de los fármacos , Membranas Mitocondriales/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Resultado del Tratamiento
8.
Brain ; 136(Pt 8): 2432-43, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23794606

RESUMEN

X-linked adrenoleukodystrophy is a neurometabolic disorder caused by inactivation of the peroxisomal ABCD1 transporter of very long-chain fatty acids. In mice, ABCD1 loss causes late onset axonal degeneration in the spinal cord in association with locomotor disability resembling the most common phenotype in patients, adrenomyeloneuropathy. Increasing evidence indicates that oxidative stress and bioenergetic failure play major roles in the pathogenesis of X-linked adrenoleukodystrophy. In this study, we aimed to evaluate whether mitochondrial biogenesis is affected in X-linked adrenoleukodystrophy. We demonstrated that Abcd1 null mice show reduced mitochondrial DNA concomitant with downregulation of mitochondrial biogenesis pathway driven by PGC-1α/PPARγ and reduced expression of mitochondrial proteins cytochrome c, NDUFB8 and VDAC. Moreover, we show that the oral administration of pioglitazone, an agonist of PPARγ, restored mitochondrial content and expression of master regulators of biogenesis, neutralized oxidative damage to proteins and DNA, and reversed bioenergetic failure in terms of ATP levels, NAD+/NADH ratios, pyruvate kinase and glutathione reductase activities. Most importantly, the treatment halted locomotor disability and axonal damage in X-linked adrenoleukodystrophy mice. These results lend support to the use of pioglitazone in clinical trials with patients with adrenomyeloneuropathy and reveal novel molecular mechanisms of action of pioglitazone in neurodegeneration. Future studies should address the effects of this anti-diabetic drug on other axonopathies in which oxidative stress and mitochondrial dysfunction are contributing factors.


Asunto(s)
Adrenoleucodistrofia/tratamiento farmacológico , Axones/efectos de los fármacos , Hipoglucemiantes/uso terapéutico , Degeneración Nerviosa/tratamiento farmacológico , Tiazolidinedionas/uso terapéutico , Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP , Transportadoras de Casetes de Unión a ATP/genética , Adrenoleucodistrofia/genética , Adrenoleucodistrofia/patología , Animales , Axones/metabolismo , Axones/patología , Modelos Animales de Enfermedad , Ácidos Grasos/metabolismo , Glutatión Reductasa/metabolismo , Humanos , Hipoglucemiantes/farmacología , Ratones , Ratones Noqueados , Degeneración Nerviosa/genética , Degeneración Nerviosa/patología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Pioglitazona , Tiazolidinedionas/farmacología , Resultado del Tratamiento
9.
Biomolecules ; 14(5)2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38785940

RESUMEN

Ginseng, a popular herbal supplement among athletes, is believed to enhance exercise capacity and performance. This study investigated the short-term effects of Panax ginseng extract (PG) on aerobic capacity, lipid profile, and cytokines. In a 14-day randomized, double-blind trial, male participants took 500 mg of PG daily. Two experiments were conducted: one in 10 km races (n = 31) and another in a laboratory-controlled aerobic capacity test (n = 20). Blood lipid and cytokine profile, ventilation, oxygen consumption, hemodynamic and fatigue parameters, and race time were evaluated. PG supplementation led to reduced total blood lipid levels, particularly in triacylglycerides (10 km races -7.5 mg/dL (95% CI -42 to 28); sub-maximal aerobic test -14.2 mg/dL (95% CI -52 to 23)), while post-exercise blood IL-10 levels were increased (10 km 34.0 pg/mL (95% CI -2.1 to 70.1); sub-maximal aerobic test 4.1 pg/mL (95% CI -2.8 to 11.0)), and oxygen consumption decreased during the sub-maximal aerobic test (VO2: -1.4 mL/min/kg (95% CI -5.8 to -0.6)). No significant differences were noted in race time, hemodynamic, or fatigue parameters. Overall, PG supplementation for 2 weeks showed benefits in blood lipid profile and energy consumption during exercise among recreational athletes. This suggests a potential role for PG in enhancing exercise performance and metabolic health in this population.


Asunto(s)
Atletas , Suplementos Dietéticos , Ejercicio Físico , Consumo de Oxígeno , Panax , Extractos Vegetales , Triglicéridos , Humanos , Masculino , Panax/química , Extractos Vegetales/farmacología , Extractos Vegetales/administración & dosificación , Adulto , Consumo de Oxígeno/efectos de los fármacos , Triglicéridos/sangre , Método Doble Ciego , Adulto Joven , Ayuno/sangre
10.
J Proteome Res ; 12(6): 2679-89, 2013 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-23590626

RESUMEN

Membrane lipid composition is an important correlate of the rate of aging of animals. Dietary methionine restriction (MetR) increases lifespan in rodents. The underlying mechanisms have not been elucidated but could include changes in tissue lipidomes. In this work, we demonstrate that 80% MetR in mice induces marked changes in the brain, spinal cord, and liver lipidomes. Further, at least 50% of the lipids changed are common in the brain and spinal cord but not in the liver, suggesting a nervous system-specific lipidomic profile of MetR. The differentially expressed lipids includes (a) specific phospholipid species, which could reflect adaptive membrane responses, (b) sphingolipids, which could lead to changes in ceramide signaling pathways, and (c) the physiologically redox-relevant ubiquinone 9, indicating adaptations in phase II antioxidant response metabolism. In addition, specific oxidation products derived from cholesterol, phosphatidylcholine, and phosphatidylethanolamine were significantly decreased in the brain, spinal cord, and liver from MetR mice. These results demonstrate the importance of adaptive responses of membrane lipids leading to increased stress resistance as a major mechanistic contributor to the lowered rate of aging in MetR mice.


Asunto(s)
Adaptación Fisiológica , Envejecimiento/metabolismo , Encéfalo/metabolismo , Metabolismo de los Lípidos , Metionina/deficiencia , Animales , Colesterol/aislamiento & purificación , Colesterol/metabolismo , Femenino , Hígado/metabolismo , Longevidad , Masculino , Ratones , Ratones Endogámicos C57BL , Oxidación-Reducción , Estrés Oxidativo , Fosfatidilcolinas/aislamiento & purificación , Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas/aislamiento & purificación , Fosfatidiletanolaminas/metabolismo , Especies Reactivas de Oxígeno , Médula Espinal/metabolismo , Ubiquinona/metabolismo
11.
Amino Acids ; 44(2): 361-71, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22722543

RESUMEN

Maillard reaction contributes to the chemical modification and cross-linking of proteins. This process plays a significant role in the aging process and determination of animal longevity. Oxidative conditions promote the Maillard reaction. Mitochondria are the primary site of oxidants due to the reactive molecular species production. Mitochondrial proteome cysteine residues are targets of oxidative attack due to their specific chemistry and localization. Their chemical, non-enzymatic modification leads to dysfunctional proteins, which entail cellular senescence and organismal aging. Previous studies have consistently shown that caloric and methionine restrictions, nutritional interventions that increase longevity, decrease the rate of mitochondrial oxidant production and the physiological steady-state levels of markers of oxidative damage to macromolecules. In this scenario, we have detected S-(carboxymethyl)-cysteine (CMC) as a new irreversible chemical modification in mitochondrial proteins. CMC content in mitochondrial proteins significantly correlated with that of the lysine-derived analog N (ε)-(carboxymethyl)-lysine. The concentration of CMC is, however, one order of magnitude lower compared with CML likely due in part to the lower content of cysteine with respect to lysine of the mitochondrial proteome. CMC concentrations decreases in liver mitochondrial proteins of rats subjected to 8.5 and 25 % caloric restriction, as well as in 40 and 80 % methionine restriction. This is associated with a concomitant and significant increase in the protein content of sulfhydryl groups. Data presented here evidence that CMC, a marker of Cys-AGE formation, could be candidate as a biomarker of mitochondrial damage during aging.


Asunto(s)
Carbocisteína/metabolismo , Hígado/metabolismo , Metionina/metabolismo , Proteínas Mitocondriales/metabolismo , Animales , Restricción Calórica , Carbocisteína/química , Hígado/química , Masculino , Metionina/análisis , Mitocondrias/metabolismo , Proteínas Mitocondriales/química , Estructura Molecular , Estrés Oxidativo , Ratas , Ratas Wistar
12.
Proc Natl Acad Sci U S A ; 107(20): 9105-10, 2010 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-20435911

RESUMEN

Mutations in mitochondrial oxidative phosphorylation complex I are associated with multiple pathologies, and complex I has been proposed as a crucial regulator of animal longevity. In yeast, the single-subunit NADH dehydrogenase Ndi1 serves as a non-proton-translocating alternative enzyme that replaces complex I, bringing about the reoxidation of intramitochondrial NADH. We have created transgenic strains of Drosophila that express yeast NDI1 ubiquitously. Mitochondrial extracts from NDI1-expressing flies displayed a rotenone-insensitive NADH dehydrogenase activity, and functionality of the enzyme in vivo was confirmed by the rescue of lethality resulting from RNAi knockdown of complex I. NDI1 expression increased median, mean, and maximum lifespan independently of dietary restriction, and with no change in sirtuin activity. NDI1 expression mitigated the aging associated decline in respiratory capacity and the accompanying increase in mitochondrial reactive oxygen species production, and resulted in decreased accumulation of markers of oxidative damage in aged flies. Our results support a central role of mitochondrial oxidative phosphorylation complex I in influencing longevity via oxidative stress, independently of pathways connected to nutrition and growth signaling.


Asunto(s)
Envejecimiento/metabolismo , Drosophila melanogaster/fisiología , Complejo I de Transporte de Electrón/metabolismo , Longevidad/fisiología , Especies Reactivas de Oxígeno/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Animales , Western Blotting , Restricción Calórica , Drosophila melanogaster/enzimología , Complejo I de Transporte de Electrón/genética , Histocitoquímica , Longevidad/genética , Mitocondrias/metabolismo , Estrés Oxidativo/genética , Estrés Oxidativo/fisiología , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
13.
Int J Mol Sci ; 14(2): 3285-313, 2013 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-23385235

RESUMEN

Non-enzymatic modification of aminophospholipids by lipid peroxidation-derived aldehydes and reducing sugars through carbonyl-amine reactions are thought to contribute to the age-related deterioration of cellular membranes and to the pathogenesis of diabetic complications. Much evidence demonstrates the modification of aminophospholipids by glycation, glycoxidation and lipoxidation reactions. Therefore, a number of early and advanced Maillard reaction-lipid products have been detected and quantified in different biological membranes. These modifications may be accumulated during aging and diabetes, introducing changes in cell membrane physico-chemical and biological properties.

14.
Hum Mol Genet ; 19(10): 2005-14, 2010 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-20179078

RESUMEN

X-linked adrenoleukodystrophy (X-ALD) is a fatal, axonal demyelinating, neurometabolic disease. It results from the functional loss of a member of the peroxisomal ATP-binding cassette transporter subfamily D (ABCD1), which is involved in the metabolism of very long-chain fatty acids (VLCFA). Oxidative damage of proteins caused by excess of the hexacosanoic acid, the most prevalent VLCFA accumulating in X-ALD, is an early event in the neurodegenerative cascade. We demonstrate here that valproic acid (VPA), a widely used anti-epileptic drug with histone deacetylase inhibitor properties, induced the expression of the functionally overlapping ABCD2 peroxisomal transporter. VPA corrected the oxidative damage and decreased the levels of monounsaturated VLCFA (C26:1 n-9), but not saturated VLCFA. Overexpression of ABCD2 alone prevented oxidative lesions to proteins in a mouse model of X-ALD. A 6-month pilot trial of VPA in X-ALD patients resulted in reversion of the oxidative damage of proteins in peripheral blood mononuclear cells. Thus, we propose VPA as a promising novel therapeutic approach that warrants further clinical investigation in X-ALD.


Asunto(s)
Adrenoleucodistrofia/tratamiento farmacológico , Antioxidantes/uso terapéutico , Ácido Valproico/uso terapéutico , Subfamilia D de Transportadores de Casetes de Unión al ATP , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Acetiltransferasas/genética , Acetiltransferasas/metabolismo , Adolescente , Adrenoleucodistrofia/enzimología , Adrenoleucodistrofia/patología , Animales , Antioxidantes/farmacología , Biomarcadores/metabolismo , Niño , Elongasas de Ácidos Grasos , Ácidos Grasos/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Ratones , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Médula Espinal/efectos de los fármacos , Médula Espinal/patología , Ácido Valproico/farmacología
15.
Ann Neurol ; 70(1): 84-92, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21786300

RESUMEN

OBJECTIVE: Axonal degeneration is a main contributor to disability in progressive neurodegenerative diseases in which oxidative stress is often identified as a pathogenic factor. We aim to demonstrate that antioxidants are able to improve axonal degeneration and locomotor deficits in a mouse model of X-adrenoleukodystrophy (X-ALD). METHODS: X-ALD is a lethal disease caused by loss of function of the ABCD1 peroxisomal transporter of very long chain fatty acids (VLCFA). The mouse model for X-ALD exhibits a late onset neurological phenotype with locomotor disability and axonal degeneration in spinal cord resembling the most common phenotype of the disease, adrenomyeloneuropathy (X-AMN). Recently, we identified oxidative damage as an early event in life, and the excess of VLCFA as a generator of radical oxygen species (ROS) and oxidative damage to proteins in X-ALD. RESULTS: Here, we prove the capability of the antioxidants N-acetyl-cysteine, α-lipoic acid, and α-tocopherol to scavenge VLCFA-dependent ROS generation in vitro. Furthermore, in a preclinical setting, the cocktail of the 3 compounds reversed: (1) oxidative stress and lesions to proteins, (2) immunohistological signs of axonal degeneration, and (3) locomotor impairment in bar cross and treadmill tests. INTERPRETATION: We have established a direct link between oxidative stress and axonal damage in a mouse model of neurodegenerative disease. This conceptual proof of oxidative stress as a major disease-driving factor in X-AMN warrants translation into clinical trials for X-AMN, and invites assessment of antioxidant strategies in axonopathies in which oxidative damage might be a contributing factor.


Asunto(s)
Adrenoleucodistrofia/metabolismo , Antioxidantes/uso terapéutico , Axones/metabolismo , Modelos Animales de Enfermedad , Degeneración Nerviosa/metabolismo , Adrenoleucodistrofia/tratamiento farmacológico , Adrenoleucodistrofia/patología , Animales , Antioxidantes/farmacología , Axones/efectos de los fármacos , Axones/patología , Células Cultivadas , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/patología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Distribución Aleatoria
16.
Biogerontology ; 13(4): 399-411, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22580750

RESUMEN

It is known that a global decrease in food ingestion (dietary restriction, DR) lowers mitochondrial ROS generation (mitROS) and oxidative stress in young immature rats. This seems to be caused by the decreased methionine ingestion of DR animals. This is interesting since isocaloric methionine restriction in the diet (MetR) also increases, like DR, rodent maximum longevity. However, it is not known if old rats maintain the capacity to lower mitROS generation and oxidative stress in response to MetR similarly to young immature animals, and whether MetR implemented at old age can reverse aging-related variations in oxidative stress. In this investigation the effects of aging and 7 weeks of MetR were investigated in liver mitochondria of Wistar rats. MetR implemented at old age decreased mitROS generation, percent free radical leak at the respiratory chain and mtDNA oxidative damage without changing oxygen consumption. Protein oxidation, lipoxidation and glycoxidation increased with age, and MetR in old rats partially or totally reversed these age-related increases. Aging increased the amount of SIRT1, and MetR decreased SIRT1 and TFAM and increased complex IV. No changes were observed in the protein amounts of PGC1, Nrf2, MnSOD, AIF, complexes I, II and III, and in the extent of genomic DNA methylation. In conclusion, treating old rats with isocaloric short-term MetR lowers mitROS production and free radical leak and oxidative damage to mtDNA, and reverses aging-related increases in protein modification. Aged rats maintain the capacity to lower mitochondrial ROS generation and oxidative stress in response to a short-term exposure to restriction of a single dietary substance: methionine.


Asunto(s)
Envejecimiento/metabolismo , Metionina/deficiencia , Mitocondrias Hepáticas/enzimología , Estrés Oxidativo/fisiología , Especies Reactivas de Oxígeno/metabolismo , Animales , ADN Mitocondrial/metabolismo , Masculino , Modelos Animales , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Proteínas de Unión al ARN/metabolismo , Ratas , Ratas Wistar , Sirtuina 1/metabolismo , Superóxido Dismutasa/metabolismo , Factores de Transcripción/metabolismo
17.
Nutrients ; 14(3)2022 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-35276915

RESUMEN

The fatty acid elongase elongation of very long-chain fatty acids protein 2 (ELOVL2) controls the elongation of polyunsaturated fatty acids (PUFA) producing precursors for omega-3, docosahexaenoic acid (DHA), and omega-6, docosapentaenoic acid (DPAn-6) in vivo. Expectedly, Elovl2-ablation drastically reduced the DHA and DPAn-6 in liver mitochondrial membranes. Unexpectedly, however, total PUFAs levels decreased further than could be explained by Elovl2 ablation. The lipid peroxidation process was not involved in PUFAs reduction since malondialdehyde-lysine (MDAL) and other oxidative stress biomarkers were not enhanced. The content of mitochondrial respiratory chain proteins remained unchanged. Still, membrane remodeling was associated with the high voltage-dependent anion channel (VDAC) and adenine nucleotide translocase 2 (ANT2), a possible reflection of the increased demand on phospholipid transport to the mitochondria. Mitochondrial function was impaired despite preserved content of the respiratory chain proteins and the absence of oxidative damage. Oligomycin-insensitive oxygen consumption increased, and coefficients of respiratory control were reduced by 50%. The mitochondria became very sensitive to fatty acid-induced uncoupling and permeabilization, where ANT2 is involved. Mitochondrial volume and number of peroxisomes increased as revealed by transmission electron microscopy. In conclusion, the results imply that endogenous DHA production is vital for the normal function of mouse liver mitochondria and could be relevant not only for mice but also for human metabolism.


Asunto(s)
Mitocondrias Hepáticas , Membranas Mitocondriales , Animales , Ácidos Grasos , Hígado , Ratones , Mitocondrias
18.
J Bioenerg Biomembr ; 43(6): 699-708, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22006472

RESUMEN

Methionine dietary restriction (MetR), like dietary restriction (DR), increases rodent maximum longevity. However, the mechanism responsible for the retardation of aging with MetR is still not entirely known. As DR decreases oxidative damage and mitochondrial free radical production, it is plausible to hypothesize that a decrease in oxidative stress is the mechanism for longevity extension with MetR. In the present investigation male Wistar rats were subjected to isocaloric 40% MetR during 7 weeks. It was found that 40% MetR decreases heart mitochondrial ROS production at complex I during forward electron flow, lowers oxidative damage to mitochondrial DNA and proteins, and decreases the degree of methylation of genomic DNA. No significant changes occurred for mitochondrial oxygen consumption, the amounts of the four respiratory complexes (I to IV), and the mitochondrial protein apoptosis-inducing factor (AIF). These results indicate that methionine can be the dietary factor responsible for the decrease in mitochondrial ROS generation and oxidative stress, and likely for part of the increase in longevity, that takes place during DR. They also highlight some of the mechanisms involved in the generation of these beneficial effects.


Asunto(s)
Metilación de ADN , ADN Mitocondrial/metabolismo , Complejo I de Transporte de Electrón/metabolismo , Metionina , Mitocondrias Cardíacas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Animales , Factor Inductor de la Apoptosis/metabolismo , Daño del ADN , Longevidad , Masculino , Oxidación-Reducción , Ratas , Ratas Wistar , Factores de Tiempo
19.
Acta Neuropathol ; 122(3): 259-70, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21706176

RESUMEN

TDP-43 has been implicated in the pathogenesis of amyotrophic lateral sclerosis and other neurodegenerative diseases. Here we demonstrate, using neuronal and spinal cord organotypic culture models, that chronic excitotoxicity, oxidative stress, proteasome dysfunction and endoplasmic reticulum stress mechanistically induce mislocalization, phosphorylation and aggregation of TDP-43. This is compatible with a lack of function of this protein in the nucleus, specially in motor neurons. The relationship between cell stress and pathological changes of TDP-43 also includes a dysfunction in the survival pathway mediated by mitogen-activated protein kinase/extracellular signal-regulated kinases (ERK1/2). Thus, under stress conditions, neurons and other spinal cord cells showed cytosolic aggregates containing ERK1/2. Moreover, aggregates of abnormal phosphorylated ERK1/2 were also found in the spinal cord in amyotrophic lateral sclerosis (ALS), specifically in motor neurons with abnormal immunoreactive aggregates of phosphorylated TDP-43. These results demonstrate that cellular stressors are key factors in neurodegeneration associated with TDP-43 and disclose the identity of ERK1/2 as novel players in the pathogenesis of ALS.


Asunto(s)
Esclerosis Amiotrófica Lateral/patología , Proteínas de Unión al ADN/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Transducción de Señal/fisiología , Médula Espinal/metabolismo , Médula Espinal/patología , Anciano , Animales , Animales Recién Nacidos , Estudios de Casos y Controles , Línea Celular Transformada , Proteínas de Unión al ADN/genética , Inhibidores Enzimáticos/farmacología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Humanos , Peróxido de Hidrógeno/farmacología , Masculino , Persona de Mediana Edad , Proteínas Quinasas Activadas por Mitógenos/genética , Neuronas Motoras/metabolismo , Neuronas/citología , Neuronas/efectos de los fármacos , Oligopéptidos/farmacología , Técnicas de Cultivo de Órganos , Oxidantes/farmacología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Ratas , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Tapsigargina/farmacología , Transfección/métodos
20.
Hum Mol Genet ; 17(12): 1762-73, 2008 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-18344354

RESUMEN

X-linked adrenoleukodystrophy (X-ALD) is a fatal neurodegenerative disorder, characterized by progressive cerebral demyelination cerebral childhood adrenoleukodystrophy (CCALD) or spinal cord neurodegeneration (adrenomyeloneuropathy, AMN), adrenal insufficiency and accumulation of very long-chain fatty acids (VLCFA) in tissues. The disease is caused by mutations in the ABCD1 gene, which encodes a peroxisomal transporter that plays a role in the import of VLCFA or VLCFA-CoA into peroxisomes. The Abcd1 knockout mice develop a spinal cord disease that mimics AMN in adult patients, with late onset at 20 months of age. The mechanisms underlying cerebral demyelination or axonal degeneration in spinal cord are unknown. Here, we present evidence by gas chromatography/mass spectrometry that malonaldehyde-lysine, a consequence of lipoxidative damage to proteins, accumulates in the spinal cord of Abcd1 knockout mice as early as 3.5 months of age. At 12 months, Abcd1- mice accumulate additional proteins modified by oxidative damage arising from metal-catalyzed oxidation and glycoxidation/lipoxidation. While we show that VLCFA excess activates enzymatic antioxidant defenses at the protein expression levels, both in neural tissue, in ex vivo organotypic spinal cord slices from Abcd1- mice, and in human ALD fibroblasts, we also demonstrate that the loss of Abcd1 gene function hampers oxidative stress homeostasis. We find that the alpha-tocopherol analog Trolox is able to reverse oxidative lesions in vitro, thus providing therapeutic hope. These results pave the way for the identification of therapeutic targets that could reverse the deregulated response to oxidative stress in X-ALD.


Asunto(s)
Adrenoleucodistrofia/metabolismo , Oxidación-Reducción , Médula Espinal/metabolismo , Animales , Catalasa/metabolismo , Quimiocina CCL22/genética , Quimiocina CCL22/metabolismo , Cromanos/farmacología , Ácidos Grasos/metabolismo , Fibroblastos/metabolismo , Humanos , Técnicas In Vitro , Lisina/metabolismo , Malondialdehído/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Neuronas Motoras/enzimología , Neuronas Motoras/metabolismo , Estrés Oxidativo , Superóxido Dismutasa
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