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1.
EBioMedicine ; 42: 511-523, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30898651

RESUMO

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).


Assuntos
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/metabolismo
2.
J Neurol Sci ; 396: 112-118, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30448717

RESUMO

OBJECTIVE: To describe the phenotype and the response to folinic acid supplementation of cerebral folate deficiency (CFD) in adults, a disorder diagnosed on low 5-methyltetrahydro-folate (5MTHF) in cerebrospinal fluid (CSF), which can correspond to a inherited disorder of folate metabolism (IDFM) or to a metabolic consequence of various neurological diseases. METHODS: We conducted a retrospective study on 224 adult patients with neurological symptoms who had a 5MTHF CSF dosage, collecting their neurologic and neuroimaging data. RESULTS: 69 patients had CFD (CSF 5MTHF level < 41 nmol/L), 25 of them had severe CFD (sCFD; ≤25 nmol/L) with adult onset neurological symptoms in 41%. 56% of sCFD patients had an underlying identified neurologic disorder, mainly mitochondrial diseases, hepatic encephalopathy and primary brain calcifications (no identified IDFM), the others were classified as undiagnosed. sCFD patients presented most frequently pyramidal syndrome (75%), movement disorders (56%), cerebellar syndrome (50%) and intellectual disability (46%). MRI findings mostly showed white matter abnormalities (WMA; 32%) and calcifications (12%), and were normal in 23%. The clinico-radiological phenotype of sCFD patients was not clearly different from non CFD patients in terms of manifestations frequency. However, their neurological picture was more complex with a higher number of combined neurological symptoms (4.7±1.6 vs 3.4±1.7, p = .01). In Magnetic Resonance Spectroscopy (MRS), Choline/Creatine (Cho/Cr) ratio was lower in sCFD patients (n = 7) compared to non-CFD patients (n = 73) (p = .005), with good sensitivity (71%) and excellent specificity (92%). Among twenty-one CFD patients treated with folinic acid, nine had a sustained improvement, all with sCFD but one (50% of sCFD patients improved). In two undiagnosed patients with extremely low 5MTHF CSF values, MRI WMA and low Cho/Cr ratios, folinic acid treatment leaded to a dramatic clinical and radiological improvement. CONCLUSION: CSF 5MTHF dosage should be considered in patients with mitochondrial diseases, primary brain calcifications and unexplained complex neurological disorders especially if associated with WMA, since folinic acid supplementation in patients with sCFD is frequently efficient.


Assuntos
Doenças Cerebelares/complicações , Deficiência de Ácido Fólico/complicações , Deficiência de Ácido Fólico/genética , Mutação/genética , Proteínas/genética , Adolescente , Adulto , Idoso , Calcinose/diagnóstico por imagem , Calcinose/etiologia , Calcinose/genética , Doenças Cerebelares/líquido cefalorraquidiano , Doenças Cerebelares/diagnóstico por imagem , Doenças Cerebelares/genética , Criança , Pré-Escolar , Feminino , Ácido Fólico/líquido cefalorraquidiano , Deficiência de Ácido Fólico/líquido cefalorraquidiano , Deficiência de Ácido Fólico/diagnóstico por imagem , Seguimentos , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/diagnóstico por imagem , Doenças Mitocondriais/etiologia , Estudos Retrospectivos , Tetra-Hidrofolatos/líquido cefalorraquidiano , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Adulto Jovem
3.
Rejuvenation Res ; 22(1): 60-70, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29943667

RESUMO

Brain aging is an intricate and natural phenomenon exclusively characterized by oxidative stress, accumulation of oxidatively damaged macromolecules, and alterations in structure and function of neurons that further increase the risk factor for most of the neurodegenerative diseases. In addition, age-dependent defective autophagy has also been implicated to favor the pathogenesis and prevalence of the neurological diseases. Therefore, the development of strategies that delay aging and the concomitant neurological disorders remain elusive. Thus, the present study was undertaken to investigate the effect of rapamycin-induced activation of autophagy on aging-related oxidative stress, cell death, neuroinflammation, and neurodegeneration in rat brain. Our data demonstrated the significant age-related oxidative stress, apoptotic cell death, elevated inflammatory response, and reduced level of markers associated with rejuvenation and neural integrity, including the activities of ion channel transporters (Na+/K+-ATPase and Ca2+-ATPase) and acetylcholinesterase in the brain of old aged rats. Furthermore, rapamycin (0.5 mg/kg b.w. for 28 days) induced activation of autophagy provided significant protection to aging rat brain by reducing the aging-induced oxidative stress, apoptotic cell death, and markers of neurodegeneration. Thus, our data confirmed that autophagy plays a pivotal role in delaying brain aging plausibly by maintaining the cellular homeostasis, and structural and functional integrity of cells in the brain.


Assuntos
Envelhecimento/patologia , Autofagia , Doenças Mitocondriais/prevenção & controle , Doenças Neurodegenerativas/prevenção & controle , Neuroproteção , Estresse Oxidativo/efeitos dos fármacos , Sirolimo/farmacologia , Animais , Imunossupressores/farmacologia , Masculino , Doenças Mitocondriais/etiologia , Doenças Neurodegenerativas/etiologia , Ratos , Ratos Wistar
4.
Transl Stroke Res ; 10(1): 78-90, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29569040

RESUMO

Diabetes significantly increases the risk of stroke and post-stroke mortality. Recurrent hypoglycemia (RH) is common among diabetes patients owing to glucose-lowering therapies. Earlier, we showed that RH in a rat model of insulin-dependent diabetes exacerbates cerebral ischemic damage. Impaired mitochondrial function has been implicated as a central player in the development of cerebral ischemic damage. Hypoglycemia is also known to affect mitochondrial functioning. The present study tested the hypothesis that prior exposure of insulin-treated diabetic (ITD) rats to RH exacerbates brain damage via enhanced post-ischemic mitochondrial dysfunction. In a rat model of streptozotocin-induced diabetes, we evaluated post-ischemic mitochondrial function in RH-exposed ITD rats. Rats were exposed to five episodes of moderate hypoglycemia prior to the induction of cerebral ischemia. We also evaluated the impact of RH, both alone and in combination with cerebral ischemia, on cognitive function using the Barnes circular platform maze test. We observed that RH exposure to ITD rats leads to increased cerebral ischemic damage and decreased mitochondrial complex I activity. Exposure of ITD rats to RH impaired spatial learning and memory. Our results demonstrate that RH exposure to ITD rats potentially increases post-ischemic damage via enhanced post-ischemic mitochondrial dysfunction.


Assuntos
Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Diabetes Mellitus Experimental/complicações , Hipoglicemia/complicações , Animais , Glicemia , Região CA1 Hipocampal/patologia , Diabetes Mellitus Experimental/tratamento farmacológico , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Glucose/administração & dosagem , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Masculino , Metaloproteinases da Matriz/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Doenças Mitocondriais/etiologia , Neurônios/patologia , Distribuição Aleatória , Ratos , Ratos Wistar
6.
Mil Med Res ; 5(1): 41, 2018 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-30474573

RESUMO

Recently, the definition of sepsis was concluded to be a life-threatening organ dysfunction caused by a dysregulated host response to infection. Severe patients always present with uncorrectable hypotension or hyperlactacidemia, which is defined as septic shock. The new definition emphasizes dysregulation of the host response and multiple organ dysfunction, which is partially attributed to metabolic disorders induced by energy crisis and oxidative stress. Mitochondria are a cellular organelle that are well known as the center of energy production, and mitochondrial damage or dysfunction is commonly induced in septic settings and is a predominant factor leading to a worse prognosis. In the present review, we determine the major mitochondrial disorders from morphology to functions in sepsis. In the following, several clinical or pre-clinical assays for monitoring mitochondrial function are demonstrated according to accumulated evidence, which is the first step of specific therapy targeting to modulate mitochondrial function. Accordingly, various reagents used for regulating mitochondrial enzyme activities and promoting biogenesis have been documented, among which mitochondria-targeted cation, TPP-conjugated antioxidants are the most valuable for future trials and clinical treatment to improve mitochondrial function as they may take advantage of the prognosis associated with septic complications.


Assuntos
Antioxidantes/uso terapêutico , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/etiologia , Insuficiência de Múltiplos Órgãos/etiologia , Choque Séptico/complicações , Animais , Humanos , Doenças Mitocondriais/metabolismo , Insuficiência de Múltiplos Órgãos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Choque Séptico/metabolismo
7.
Handb Clin Neurol ; 158: 51-61, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30482375

RESUMO

The majority of the 3.8 million estimated annual traumatic brain injuries (TBI) in the United States are mild TBIs, or concussions, and they occur primarily in adolescents and young adults. A concussion is a brain injury associated with rapid brain movement and characteristic clinical symptoms, with no associated objective biomarkers or overt pathologic brain changes, thereby making it difficult to diagnose by neuroimaging or other objective diagnostic tests. Most concussion symptoms are transient and resolve within 1-2 weeks. Concussions share similar acute pathophysiologic perturbations to more severe TBI: there is a rapid release of neurotransmitters, which causes ionic disequilibrium across neuronal membranes. Re-establishing ionic homeostasis consumes energy and leads to dynamic changes in cerebral glucose uptake. The magnitude and duration of these changes are related to injury severity, with milder injuries showing faster normalization. Cerebral sex differences add further variation to concussion manifestation. Relative to the male brain, the female brain has higher overall cerebral blood flow, and demonstrates regional differences in glucose metabolism, inflammatory responses, and connectivity. Understanding the pathophysiology and clinical translation of concussion can move research towards management paradigms that will minimize the risk for prolonged recovery and repeat injury.


Assuntos
Concussão Encefálica/etiologia , Lesões Encefálicas Traumáticas/complicações , Pesquisa Médica Translacional , Animais , Concussão Encefálica/diagnóstico por imagem , Concussão Encefálica/patologia , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Circulação Cerebrovascular , Transtornos Cognitivos/etiologia , Feminino , Humanos , Inflamação/etiologia , Masculino , Doenças Mitocondriais/etiologia , Transtornos dos Movimentos/etiologia , Neuroimagem , Caracteres Sexuais
8.
Mov Disord ; 33(10): 1580-1590, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30294923

RESUMO

BACKGROUND: Although primarily a neurodegenerative process, there is increasing awareness of peripheral disease mechanisms in Parkinson's disease. To investigate disease processes in accessible patient cells, we studied peripheral blood mononuclear cells in recently diagnosed PD patients and rapid eye movement-sleep behavior disorder patients who have a greatly increased risk of developing PD. We hypothesized that peripheral blood mononuclear cells may recapitulate cellular pathology found in the PD brain and investigated these cells for mitochondrial dysfunction and oxidative stress. METHODS: Peripheral blood mononuclear cells were isolated and studied from PD patients, rapid eye movement-sleep behavior disorder patients and age- and sex-matched control individuals from the well-characterized Oxford Discovery cohort. All participants underwent thorough clinical assessment. RESULTS: Initial characterization showed that PD patients had elevated levels of CD14 + monocytes and monocytes expressing C-C motif chemokine receptor 2. Mitochondrial dysfunction and oxidative stress were increased in PD patient peripheral blood mononuclear cells, with elevated levels of mitochondrial reactive oxygen species specifically in patient monocytes. This was combined with reduced levels of the antioxidant superoxide dismutase in blood cells from PD patients and, importantly, also in rapid eye movement-sleep behavior disorder patients. This mitochondrial dysfunction was associated with a concomitant increase in glycolysis in both PD and rapid eye movement-sleep behavior disorder patient blood cells independent of glucose uptake or monocyte activation. CONCLUSIONS: This work demonstrates functional bioenergetic deficits in PD and rapid eye movement-sleep behavior disorder patient blood cells during the early stages of human disease. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Glicólise/fisiologia , Leucócitos Mononucleares/ultraestrutura , Doenças Mitocondriais/etiologia , Doença de Parkinson/sangue , Doença de Parkinson/complicações , Estudos de Casos e Controles , Citocinas/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Inibidores Enzimáticos/farmacologia , Feminino , Citometria de Fluxo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Glucose/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Humanos , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Consumo de Oxigênio/fisiologia , Doença de Parkinson/patologia , Sintomas Prodrômicos , Transtorno do Comportamento do Sono REM/sangue , Transtorno do Comportamento do Sono REM/complicações , Transtorno do Comportamento do Sono REM/patologia , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores CCR2/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
9.
J Neuroinflammation ; 15(1): 242, 2018 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-30153825

RESUMO

BACKGROUND: Nod-like receptor protein 3 (NLRP3) inflammasome is a crucial factor in mediating inflammatory responses after cerebral ischemia/reperfusion (I/R), but the cellular location of NLRP3 inflammasome in cerebral I/R has yet come to a conclusion, and there is still no specific evidence to state the relationship between mitochondria and the NLRP3 inflammasome in cerebral I/R. METHODS: In the present study, we detected the cellular localization of NLRP3 inflammasomes in a transient middle cerebral artery occlusion (tMCAO) rat model and a transwell co-culture cell system under oxygen-glucose deprivation/reoxygenation (OGD/R) conditions. Then, we investigated the relationship between mitochondrial dysfunction and the activation of NLRP3 inflammasomes in different cell types after OGD/R and cerebral I/R injury. RESULTS: Our results showed that NLRP3 inflammasomes were first activated in microglia soon after cerebral I/R injury onset and then were expressed in neurons and microvascular endothelial cells later, but they were mainly in neurons. Furthermore, mitochondrial dysfunction played an important role in activating NLRP3 inflammasomes in microglia after OGD/R, and mitochondrial protector could inhibit the activation of NLRP3 inflammasomes in cerebral I/R rats. CONCLUSION: Our findings may provide novel insights into the cell type-dependent activation of NLRP3 inflammasomes at different stages of cerebral I/R injury and the role of mitochondrial dysfunction in activating the NLRP3 inflammasome pathway.


Assuntos
Infarto da Artéria Cerebral Média/complicações , Doenças Mitocondriais/etiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Animais , Hipóxia Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Infarto da Artéria Cerebral Média/tratamento farmacológico , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/genética , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Doenças Mitocondriais/fisiopatologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oxigênio/administração & dosagem , Ratos , Ratos Sprague-Dawley
10.
Exp Neurol ; 309: 67-78, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30076829

RESUMO

Mitochondrial dysfunction is considered as a critical mechanism in the pathogenesis of Parkinson's disease (PD). Increasing evidence supports the notion of mitochondria-associated membranes (MAMs) in mitochondrial dysfunction; yet little is known about the role of MAMs-related proteins in the pathogenesis of PD. Herein we exposed the nematode Caenorhabditis elegans to 0.5-10.0 µM rotenone (RO) or 0.2-1.6 mM paraquat (PQ) for 3 days. Our results showed that both RO and PQ induced similar Parkinsonism including motor deficits and dopaminergic degeneration. RO/PQ caused mitochondrial damages characterized by the increase of vacuole areas and autophagy vesicles, but the decrease of mitochondrial cristae. RO/PQ-impacted mitochondrial function was also demonstrated by the decrease of ATP level and mitochondrial membrane potential. Additionally, the attachment or surrounding of endoplasmic reticulum to the damaged mitochondria indicates ultrastructural alterations in MAMs. Using fluorescently labeled transgenic nematodes, we further found that the expression of tomm-7 and genes of Complex I, II and III was reduced, whereas the expression of pink-1 was increased in the exposed animals. To determine MAMs in toxicity toward PD, we investigated the mutants of hop-1 and pink-1, encoding presenilin and PTEN-induced putative kinase 1 (PINK1) in mitochondria-associated membranes, respectively. Results demonstrated that the mutation of both hop-1 and pink-1 reduced the vulnerability of lethal, behavioral, and mitochondrial toxicity induced by RO/PQ. These findings suggest that presenilin and PINK1 play important roles in the RO/PQ-induced neurotoxicity through the mechanisms involved in mitochondria-associated membranes.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Proteínas de Membrana/metabolismo , Doenças Mitocondriais/etiologia , Mutação/genética , Transtornos Parkinsonianos , Proteínas Serina-Treonina Quinases/genética , Trifosfato de Adenosina/metabolismo , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans , Modelos Animais de Doenças , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/genética , Proteínas de Membrana/genética , Microscopia Eletrônica de Transmissão , Mitocôndrias/patologia , Mitocôndrias/ultraestrutura , Doenças Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Movimento/efeitos dos fármacos , Movimento/fisiologia , Paraquat/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/complicações , Transtornos Parkinsonianos/patologia , Rotenona/análogos & derivados , Rotenona/toxicidade
11.
J Alzheimers Dis ; 65(1): 193-205, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30040709

RESUMO

In 2017, approximately 5 million Americans were living with Alzheimer's disease (AD), and it is estimated that by 2050 this number could increase to 16 million. In this study, we apply mathematical optimization to approach microarray analysis to detect differentially expressed genes and determine the most correlated structure among their expression changes. The analysis of GSE4757 microarray dataset, which compares expression between AD neurons without neurofibrillary tangles (controls) and with neurofibrillary tangles (cases), was casted as a multiple criteria optimization (MCO) problem. Through the analysis it was possible to determine a series of Pareto efficient frontiers to find the most differentially expressed genes, which are here proposed as potential AD biomarkers. The Traveling Sales Problem (TSP) model was used to find the cyclical path of maximal correlation between the expression changes among the genes deemed important from the previous stage. This leads to a structure capable of guiding biological exploration with enhanced precision and repeatability. Ten genes were selected (FTL, GFAP, HNRNPA3, COX1, ND2, ND3, ND4, NUCKS1, RPL41, and RPS10) and their most correlated cyclic structure was found in our analyses. The biological functions of their products were found to be linked to inflammation and neurodegenerative diseases and some of them had not been reported for AD before. The TSP path connects genes coding for mitochondrial electron transfer proteins. Some of these proteins are closely related to other electron transport proteins already reported as important for AD.


Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Transtornos Mentais/etiologia , Biomarcadores , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Análise em Microsséries , Doenças Mitocondriais/etiologia , Doenças Mitocondriais/genética , Complexos Multienzimáticos/genética , Emaranhados Neurofibrilares/genética , Emaranhados Neurofibrilares/patologia
12.
J Alzheimers Dis ; 64(4): 1247-1259, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29991132

RESUMO

BACKGROUND: Alzheimer's disease (AD), the most common cause of dementia, is characterized by the intra- and extracellular aggregation and accumulation of proteins. The major molecular hallmark is the aggregation of amyloid-ß (Aß) and hyperphosphorylated tau proteins into plaques and tangles, respectively. Evidence points to the pre-fibrillary states of protein aggregates harboring the greatest neurotoxicity. OBJECTIVE: This study was designed to identify and quantify pre-fibrillary protein species enriched by their insolubility in the detergent sarkosyl in the APPSWE/PS1ΔE9 (APP/PS1) transgenic mouse model of AD. Sarkosyl insoluble fractions were isolated from the brains of APP/PS1 and littermate wild type (Wt) mice to identify pre-fibrillary protein species associated with AD. METHODS: Pre-fibrillary protein species were isolated from the brains of 3- and 24-month-old APP/PS1 and littermate Wt mice using sarkosyl extraction and subjected to quantitative proteomics analysis by the use of isobaric tags for relative and absolute quantitation (iTRAQ). RESULTS: The sarkosyl-insoluble pre-fibrillary proteome showed differential age- and genotype-induced effects. In addition to Aß and tau, old APP/PS1 mice showed significant enrichment in proteins in the sarkosyl fraction involved in oxidative phosphorylation and mitochondrial function. CONCLUSION: The results of this study implicate dysfunctional mitochondria as playing a key role of Aß- and potentially tau-induced pathological events in the APP/PS1 transgenic mouse model of AD.


Assuntos
Envelhecimento , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Encéfalo/metabolismo , Doenças Mitocondriais/etiologia , Proteoma/metabolismo , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Ontologia Genética , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Doenças Mitocondriais/genética , Mutação/genética , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Presenilina-1/genética , Proteoma/efeitos dos fármacos , Sarcosina/análogos & derivados , Sarcosina/farmacologia
14.
CNS Neurol Disord Drug Targets ; 17(9): 689-695, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29952272

RESUMO

BACKGROUND & OBJECTIVE: Traumatic Brain Injury (TBI) is one of the major causes of mortality and morbidity worldwide. It represents mild, moderate and severe effects of physical assault to brain which may cause sequential, primary or secondary ramifications. Primary injury can be due to the first physical hit, blow or jolt to one of the brain compartments. The primary injury is then followed by secondary injury which leads to biochemical, cellular, and physiological changes like blood brain barrier disruption, inflammation, excitotoxicity, necrosis, apoptosis, mitochondrial dysfunction and generation of oxidative stress. Apart from this, there is also an immediate increase in glutamate at the synapses following severe TBI. Excessive glutamate at synapses in turn activates corresponding NMDA and AMPA receptors that facilitate excessive calcium influx into the neuronal cells. This leads to the generation of oxidative stress which further leads to mitochondrial dysfunction, lipid peroxidation and oxidation of proteins and DNA. As a consequence, neuronal cell death takes place and ultimately people start facing some serious disabilies. CONCLUSION: In the present review we provide extensive overview of the role of reactive oxygen species (ROS)-induced oxidative stress and its fatal effects on brain after TBI.


Assuntos
Lesões Encefálicas Traumáticas/terapia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/farmacologia , Animais , Lesões Encefálicas Traumáticas/complicações , Humanos , Doenças Mitocondriais/etiologia
15.
CNS Neurol Disord Drug Targets ; 17(8): 571-589, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29952273

RESUMO

BACKGROUND & OBJECTIVE: Over the last two decades, Alzheimer disease (AD) associated research has accomplished an overwhelming momentum, as it is one of the major current healthcare issues in the developed world. AD is characterized by the presence of Aß mediated extracellular amyloid fibrils and tau-mediated intracellular neurofibrillar tangles and reports have highlighted their subsequent effects on neuronal synaptic activity, antioxidant response and recently explored mitochondrial dysfunction. Additionally, recent reports have demonstrated the mitochondrial dysfunction and associated physiological as well as cellular alterations triggered by fibrillar structures inside the brain tissue. Accumulated evidence indicated that mitochondrial dysfunction also plays a detrimental role in AD pathogenesis and reduction in mitochondrial dysfunction may provide an additional beneficial effect in AD patients. Currently available drugs are ineffective in disease progression and more symptomatic while mechanism oriented drug explorations have been intensively investigated. Therefore, search for effective therapeutic approaches in Alzheimer disease has directed the ongoing research more towards specific biomarker selection, physicochemical properties of drugs and its subsequent interaction with target molecules. CONCLUSION: In present review, we have comprised an overview of the therapeutic advancement in Alzheimer disease with a prevalent hypothesis and current ongoing putative therapeutic approaches to provide recent insights in AD pathogenesis.


Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Antipsicóticos/uso terapêutico , Doenças Mitocondriais/etiologia , Peptídeos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Antipsicóticos/farmacologia , Humanos
16.
Lancet ; 391(10139): 2560-2574, 2018 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-29903433

RESUMO

Mitochondria are dynamic bioenergetic organelles whose maintenance requires around 1500 proteins from two genomes. Mutations in either the mitochondrial or nuclear genome can disrupt a plethora of cellular metabolic and homoeostatic functions. Mitochondrial diseases represent one of the most common and severe groups of inherited genetic disorders, characterised by clinical, biochemical, and genetic heterogeneity, diagnostic odysseys, and absence of disease-modifying curative therapies. This Review aims to discuss recent advances in mitochondrial biology and medicine arising from widespread use of high-throughput omics technologies, and also includes a broad discussion of emerging therapies for mitochondrial disease. New insights into both bioenergetic and biosynthetic mitochondrial functionalities have expedited the genetic diagnosis of primary mitochondrial disorders, and identified novel mitochondrial pathomechanisms and new targets for therapeutic intervention. As we enter this new era of mitochondrial medicine, underpinned by global unbiased approaches and multifaceted investigation of mitochondrial function, omics technologies will continue to shed light on unresolved mitochondrial questions, paving the way for improved outcomes for patients with mitochondrial diseases.


Assuntos
Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Terapia Genética , Genômica , Humanos , Metabolômica , Doenças Mitocondriais/etiologia , Mutação , Proteômica
17.
J Alzheimers Dis ; 63(3): 1075-1088, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29710722

RESUMO

Growing evidence suggests that mitochondrial dysfunction is an early event in sporadic Alzheimer's disease (AD), but the impact of mitochondrial dysfunction on the transition from healthy aging to AD remains elusive. Here we estimated the influence of mitochondrial dysfunction on the initiation of AD signs in OXYS rats, which simulate key characteristics of sporadic AD. We assessed the mitochondrial ultrastructure of pyramidal neurons of the hippocampus at the age preceding the development (age 20 days), during manifestation (4-5 months), and at the well-pronounced stages (18-24 months) of the AD-like pathology in OXYS rats. Ultrastructural alterations were collated with the amounts of proteins mediating mitochondrial dynamics [mitofusins (MFN1 and MFN2) and dynamin-1-like protein (DRP1)]; with activity of respiratory chain complexes I, IV, and V in the hippocampal mitochondria; with reactive oxygen species (ROS) production; and with expression of uncoupling protein 2 (UCP2) regulating ROS production. Already at the preclinical stage, OXYS rats showed some characteristic changes in hippocampal mitochondria, which increased in size with the manifestation and progression of AD-like pathology, including decreased activity of respiratory complexes against the background of greater fusion and formation of larger mitochondria. Signs of AD developed simultaneously with increasing dysfunction of mitochondria, with a dramatic decrease in their number, and with increased fission but without upregulation of ROS production (observed only in 20-day-old OXYS rats). Summarizing the data from our present and previous studies, we conclude that mitochondrial dysfunction appears to mediate or possibly even initiate pathological molecular cascades of AD-like pathology in OXYS rats and can be considered a predictor of the early development of the late-onset form of AD in humans.


Assuntos
Envelhecimento/patologia , Doença de Alzheimer/complicações , Doença de Alzheimer/patologia , Hipocampo/patologia , Doenças Mitocondriais/etiologia , Fatores Etários , Animais , Modelos Animais de Doenças , Dinaminas/metabolismo , Dinaminas/ultraestrutura , Hipocampo/ultraestrutura , Masculino , Proteínas de Membrana/metabolismo , Proteínas de Membrana/ultraestrutura , Microscopia Eletrônica , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/ultraestrutura , Complexos Multienzimáticos/metabolismo , Complexos Multienzimáticos/ultraestrutura , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
18.
Life Sci ; 204: 55-64, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29733848

RESUMO

AIMS: Ischemic acute kidney injury (AKI) is a serious clinical problem and no efficient therapeutics is available in clinic now. Natural polyacetylene glycosides (PGAs) had shown antioxidant and anti-inflammatory properties, but their effects on kidney injury have not been evaluated. This study aimed to investigate the protective effect of PGA on ischemic kidney injury in renal tubular epithelial cells (TECs) and mice. MAIN METHODS: Hypoxic HK-2 cells and renal ischemia/reperfusion injury (IRI) mice were treated with PGA from Coreopsis tinctoria, and the cell viability, renal function, apoptosis, inflammation, mitochondrial injury, lipids metabolism were analyzed. KEY FINDINGS: In vitro results showed that PGA improved cell viability and reduced oxidative stress, pro-apoptotic/pro-inflammatory factors expression and NFκB activation in TECs under hypoxia/reperfusion (H/R). Moreover, PGA reduced mitochondria oxidative stress and improved ATP production, ΔΨm and mitochondria biogenesis, and inhibited lipids uptake, biosynthesis and accumulation in hypoxic TECs. In vivo, PGA significantly attenuated kidney injury and reduced blood urea nitrogen (BUN), serum creatinine (CREA) and urinary albumin (Alb), and increased creatinine clearance (CC) in IRI mice. PGA also decreased cell apoptosis, mitochondria oxidative stress, inflammatory response and lipid droplets accumulation, and promoted ATP generation in kidney of IRI mice. SIGNIFICANCE: Our results proved that PGA ameliorated ischemic kidney injury via synergic anti-inflammation, mitochondria protection and anti-lipotoxicity actions, and it might be a promising multi-target therapy for ischemic AKI.


Assuntos
Lesão Renal Aguda/prevenção & controle , Anti-Inflamatórios não Esteroides/farmacologia , Transtornos do Metabolismo dos Lipídeos/tratamento farmacológico , Doenças Mitocondriais/tratamento farmacológico , Poli-Inos/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Lesão Renal Aguda/complicações , Albuminúria/prevenção & controle , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Nitrogênio da Ureia Sanguínea , Sobrevivência Celular/efeitos dos fármacos , Coreopsis/química , Creatinina/sangue , Inflamação , Testes de Função Renal , Transtornos do Metabolismo dos Lipídeos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doenças Mitocondriais/etiologia , Estresse Oxidativo/efeitos dos fármacos , Poli-Inos/química , Circulação Renal , Traumatismo por Reperfusão/complicações
19.
Hum Mol Genet ; 27(15): 2739-2754, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29767723

RESUMO

Multiple mitochondrial dysfunction syndromes (MMDS) comprise a group of severe autosomal recessive diseases characterized by impaired respiration and lipoic acid metabolism, resulting in infantile-onset mitochondrial encephalopathy, non-ketotic hyperglycinemia, myopathy, lactic acidosis and early death. Four different MMDS have been analyzed in detail according to the genes involved in the disease, MMDS1 (NFU1), MMDS2 (BOLA3), MMDS3 (IBA57) and MMDS4 (ISCA2). MMDS5 has recently been described in a clinical case report of patients carrying a mutation in ISCA1, but with no further functional analysis. ISCA1 encodes a mitochondrial protein essential for the assembly of [4Fe-4S] clusters in key metabolic and respiratory enzymes. Here, we describe a patient with a severe early onset leukodystrophy, multiple defects of respiratory complexes and a severe impairment of lipoic acid synthesis. A homozygous missense mutation in ISCA1 (c.29T>G; p.V10G) identified by targeted MitoExome sequencing resulted in dramatic reduction of ISCA1 protein level. The mutation located in the uncleaved presequence severely affected both mitochondrial import and stability of ISCA1. Down-regulation of ISCA1 in HeLa cells by RNAi impaired the biogenesis of mitochondrial [4Fe-4S] proteins, yet could be complemented by expression of wild-type ISCA1. In contrast, the ISCA1 p.V10G mutant protein only partially complemented the defects, closely resembling the biochemical phenotypes observed for ISCA1 patient fibroblasts. Collectively, our comprehensive clinical and biochemical investigations show that the ISCA1 p.V10G mutation functionally impaired mitochondrial [4Fe-4S] protein assembly and hence was causative for the observed clinical defects.


Assuntos
Proteínas com Ferro-Enxofre/metabolismo , Leucoencefalopatias/genética , Doenças Mitocondriais/etiologia , Proteínas Mitocondriais/metabolismo , Mutação , Idade de Início , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Feminino , Teste de Complementação Genética , Células HeLa , Homozigoto , Humanos , Proteínas com Ferro-Enxofre/genética , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética
20.
Int J Dev Neurosci ; 68: 39-44, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29689339

RESUMO

Neural tube defects (NTDs) are the most common and severe congenital malformations, which result from failure of the neural tube to close during embryonic development. The etiology of NTDs is complex, caused by interactions between genetic defects and environmental factors, but the exact mechanisms of this disease are still not fully understood. We herein employ a Seahorse Bioscience microplate-based extracellular flux (XF) analyzer to determine mitochondrial function and quantify respiratory coupling to various bioenergetic functions using specific pharmacological inhibitors of bioenergetic pathways. We demonstrate that changes in coupling between ATP turnover and proton leak are correlated with NTDs. Further, we determined that the ATP content and oxidative stress levels in posterior spinal cords of rat embryos with NTDs between E11 and E14 was lower than that of normal controls. The present study reveals that mitochondrial dysfunction is associated with all-trans retinoic acid (atRA)-induced NTDs in rat embryos. Oxidative stress results from decreased antioxidant enzyme activity. This study provides a novel viewpoint for exploring the embryonic pathogenesis of atRA-induced NTDs.


Assuntos
Ceratolíticos/toxicidade , Doenças Mitocondriais/etiologia , Espinha Bífida Cística/induzido quimicamente , Espinha Bífida Cística/complicações , Tretinoína/toxicidade , Trifosfato de Adenosina/metabolismo , Fatores Etários , Animais , Catalase/metabolismo , Ciclo-Oxigenase 1/metabolismo , Embrião de Mamíferos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Ratos , Ratos Wistar , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Superóxido Dismutase/metabolismo
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