RESUMO
Mitochondrial oxidative phosphorylation disorders are extremely heterogeneous conditions. Their clinical and genetic variability makes the identification of reliable and specific biomarkers very challenging. Until now, only a few studies have focused on the effect of a defective oxidative phosphorylation functioning on the cell's secretome, although it could be a promising approach for the identification and pre-selection of potential circulating biomarkers for mitochondrial diseases. Here, we review the insights obtained from secretome studies with regard to oxidative phosphorylation dysfunction, and the biomarkers that appear, so far, to be promising to identify mitochondrial diseases. We propose two new biomarkers to be taken into account in future diagnostic trials.
Assuntos
DNA Mitocondrial/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Fator 15 de Diferenciação de Crescimento/metabolismo , Interleucina-6/metabolismo , Doenças Mitocondriais/metabolismo , Fosforilação Oxidativa , Fator A de Crescimento do Endotélio Vascular/metabolismo , Biomarcadores/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Fator 15 de Diferenciação de Crescimento/genética , Humanos , Doenças Mitocondriais/genética , Via Secretória/efeitos dos fármacos , Via Secretória/genética , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
Population frequency has been one of the most widely used criteria to help assign pathogenicity to newly described mitochondrial DNA variants. However, after sequencing this molecule in thousands of healthy individuals, it has been observed that a very large number of genetic variants have a very low population frequency, which has raised doubts about the utility of this criterion. By analyzing the genetic variation of mitochondrial DNA-encoded genes for oxidative phosphorylation subunits in 195,983 individuals from HelixMTdb that were not sequenced based on any medical phenotype, we show that rare variants are deleterious and, along with other criteria, population frequency is still a useful criterion to assign pathogenicity to newly described variants.
Assuntos
DNA Mitocondrial , Mitocôndrias , DNA Mitocondrial/genética , Mitocôndrias/genética , Fenótipo , VirulênciaRESUMO
Traditional culture media do not resemble the metabolic composition of human blood. The concentration of different metabolites in these media influences mitochondrial biogenesis and oxidative phosphorylation (OXPHOS) function. This knowledge is essential for the interpretation of results obtained from cellular models used for the study of OXPHOS function.
Assuntos
Biogênese de Organelas , Fosforilação Oxidativa , Técnicas de Cultura de Células , HumanosRESUMO
Down syndrome is the most common genomic disorder of intellectual disability and is caused by trisomy of chromosome 21. Several genes in this chromosome repress mitochondrial biogenesis. The goal of this study was to evaluate whether early overexpression of these genes may cause a prenatal impairment of oxidative phosphorylation negatively affecting neurogenesis. Reduction in the mitochondrial energy production and a lower mitochondrial function have been reported in diverse tissues or cell types, and also at any age, including early fetuses, suggesting that a defect in oxidative phosphorylation is an early and general event in Down syndrome individuals. Moreover, many of the medical conditions associated with Down syndrome are also frequently found in patients with oxidative phosphorylation disease. Several drugs that enhance mitochondrial biogenesis are nowadays available and some of them have been already tested in mouse models of Down syndrome restoring neurogenesis and cognitive defects. Because neurogenesis relies on a correct mitochondrial function and critical periods of brain development occur mainly in the prenatal and early neonatal stages, therapeutic approaches intended to improve oxidative phosphorylation should be provided in these periods.
Assuntos
Síndrome de Down , Animais , Modelos Animais de Doenças , Síndrome de Down/metabolismo , Humanos , Recém-Nascido , Camundongos , Mitocôndrias/metabolismo , Neurogênese , Fosforilação OxidativaRESUMO
Dilated cardiomyopathy is a frequent and extremely heterogeneous medical condition. Deficits in the oxidative phosphorylation system have been described in patients suffering from dilated cardiomyopathy. Hence, mutations in proteins related to this biochemical pathway could be etiological factors for some of these patients. Here, we review the clinical phenotypes of patients harboring pathological mutations in genes related to the oxidative phosphorylation system, either encoded in the mitochondrial or in the nuclear genome, presenting with dilated cardiomyopathy. In addition to the clinical heterogeneity of these patients, the large genetic heterogeneity has contributed to an improper allocation of pathogenicity for many candidate mutations. We suggest criteria to avoid incorrect assignment of pathogenicity to newly found mutations and discuss possible therapies targeting the oxidative phosphorylation function.
Assuntos
Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/patologia , DNA Mitocondrial/genética , Humanos , Mitocôndrias/genética , Mitocôndrias/patologia , Mutação , Fosforilação Oxidativa , FenótipoRESUMO
BACKGROUND: Leigh syndrome (LS) is a serious genetic disease that can be caused by mutations in dozens of different genes. METHODS: Clinical study of a deafness pedigree in which some members developed LS. Cellular, biochemical and molecular genetic analyses of patients' tissues and cybrid cell lines were performed. RESULTS: mitochondrial DNA (mtDNA) m.1555A>G/MT-RNR1 and m.9541T>C/MT-CO3 mutations were found. The first one is a well-known pathologic mutation. However, the second one does not appear to contribute to the high hearing loss penetrance and LS phenotype observed in this family. CONCLUSION: The m.1555A>G pathological mutation, accompanied with an unknown nuclear DNA (nDNA) factor, could be the cause of the phenotypic manifestations in this pedigree.
Assuntos
Doença de Leigh/genética , Mutação , RNA Mitocondrial/genética , Adulto , Pré-Escolar , Feminino , Humanos , Lactente , Doença de Leigh/patologia , Masculino , Linhagem , Fenótipo , RNA Ribossômico , Adulto JovemRESUMO
Pathological mutations in subunits of the oxidative phosphorylation (OXPHOS) system, or inhibitors of this biochemical pathway, increase the production of vascular endothelial growth factor (VEGF) and pathological angiogenesis. In many angiogenesis-related diseases, such as retinal, rheumatoid diseases, or cancer, OXPHOS dysfunction can be found. Thus, enhancing OXPHOS might be a promising therapeutic approach for pathologic angiogenesis.
Assuntos
Doenças Mitocondriais/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/etiologia , Inibidores da Angiogênese/farmacologia , Animais , Humanos , Neoplasias/tratamento farmacológico , Doenças Retinianas/tratamento farmacológico , Estudos Retrospectivos , Doenças Reumáticas/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: The vision loss in Leber hereditary optic neuropathy patients is due to mitochondrial DNA mutations. No treatment has shown a clear-cut benefit on a clinically meaningful end-point. However, clinical evidences suggest two therapeutic approaches: the reduction of the mutation load in heteroplasmic patients or the elevation of mitochondrial DNA amount in homoplasmic patients. RESULTS: Here we show that ketogenic treatment, in cybrid cell lines, reduces the percentage of the m.13094 T > C heteroplasmic mutation and also increases the mitochondrial DNA levels of the m.11778G > A mitochondrial genotype. CONCLUSIONS: These results suggest that ketogenic diet could be a therapeutic strategy for Leber hereditary optic neuropathy.
Assuntos
DNA Mitocondrial/genética , Mutação/genética , Atrofia Óptica Hereditária de Leber/genética , Dieta Cetogênica , Feminino , Humanos , Masculino , Mutação Puntual/genéticaRESUMO
Neuronal differentiation appears to be dependent on oxidative phosphorylation capacity. Several drugs inhibit oxidative phosphorylation and might be detrimental for neuronal differentiation. Some pregnant women take these medications during their first weeks of gestation when fetal nervous system is being developed. These treatments might have later negative consequences on the offspring's health. To analyze a potential negative effect of three widely used medications, we studied in vitro dopaminergic neuronal differentiation of cells exposed to pharmacologic concentrations of azidothymidine for acquired immune deficiency syndrome; linezolid for multidrug-resistant tuberculosis; and atovaquone for malaria. We also analyzed the dopaminergic neuronal differentiation in brains of fetuses from pregnant mice exposed to linezolid. The drugs reduced the in vitro oxidative phosphorylation capacity and dopaminergic neuronal differentiation. This differentiation process does not appear to be affected in the prenatally exposed fetus brain. Nevertheless, the global DNA methylation in fetal brain was significantly altered, perhaps linking an early exposure to a negative effect in older life. Uridine was able to prevent the negative effects on in vitro dopaminergic neuronal differentiation and on in vivo global DNA methylation. Uridine could be used as a protective agent against oxidative phosphorylation-inhibiting pharmaceuticals provided during pregnancy when dopaminergic neuronal differentiation is taking place.
Assuntos
Neurônios Dopaminérgicos/citologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Fármacos Neuroprotetores/farmacologia , Fosforilação Oxidativa/efeitos dos fármacos , Uridina/farmacologia , Xenobióticos/farmacologia , Animais , Biomarcadores , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Linhagem Celular , Células Cultivadas , Metilação de DNA , Glucose/farmacologia , Humanos , Imuno-Histoquímica , Camundongos , Mitocôndrias/genética , Mitocôndrias/imunologiaRESUMO
Many patients suffering late-onset Alzheimer disease show a deficit in respiratory complex IV activity. The de novo pyrimidine biosynthesis pathway connects with the mitochondrial respiratory chain upstream from respiratory complex IV. We hypothesized that these patients would have decreased pyrimidine nucleotide levels. Then, different cell processes for which these compounds are essential, such as neuronal membrane generation and maintenance and synapses production, would be compromised. Using a cell model, we show that inhibiting oxidative phosphorylation function reduces neuronal differentiation. Linking these processes to pyrimidine nucleotides, uridine treatment recovers neuronal differentiation. To unmask the importance of these pathways in Alzheimer disease, we firstly confirm the existence of the de novo pyrimidine biosynthesis pathway in adult human brain. Then, we report altered mRNA levels for genes from both de novo pyrimidine biosynthesis and pyrimidine salvage pathways in brain from patients with Alzheimer disease. Thus, uridine supplementation might be used as a therapy for those Alzheimer disease patients with low respiratory complex IV activity.
Assuntos
Doença de Alzheimer , Complexo IV da Cadeia de Transporte de Elétrons/fisiologia , Neurônios/fisiologia , Fosforilação Oxidativa/efeitos dos fármacos , Pirimidinas/biossíntese , Uridina , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Diferenciação Celular/efeitos dos fármacos , Desenho de Fármacos , Humanos , Mitocôndrias/metabolismo , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/efeitos dos fármacos , Uridina/metabolismo , Uridina/farmacologiaRESUMO
Mitochondrial DNA mutations in genes encoding respiratory complex I polypeptides can cause Leber hereditary optic neuropathy. Toxics affecting oxidative phosphorylation system can also cause mitochondrial optic neuropathy. Some complex I inhibitors found in edible plants might differentially interact with these pathologic mutations and modify their penetrance. To analyze this interaction, we have compared the effect of rotenone, capsaicin and rolliniastatin-1 on cybrids harboring the most frequent Leber hereditary optic neuropathy mutations and found that m.3460Gâ¯>â¯A mutation increases rotenone resistance but capsaicin and rolliniastatin-1 susceptibility. Thus, to explain the pathogenicity of mitochondrial diseases due to mitochondrial DNA mutations, their potential interactions with environment factors will have to be considered.
Assuntos
Complexo I de Transporte de Elétrons/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Análise de Alimentos , Atrofia Óptica Hereditária de Leber/genética , Mutação Puntual , Xenobióticos/toxicidade , Apoptose/efeitos dos fármacos , Capsaicina/farmacologia , Linhagem Celular , DNA Mitocondrial/genética , Complexo I de Transporte de Elétrons/metabolismo , Furanos/farmacologia , Interação Gene-Ambiente , Humanos , Fosforilação Oxidativa , Consumo de Oxigênio/efeitos dos fármacos , Rotenona/farmacologiaRESUMO
Late-onset Parkinson disease is a multifactorial and multietiological disorder, age being one of the factors implicated. Genetic and/or environmental factors, such as pesticides, can also be involved. Up to 80% of dopaminergic neurons of the substantia nigra are lost before motor features of the disorder begin to appear. In humans, these neurons are only formed a few weeks after fertilization. Therefore, prenatal exposure to pesticides or industrial chemicals during crucial steps of brain development might also alter their proliferation and differentiation. Oxidative phosphorylation is one of the metabolic pathways sensitive to environmental toxicants and it is crucial for neuronal differentiation. Many inhibitors of this biochemical pathway, frequently found as persistent organic pollutants, affect dopaminergic neurogenesis, promote the degeneration of these neurons and increase the risk of suffering late-onset Parkinson disease. Here, we discuss how an early, prenatal, exposure to these oxidative phosphorylation xenobiotics might trigger a late-onset, old age, Parkinson disease.
Assuntos
Fosforilação Oxidativa/efeitos dos fármacos , Doença de Parkinson Secundária/metabolismo , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Xenobióticos/efeitos adversos , Idade de Início , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Feminino , Humanos , Neurogênese/efeitos dos fármacos , Neurogênese/fisiologia , Doença de Parkinson Secundária/epidemiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Substância Negra/patologiaRESUMO
The onset of Leber hereditary optic neuropathy is relatively rare in childhood and, interestingly, the rate of spontaneous visual recovery is very high in this group of patients. Here, we report a child harboring a rare pathological mitochondrial DNA mutation, present in heteroplasmy, associated with the disease. A patient follow-up showed a rapid recovery of the vision accompanied by a decrease of the percentage of mutated mtDNA. A retrospective study on the age of recovery of all childhood-onset Leber hereditary optic neuropathy patients reported in the literature suggested that this process was probably related with pubertal changes.
RESUMO
The oxidative phosphorylation system is important for adipocyte differentiation. Therefore, xenobiotics inhibitors of the oxidative phosphorylation system could affect adipocyte differentiation and adipokine secretion. As adipokines impact the overall health status, these xenobiotics may have wide effects on human health. Some of these xenobiotics are widely used therapeutic drugs, such as ribosomal antibiotics. Because of its similarity to the bacterial one, mitochondrial translation system is an off-target for these compounds. To study the influence of the ribosomal antibiotic linezolid on adipokine production, we analyzed its effects on adipocyte secretome. Linezolid, at therapeutic concentrations, modifies the levels of apolipoprotein E and several adipokines and proteins related with the extracellular matrix. This antibiotic also alters the global methylation status of human adipose tissue-derived stem cells and, therefore, its effects are not limited to the exposure period. Besides their consequences on other tissues, xenobiotics acting on the adipocyte oxidative phosphorylation system alter apolipoprotein E and adipokine production, secondarily contributing to their systemic effects.
Assuntos
Adipócitos/efeitos dos fármacos , Adipocinas/metabolismo , Linezolida/farmacologia , Fosforilação Oxidativa , Inibidores da Síntese de Proteínas/farmacologia , Adipócitos/metabolismo , Células Cultivadas , Exocitose , HumanosRESUMO
Oxidative phosphorylation dysfunction has been found in many different disorders. This biochemical pathway depends on mitochondrial protein synthesis. Thus, mutations in components of the mitochondrial translation system can be responsible for some of these pathologies. We identified a new homozygous missense mutation in the mitochondrial translation elongation factor Ts gene in a patient suffering from slowly progressive childhood ataxia and hypertrophic cardiomyopathy. Using cell, biochemical and molecular-genetic protocols, we confirm it as the etiologic factor of this phenotype. Moreover, as an important functional confirmation, we rescued the normal molecular phenotype by expression of the wild-type TSFM cDNA in patient's fibroblasts. Different TSFM mutations can produce the same or very different clinical phenotypes, going from abortions to moderately severe presentations. On the other hand, the same TSFM mutation can also produce same or different phenotypes within the same range of presentations, therefore suggesting the involvement of unknown factors.
Assuntos
Ataxia/genética , Cardiomiopatias/genética , Mitocôndrias/genética , Proteínas Mitocondriais/genética , Fosforilação Oxidativa , Elongação Traducional da Cadeia Peptídica/genética , Fatores de Alongamento de Peptídeos/genética , Adulto , Sequência de Aminoácidos , Ataxia/patologia , Biópsia , Cardiomiopatias/patologia , DNA Mitocondrial/genética , Fibroblastos , Regulação da Expressão Gênica , Homozigoto , Humanos , Masculino , Mitocôndrias/patologia , Músculos/metabolismo , Músculos/patologia , Mutação , Linhagem , Fenótipo , Adulto JovemRESUMO
The advances obtained through the genetic tools available in yeast for studying the oxidative phosphorylation (OXPHOS) biogenesis and in particular the role of the mtDNA encoded genes, strongly contrast with the very limited benefits that similar approaches have generated for the study of mammalian mtDNA. Here we review the use of the genetic manipulation in mammalian mtDNA, its difficulty and the main types of mutants accumulated in the past 30 years and the information derived from them. We also point out the need for a substantial improvement in this field in order to obtain new tools for functional genetic studies and for the generation of animal models of mtDNA-linked diseases.
RESUMO
We present a new hypothesis on the contribution of a dysfunction of the oxidative phosphorylation system, through a decrease in the de novo synthesis of pyrimidine nucleotides, to the pathogenesis of late onset Alzheimer's disease (AD). In the light of this proposition, different treatments for AD patients, such as enhancing the electron flow downstream the coenzyme Q10 of the mitochondrial respiratory chain or increasing mitochondrial biogenesis or directly providing pyrimidines, would be possible. AD is a multifactorial disorder and not all patients would benefit from these treatments. Those healthy individuals harboring mtDNA haplotypes related to a coupled OXPHOS function would probably be the better candidates for these preventive therapies.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Fosforilação Oxidativa/efeitos dos fármacos , Nucleotídeos de Pirimidina , Doença de Alzheimer/metabolismo , Animais , DNA Mitocondrial/metabolismo , Humanos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Nootrópicos/farmacologia , Nootrópicos/uso terapêutico , Farmacogenética/métodos , Nucleotídeos de Pirimidina/biossínteseRESUMO
Several homoplasmic pathologic mutations in mitochondrial DNA, such as those causing Leber hereditary optic neuropathy or non-syndromic hearing loss, show incomplete penetrance. Therefore, other elements must modify their pathogenicity. Discovery of these modifying factors is not an easy task because in multifactorial diseases conventional genetic approaches may not always be informative. Here, we have taken an evolutionary approach to unmask putative modifying factors for a particular homoplasmic pathologic mutation causing aminoglycoside-induced and non-syndromic hearing loss, the m.1494C>T transition in the mitochondrial DNA. The mutation is located in the decoding site of the mitochondrial ribosomal RNA. We first looked at mammalian species that had fixed the human pathologic mutation. These mutations are called compensated pathogenic deviations because an organism carrying one must also have another that suppresses the deleterious effect of the first. We found that species from the primate family Cercopithecidae (old world monkeys) harbor the m.1494T allele even if their auditory function is normal. In humans the m.1494T allele increases the susceptibility to aminoglycosides. However, in primary fibroblasts from a Cercopithecidae species, aminoglycosides do not impair cell growth, respiratory complex IV activity and quantity or the mitochondrial protein synthesis. Interestingly, this species also carries a fixed mutation in the mitochondrial ribosomal protein S12. We show that the expression of this variant in a human m.1494T cell line reduces its susceptibility to aminoglycosides. Because several mutations in this human protein have been described, they may possibly explain the absence of pathologic phenotype in some pedigree members with the most frequent pathologic mutations in mitochondrial ribosomal RNA.