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1.
Life Sci ; 244: 117322, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31958419

RESUMO

AIMS: Mitochondrial dysfunction is an early prominent feature of Alzheimer's disease (AD). In the present study, we sought to investigate whether defective mitophagy is tightly related to amyloid-ß (Aß)-induced mitochondrial dysfunction. MAIN METHODS: Immunofluorescence, western blot and transmission electron microscopy were used to examine mitophagy. Mitochondrial membrane potential was assessed using the JC-1 dye. Mitochondrial ROS was detected using MitoSOX™ Red staining. KEY FINDINGS: Aß induced mitochondrial dysfunction in HEK293 cells. Moreover, Aß induced an increase in parkin translocation to mitochondria and led to a drastic reduction in cytosolic parkin. Furthermore, Aß-treated cells displayed a microtubule-associated protein 1 light chain 3 (LC3) punctate pattern and elevated mitochondrial LC3-II levels, suggesting the upregulation of mitophagy. Notably, Aß induced the accumulation of mitochondrial p62, which was associated with impaired mitophagy. In addition, Aß-treated cells exhibited fragmented or swollen mitochondria with severely decreased cristae. We then investigated whether overexpression of parkin could protect cells against Aß-induced mitochondrial dysfunction. Interestingly, parkin overexpression inhibited Aß-induced mitochondrial dysfunction. Besides, parkin overexpression increased cytosolic and mitochondrial parkin levels as well as mitochondrial LC3-II levels in Aß-treated cells. Additionally, parkin overexpression reversed the accumulation of p62 in mitochondria, indicating that parkin overexpression restored impaired mitophagy in Aß-treated cells. Importantly, parkin overexpression remarkably reversed Aß-induced mitochondrial fragmentation. SIGNIFICANCE: Our data demonstrate that overexpression of parkin ameliorates impaired mitophagy and promotes the removal of damaged mitochondria in Aß-treated cells, indicating that upregulation of parkin-mediated mitophagy may be a potential strategy for the therapy of AD.


Assuntos
Peptídeos beta-Amiloides/efeitos adversos , Mitocôndrias/metabolismo , Doenças Mitocondriais/prevenção & controle , Ubiquitina-Proteína Ligases/metabolismo , Células HEK293 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Doenças Mitocondriais/etiologia , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Espécies Reativas de Oxigênio/metabolismo , Ubiquitina-Proteína Ligases/genética
2.
J Pediatr Ophthalmol Strabismus ; 56: e60-e64, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31622479

RESUMO

Retinopathy of prematurity (ROP) is a biphasic disease in which the first phase is characterized by high oxygen tension leading to vaso-obliteration in the retina. Pearson syndrome is a rare multisystem mitochondrial disease with a defect in cellular respiration. The authors describe a patient with Pearson syndrome and delayed onset of ROP at a postconceptual age of 42 weeks. The proposed mechanistic theory was the increased oxygen use associated with the metabolic impairments in Pearson syndrome counterbalancing the effects of supplemental oxygen during the vaso-obliterative stage of ROP. [J Pediatr Ophthalmol Strabismus. 2019;56:e60-e64.].


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Recém-Nascido de Baixo Peso , Erros Inatos do Metabolismo Lipídico/diagnóstico , Doenças Mitocondriais/diagnóstico , Doenças Musculares/diagnóstico , Oxigênio/metabolismo , Retinopatia da Prematuridade/diagnóstico , Acil-CoA Desidrogenase de Cadeia Longa/metabolismo , Progressão da Doença , Feminino , Angiofluoresceinografia/métodos , Seguimentos , Fundo de Olho , Idade Gestacional , Humanos , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/metabolismo , Doenças Mitocondriais/metabolismo , Doenças Musculares/metabolismo , Retinopatia da Prematuridade/metabolismo , Fatores de Tempo
3.
Mar Drugs ; 17(9)2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31480724

RESUMO

Mitochondria are considered to be the powerhouses of cells. They are the most commonly damaged organelles within dopaminergic neurons in patients with Parkinson's disease (PD). Despite the importance of protecting neuronal mitochondria in PD patients, the detailed mechanisms underlying mitochondrial dysfunction during pathogenesis and pathophysiological progression of PD have not yet been elucidated. We investigated the protective action of fucoidan against the detrimental action of 1-methyl-4-phenyl-pyridinium (MPP+), a neurotoxin used to model PD, in the mitochondria of SH-SY5Y neural cells. Fucoidan increased the expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) and protected the cells from MPP+-induced apoptosis by upregulating the 5' adenosine monophosphate-activated protein kinase (AMPK)-PGC-1α axis. These effects were blocked by the silencing of the PGC-1α axis. These results indicated that fucoidan protects SH-SY5Y cells from mitochondrial dysfunction and cell death caused by MPP+ treatment, via the AMPK-PGC-1α axis. These findings also suggest that fucoidan could potentially be used as a therapeutic agent for PD.


Assuntos
1-Metil-4-fenilpiridínio/farmacologia , Morte Celular/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Neurônios/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Polissacarídeos/farmacologia , Adenilato Quinase/metabolismo , Linhagem Celular Tumoral , Neurônios Dopaminérgicos/efeitos dos fármacos , Humanos , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Neurônios/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo
4.
Biomed Pharmacother ; 117: 109083, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31387169

RESUMO

BACKGROUND: Mitochondrial dysfunction is an important mechanism of non-alcoholic fatty liver disease (NAFLD). Developing mitochondrial regulators/nutrients from natural products to remedy mitochondrial dysfunction represent attractive strategies for NAFLD therapy. In China, Polygonatum kingianum (PK) has been used as a herb and food nutrient for centuries. So far, studies in which the effects of PK on NAFLD are evaluated are lacking. Our study aims at identifying the effects and mechanism of action of PK on NAFLD based on mitochondrial regulation. METHODS: A NAFLD rat model was induced by a high-fat diet (HFD) and rats were intragastrically given PK (1, 2 and 4 g/kg) for 14 weeks. Changes in body weight, food intake, histological parameters, organ indexes, biochemical parameters and mitochondrial indicators involved in oxidative stress, energy metabolism, fatty acid metabolism, and apoptosis were investigated. RESULTS: PK significantly inhibited the HFD-induced increase of alanine transaminase, aspartate transaminase, total cholesterol (TC), and low density lipoprotein cholesterol in serum, and TC and triglyceride in the liver. In addition, PK reduced high density lipoprotein cholesterol and liver enlargement without affecting food intake. PK also remarkably inhibited the HFD-induced increase of malondialdehyde and the reduction of superoxide dismutase, glutathione peroxidase, ATP synthase, and complex I and II, in mitochondria. Moreover, mRNA expression of carnitine palmitoyl transferase-1 and uncoupling protein-2 was significantly up-regulated and down-regulated after PK treatment, respectively. Finally, PK notably inhibited the HFD-induced increase of caspase 9, caspase 3 and Bax expression in hepatocytes, and the decrease of expression of Bcl-2 in hepatocytes and cytchrome c in mitochondria. CONCLUSION: PK alleviated HFD-induced NAFLD by promoting mitochondrial functions. Thus, PK may be useful mitochondrial regulators/nutrients to remedy mitochondrial dysfunction and alleviate NAFLD.


Assuntos
Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Preparações de Plantas/farmacologia , Polygonatum/química , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Caspases/metabolismo , China , Dieta Hiperlipídica/efeitos adversos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Resistência à Insulina/fisiologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Triglicerídeos/metabolismo , Regulação para Cima/efeitos dos fármacos
5.
Med Hypotheses ; 130: 109263, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31383331

RESUMO

Ketosis is a metabolic state in which the body uses ketones derived from breakdown of fatty acids as the primary mitochondrial fuel source instead of glucose. In recent years an accumulation of evidence for the beneficial effects of the ketotic state on the brain have heightened interest in its potential for use in neurological conditions. The ketogenic diet (KD) induces ketosis and is an effective treatment for medically resistant epilepsy. There is significant comorbidity between epilepsy and bipolar disorder (BD) and both conditions are treated by anti-convulsant drugs. In addition, reports on bipolar disease online fora have highlighted subjective mood stabilization effects associated with the KD. These KD reported effects could be explained if there was a disorder in the conversion of pyruvate into Acetyl-CoA (and subsequent impairment of oxidative phosphorylation) which was bypassed by ketones providing an alternative substrate for oxidative phosphorylation. This is consistent with growing evidence that mitochondrial dysfunction plays a causal role in BD and explains the reported TCA cycle dysfunction and elevated pyruvate levels in BD. Reduced levels of ATP affects the normal operation of the Na, K-ATPase in the brain with differing levels of reduction either leading to reduced neuronal action potential and inhibition of neurotransmitter release (consistent with the depressed state in BD) or increased neuronal resting potential and hyper-excitability (consistent with a [hypo]manic mood state). We hypothesize that the mitochondrial dysfunction is due to a disorder of the Pyruvate Dehydrogenase Complex (PDC) and/or Mitochondrial Carrier Protein (MCP) shuttle which moves intracellular pyruvate into mitochondria. The resultant reduction in ATP generation could explain mood instability and cycling in BD (through mechanisms such as those delineated by Mallakh and Peters). This proposed novel causal pathway could explain mood de-stabilization in BD and the reported positive effects of KD. If true, this hypothesis would suggest that there should be increased research attention to PDC (and in particular the E1 alpha subunit) as potential therapeutic targets and further study of a possible role of KD in BD to improve mood stability. Experimental approaches, such as through a clinical trial of KD on mood stabilization in BD, are required to further investigate this hypothesis.


Assuntos
Transtorno Bipolar/enzimologia , Transtorno Bipolar/fisiopatologia , Complexo Piruvato Desidrogenase/metabolismo , Acetilcoenzima A , Potenciais de Ação , Trifosfato de Adenosina/metabolismo , Afeto , Transtorno Bipolar/complicações , Dieta Cetogênica , Epilepsia/complicações , Humanos , Cetonas/metabolismo , Cetose , Mitocôndrias/patologia , Doenças Mitocondriais/metabolismo , Modelos Biológicos , Neurônios/metabolismo , Fosforilação Oxidativa
6.
Mol Cell ; 75(4): 835-848.e8, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31378462

RESUMO

Mitochondrial dysfunction and proteostasis failure frequently coexist as hallmarks of neurodegenerative disease. How these pathologies are related is not well understood. Here, we describe a phenomenon termed MISTERMINATE (mitochondrial-stress-induced translational termination impairment and protein carboxyl terminal extension), which mechanistically links mitochondrial dysfunction with proteostasis failure. We show that mitochondrial dysfunction impairs translational termination of nuclear-encoded mitochondrial mRNAs, including complex-I 30kD subunit (C-I30) mRNA, occurring on the mitochondrial surface in Drosophila and mammalian cells. Ribosomes stalled at the normal stop codon continue to add to the C terminus of C-I30 certain amino acids non-coded by mRNA template. C-terminally extended C-I30 is toxic when assembled into C-I and forms aggregates in the cytosol. Enhancing co-translational quality control prevents C-I30 C-terminal extension and rescues mitochondrial and neuromuscular degeneration in a Parkinson's disease model. These findings emphasize the importance of efficient translation termination and reveal unexpected link between mitochondrial health and proteome homeostasis mediated by MISTERMINATE.


Assuntos
Códon de Terminação , Proteínas de Drosophila/metabolismo , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Proteínas Mitocondriais/metabolismo , Deficiências na Proteostase/metabolismo , Animais , Proteínas de Drosophila/genética , Drosophila melanogaster , Células HeLa , Humanos , Mitocôndrias/genética , Mitocôndrias/patologia , Doenças Mitocondriais/genética , Doenças Mitocondriais/patologia , Proteínas Mitocondriais/genética , Deficiências na Proteostase/genética , Deficiências na Proteostase/patologia , RNA Mitocondrial/genética , RNA Mitocondrial/metabolismo
7.
Clin Chim Acta ; 497: 88-94, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31325447

RESUMO

BACKGROUND: Primary CoQ deficiency occurs because of the defective biosynthesis of coenzyme Q, one of the key components of the mitochondrial electron transport chain. Patients with this disease present with a myriad of non-specific symptoms and signs, posing a diagnostic challenge. Whole-exome sequencing is vital in the diagnosis of these cases. CASE: Three unrelated cases presenting as either encephalopathy or cardiomyopathy have been diagnosed to harbor a common pathogenic variant c.370G > A in COQ4. COQ4 encodes a key structural component for stabilizing the multienzymatic CoQ biosynthesis complex. This variant is detected only among East and South Asian populations. CONCLUSIONS: Based on the population data and our case series, COQ4-related mitochondriopathy is likely an underrecognized condition. We recommend including the COQ4 c.370G > A variant as a part of the screening process for mitochondriopathy in Chinese populations.


Assuntos
Ataxia/diagnóstico , Ataxia/genética , Mitocôndrias/genética , Mitocôndrias/patologia , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Debilidade Muscular/diagnóstico , Debilidade Muscular/genética , Ubiquinona/deficiência , Sequenciamento Completo do Exoma , Ataxia/metabolismo , Ataxia/patologia , Feminino , Variação Genética/genética , Humanos , Lactente , Recém-Nascido , Masculino , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Debilidade Muscular/metabolismo , Debilidade Muscular/patologia , Mutação , Ubiquinona/genética , Ubiquinona/metabolismo
8.
Int J Mol Sci ; 20(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340538

RESUMO

WW domain-containing oxidoreductase (Wwox) is a putative tumor suppressor. Several germline mutations of Wwox have been associated with infant neurological disorders characterized by epilepsy, growth retardation, and early death. Less is known, however, about the pathological link between Wwox mutations and these disorders or the physiological role of Wwox in brain development. In this study, we examined age-related expression and histological localization of Wwox in forebrains as well as the effects of loss of function mutations in the Wwox gene in the immature cortex of a rat model of lethal dwarfism with epilepsy (lde/lde). Immunostaining revealed that Wwox is expressed in neurons, astrocytes, and oligodendrocytes. lde/lde cortices were characterized by a reduction in neurite growth without a reduced number of neurons, severe reduction in myelination with a reduced number of mature oligodendrocytes, and a reduction in cell populations of astrocytes and microglia. These results indicate that Wwox is essential for normal development of neurons and glial cells in the cerebral cortex.


Assuntos
Sistemas de Transporte de Aminoácidos Acídicos/deficiência , Antiporters/deficiência , Córtex Cerebral/metabolismo , Nanismo/genética , Epilepsia/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Doenças Mitocondriais/genética , Neurogênese/genética , Transtornos Psicomotores/genética , Proteínas Supressoras de Tumor/genética , Oxidorredutase com Domínios WW/genética , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/genética , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/metabolismo , Proteína da Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Sistemas de Transporte de Aminoácidos Acídicos/genética , Sistemas de Transporte de Aminoácidos Acídicos/metabolismo , Animais , Antiporters/genética , Antiporters/metabolismo , Astrócitos/metabolismo , Astrócitos/patologia , Contagem de Células , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/patologia , Modelos Animais de Doenças , Nanismo/metabolismo , Nanismo/patologia , Epilepsia/metabolismo , Epilepsia/patologia , Regulação da Expressão Gênica no Desenvolvimento , Mutação em Linhagem Germinativa , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/metabolismo , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Masculino , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Proteína Básica da Mielina/genética , Proteína Básica da Mielina/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Prosencéfalo/crescimento & desenvolvimento , Prosencéfalo/metabolismo , Prosencéfalo/patologia , Transtornos Psicomotores/metabolismo , Transtornos Psicomotores/patologia , Ratos , Ratos Transgênicos , Transdução de Sinais , Proteínas Supressoras de Tumor/deficiência , Oxidorredutase com Domínios WW/deficiência
9.
Mar Drugs ; 17(8)2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31357588

RESUMO

Toxicity of particulate matter (PM) towards the epidermis has been well established in many epidemiological studies. It is manifested in cancer, aging, and skin damage. In this study, we aimed to show the mechanism underlying the protective effects of eckol, a phlorotannin isolated from brown seaweed, on human HaCaT keratinocytes against PM2.5-induced cell damage. First, to elucidate the underlying mechanism of toxicity of PM2.5, we checked the reactive oxygen species (ROS) level, which contributed significantly to cell damage. Experimental data indicate that excessive ROS caused damage to lipids, proteins, and DNA and induced mitochondrial dysfunction. Furthermore, eckol (30 µM) decreased ROS generation, ensuring the stability of molecules, and maintaining a steady mitochondrial state. The western blot analysis showed that PM2.5 promoted apoptosis-related protein levels and activated MAPK signaling pathway, whereas eckol protected cells from apoptosis by inhibiting MAPK signaling pathway. This was further reinforced by detailed investigations using MAPK inhibitors. Thus, our results demonstrated that inhibition of PM2.5-induced cell apoptosis by eckol was through MAPK signaling pathway. In conclusion, eckol could protect skin HaCaT cells from PM2.5-induced apoptosis via inhibiting ROS generation.


Assuntos
Dioxinas/farmacologia , Queratinócitos/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Material Particulado/farmacologia , Pele/diagnóstico por imagem , Apoptose/efeitos dos fármacos , Linhagem Celular , Humanos , Queratinócitos/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Alga Marinha/química , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/metabolismo
10.
Life Sci ; 231: 116538, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176776

RESUMO

Apoptosis is a complicated process that involves activation of a series of intracellular signaling. Tissue injuries from diabetes mellitus mostly occur as a consequence of higher rate of apoptosis process due to activation of a series of molecular mechanisms. Several classes of anti-hyperglycaemic agents have been developed which could potentially modulate the apoptotic process resulting in fewer tissue damages. Novel types of anti-hyperglycaemic medications such as sodium glucose cotransporters-2 inhibitors, glucagon like peptide-1 receptor agonists and dipeptidyl peptidase 4 inhibitors have shown to provide potent anti-hyperglycaemic effects, but their influences on diabetes-induced apoptotic injuries is largely unknown. Therefore, in the current study, we reviewed the published data about the possible effects of these anti-hyperglycaemic agents on apoptosis in diabetic milieu as well as in cancer cells.


Assuntos
Apoptose/efeitos dos fármacos , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacologia , Glicemia/efeitos dos fármacos , Surdez/tratamento farmacológico , Surdez/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Inibidores da Dipeptidil Peptidase IV/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Peptídeos Semelhantes ao Glucagon/agonistas , Humanos , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
11.
Int Rev Neurobiol ; 145: 83-126, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31208528

RESUMO

Several first-line chemotherapeutic agents, including taxanes, platinum agents and proteasome inhibitors, are associated with the dose-limiting side effect of chemotherapy-induced peripheral neuropathy (CIPN). CIPN predominantly manifests as sensory symptoms, which are likely due to drug accumulation within peripheral nervous tissues rather than the central nervous system. No treatment is currently available to prevent or reverse CIPN. The causal mechanisms underlying CIPN are not yet fully understood. Mitochondrial dysfunction has emerged as a major factor contributing to the development and maintenance of CIPN. This chapter will provide an overview of both clinical and preclinical data supporting this hypothesis. We will review the studies reporting the nature of mitochondrial dysfunction evoked by chemotherapy in terms of changes in mitochondrial morphology, bioenergetics and reactive oxygen species (ROS) generation. Furthermore, we will discuss the in vivo effects of pharmacological interventions that counteract chemotherapy-evoked mitochondrial dysfunction and ameliorate pain-like behavior.


Assuntos
Antineoplásicos/efeitos adversos , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Animais , Metabolismo Energético/efeitos dos fármacos , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Espécies Reativas de Oxigênio/metabolismo
12.
Oxid Med Cell Longev ; 2019: 3403075, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31191798

RESUMO

Mitochondrial permeability transition pore (PTP), a (patho)physiological phenomenon discovered over 40 years ago, is still not completely understood. PTP activation results in a formation of a nonspecific channel within the inner mitochondrial membrane with an exclusion size of 1.5 kDa. PTP openings can be transient and are thought to serve a physiological role to allow quick Ca2+ release and/or metabolite exchange between mitochondrial matrix and cytosol or long-lasting openings that are associated with pathological conditions. While matrix Ca2+ and oxidative stress are crucial in its activation, the consequence of prolonged PTP opening is dissipation of the inner mitochondrial membrane potential, cessation of ATP synthesis, bioenergetic crisis, and cell death-a primary characteristic of mitochondrial disorders. PTP involvement in mitochondrial and cellular demise in a variety of disease paradigms has been long appreciated, yet the exact molecular entity of the PTP and the development of potent and specific PTP inhibitors remain areas of active investigation. In this review, we will (i) summarize recent advances made in elucidating the molecular nature of the PTP focusing on evidence pointing to mitochondrial FoF1-ATP synthase, (ii) summarize studies aimed at discovering novel PTP inhibitors, and (iii) review data supporting compromised PTP activity in specific mitochondrial diseases.


Assuntos
Doenças Mitocondriais/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Animais , Humanos , Membranas Mitocondriais/metabolismo
13.
Oxid Med Cell Longev ; 2019: 2105607, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31210837

RESUMO

Age is the main risk factor for a number of human diseases, including neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, which increasing numbers of elderly individuals suffer. These pathological conditions are characterized by progressive loss of neuron cells, compromised motor or cognitive functions, and accumulation of abnormally aggregated proteins. Mitochondrial dysfunction is one of the main features of the aging process, particularly in organs requiring a high-energy source such as the heart, muscles, brain, or liver. Neurons rely almost exclusively on the mitochondria, which produce the energy required for most of the cellular processes, including synaptic plasticity and neurotransmitter synthesis. The brain is particularly vulnerable to oxidative stress and damage, because of its high oxygen consumption, low antioxidant defenses, and high content of polyunsaturated fats very prone to be oxidized. Thus, it is not surprising the importance of protecting systems, including antioxidant defenses, to maintain neuronal integrity and survival. Here, we review the role of mitochondrial oxidative stress in the aging process, with a specific focus on neurodegenerative diseases. Understanding the molecular mechanisms involving mitochondria and oxidative stress in the aging and neurodegeneration may help to identify new strategies for improving the health and extending lifespan.


Assuntos
Doença de Alzheimer/metabolismo , Antioxidantes/metabolismo , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Estresse Oxidativo , Doença de Parkinson/metabolismo , Doença de Alzheimer/patologia , Humanos , Mitocôndrias/patologia , Doenças Mitocondriais/patologia , Doença de Parkinson/patologia
14.
Int J Mol Sci ; 20(9)2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31064115

RESUMO

Although the large majority of mitochondrial proteins are nuclear encoded, for their correct functioning mitochondria require the expression of 13 proteins, two rRNA, and 22 tRNA codified by mitochondrial DNA (mtDNA). Once transcribed, mitochondrial RNA (mtRNA) is processed, mito-ribosomes are assembled, and mtDNA-encoded proteins belonging to the respiratory chain are synthesized. These processes require the coordinated spatio-temporal action of several enzymes, and many different factors are involved in the regulation and control of protein synthesis and in the stability and turnover of mitochondrial RNA. In this review, we describe the essential steps of mitochondrial RNA synthesis, maturation, and degradation, the factors controlling these processes, and how the alteration of these processes is associated with human pathologies.


Assuntos
Doenças Mitocondriais/genética , Processamento Pós-Transcricional do RNA , Estabilidade de RNA , RNA Mitocondrial/genética , Animais , Humanos , Doenças Mitocondriais/metabolismo , RNA Mitocondrial/metabolismo
15.
J Zhejiang Univ Sci B ; 20(5): 449-456, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31090270

RESUMO

Mitochondrion is a semi-autonomous organelle, important for cell energy metabolism, apoptosis, the production of reactive oxygen species (ROS), and Ca2+ homeostasis. Mitochondrial DNA (mtDNA) mutation is one of the primary factors in mitochondrial disorders. Though much progress has been made, there remain many difficulties in constructing cell models for mitochondrial diseases. This seriously restricts studies related to targeted drug discovery and the mechanism and therapy for such diseases. Here we summarize the characteristics of patient-specific immortalized lymphoblastoid cells, fibroblastoid cells, cytoplasmic hybrid (cybrid) cell lines, and induced pluripotent stem cells (iPSCs)-derived differentiation cells in the study of mitochondrial disorders, as well as offering discussion of roles and advances of these cell models, particularly in the screening of drugs.


Assuntos
DNA Mitocondrial/metabolismo , Descoberta de Drogas , Doenças Mitocondriais/metabolismo , Animais , Apoptose , Cálcio/metabolismo , Diferenciação Celular , Linhagem Celular , Citoplasma/metabolismo , Metabolismo Energético , Fibroblastos/citologia , Homeostase , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Linfócitos/citologia , Mitocôndrias/metabolismo , Mutação , Fenótipo , Espécies Reativas de Oxigênio/metabolismo
16.
Mol Cell ; 74(5): 877-890.e6, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31023583

RESUMO

Endoplasmic reticulum (ER) stress and unfolded protein response are energetically challenging under nutrient stress conditions. However, the regulatory mechanisms that control the energetic demand under nutrient and ER stress are largely unknown. Here we show that ER stress and glucose deprivation stimulate mitochondrial bioenergetics and formation of respiratory supercomplexes (SCs) through protein kinase R-like ER kinase (PERK). Genetic ablation or pharmacological inhibition of PERK suppresses nutrient and ER stress-mediated increases in SC levels and reduces oxidative phosphorylation-dependent ATP production. Conversely, PERK activation augments respiratory SCs. The PERK-eIF2α-ATF4 axis increases supercomplex assembly factor 1 (SCAF1 or COX7A2L), promoting SCs and enhanced mitochondrial respiration. PERK activation is sufficient to rescue bioenergetic defects caused by complex I missense mutations derived from mitochondrial disease patients. These studies have identified an energetic communication between ER and mitochondria, with implications in cell survival and diseases associated with mitochondrial failures.


Assuntos
Fator 4 Ativador da Transcrição/genética , Metabolismo Energético/genética , Fator de Iniciação 2 em Eucariotos/genética , Mitocôndrias/genética , eIF-2 Quinase/genética , Trifosfato de Adenosina/metabolismo , Animais , Apoptose , Linhagem Celular , Sobrevivência Celular/genética , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/genética , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/genética , Glucose/metabolismo , Humanos , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Mutação de Sentido Incorreto/genética , Nutrientes/metabolismo , Fosforilação , Fatores de Processamento de Serina-Arginina/genética , Transdução de Sinais
18.
PLoS One ; 14(3): e0214250, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30921410

RESUMO

BACKGROUND: Mitochondrial disease is a family of genetic disorders characterized by defects in the generation and regulation of energy. Epilepsy is a common symptom of mitochondrial disease, and in the vast majority of cases, refractory to commonly used antiepileptic drugs. Ferroptosis is a recently-described form of iron- and lipid-dependent regulated cell death associated with glutathione depletion and production of lipid peroxides by lipoxygenase enzymes. Activation of the ferroptosis pathway has been implicated in a growing number of disorders, including epilepsy. Given that ferroptosis is regulated by balancing the activities of glutathione peroxidase-4 (GPX4) and 15-lipoxygenase (15-LO), targeting these enzymes may provide a rational therapeutic strategy to modulate seizure. The clinical-stage therapeutic vatiquinone (EPI-743, α-tocotrienol quinone) was reported to reduce seizure frequency and associated morbidity in children with the mitochondrial disorder pontocerebellar hypoplasia type 6. We sought to elucidate the molecular mechanism of EPI-743 and explore the potential of targeting 15-LO to treat additional mitochondrial disease-associated epilepsies. METHODS: Primary fibroblasts and B-lymphocytes derived from patients with mitochondrial disease-associated epilepsy were cultured under standardized conditions. Ferroptosis was induced by treatment with the irreversible GPX4 inhibitor RSL3 or a combination of pharmacological glutathione depletion and excess iron. EPI-743 was co-administered and endpoints, including cell viability and 15-LO-dependent lipid oxidation, were measured. RESULTS: EPI-743 potently prevented ferroptosis in patient cells representing five distinct pediatric disease syndromes with associated epilepsy. Cytoprotection was preceded by a dose-dependent decrease in general lipid oxidation and the specific 15-LO product 15-hydroxyeicosatetraenoic acid (15-HETE). CONCLUSIONS: These findings support the continued clinical evaluation of EPI-743 as a therapeutic agent for PCH6 and other mitochondrial diseases with associated epilepsy.


Assuntos
Carbolinas/farmacologia , Epilepsia/tratamento farmacológico , Doenças Mitocondriais/tratamento farmacológico , Ubiquinona/análogos & derivados , Araquidonato 15-Lipoxigenase/metabolismo , Linhagem Celular , Epilepsia/metabolismo , Epilepsia/patologia , Humanos , Ácidos Hidroxieicosatetraenoicos/metabolismo , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Ubiquinona/farmacologia
19.
Dis Model Mech ; 12(3)2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30833296

RESUMO

Mitochondrial DNA depletion syndromes (MDS) are a group of rare autosomal recessive disorders with early onset and no cure available. MDS are caused by mutations in nuclear genes involved in mitochondrial DNA (mtDNA) maintenance, and characterized by both a strong reduction in mtDNA content and severe mitochondrial defects in affected tissues. Mutations in MPV17, a nuclear gene encoding a mitochondrial inner membrane protein, have been associated with hepatocerebral forms of MDS. The zebrafish mpv17 null mutant lacks the guanine-based reflective skin cells named iridophores and represents a promising model to clarify the role of Mpv17. In this study, we characterized the mitochondrial phenotype of mpv17-/- larvae and found early and severe ultrastructural alterations in liver mitochondria, as well as significant impairment of the respiratory chain, leading to activation of the mitochondrial quality control. Our results provide evidence for zebrafish Mpv17 being essential for maintaining mitochondrial structure and functionality, while its effects on mtDNA copy number seem to be subordinate. Considering that a role in nucleotide availability had already been postulated for MPV17, that embryos blocked in pyrimidine synthesis do phenocopy mpv17-/- knockouts (KOs) and that mpv17-/- KOs have impaired Dihydroorotate dehydrogenase activity, we provided mpv17 mutants with the pyrimidine precursor orotic acid (OA). Treatment with OA, an easily available food supplement, significantly increased both iridophore number and mtDNA content in mpv17 -/- mutants, thus linking the loss of Mpv17 to pyrimidine de novo synthesis and opening a new simple therapeutic approach for MPV17-related MDS.


Assuntos
Pleiotropia Genética , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Proteínas Mitocondriais/química , Proteínas Mitocondriais/metabolismo , Homologia de Sequência de Aminoácidos , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Animais , Vias Biossintéticas , DNA Mitocondrial/genética , Transporte de Elétrons , Dosagem de Genes , Humanos , Larva/genética , Larva/metabolismo , Fígado/metabolismo , Proteínas de Membrana/genética , Mitocôndrias/ultraestrutura , Proteínas Mitocondriais/genética , Mutação/genética , Nucleotídeos/metabolismo , Fenótipo , Pirimidinas/biossíntese , Estresse Fisiológico , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
20.
Diabetes ; 68(5): 1084-1093, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30833467

RESUMO

Solute Carrier Family 19 Member 2 (SLC19A2) encodes thiamine transporter 1 (THTR1), which facilitates thiamine transport across the cell membrane. SLC19A2 homozygous mutations have been described as a cause of thiamine-responsive megaloblastic anemia (TRMA), an autosomal recessive syndrome characterized by megaloblastic anemia, diabetes, and sensorineural deafness. Here we describe a loss-of-function SLC19A2 mutation (c.A1063C: p.Lys355Gln) in a family with early-onset diabetes and mild TRMA traits transmitted in an autosomal dominant fashion. We show that SLC19A2-deficient ß-cells are characterized by impaired thiamine uptake, which is not rescued by overexpression of the p.Lys355Gln mutant protein. We further demonstrate that SLC19A2 deficit causes impaired insulin secretion in conjunction with mitochondrial dysfunction, loss of protection against oxidative stress, and cell cycle arrest. These findings link SLC19A2 mutations to autosomal dominant diabetes and suggest a role of SLC19A2 in ß-cell function and survival.


Assuntos
Anemia Megaloblástica/metabolismo , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Anemia Megaloblástica/genética , Pontos de Checagem do Ciclo Celular/genética , Pontos de Checagem do Ciclo Celular/fisiologia , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Humanos , Insulina/metabolismo , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Mutação/genética , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Tiamina/metabolismo
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