Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
Mais filtros











Base de dados
Intervalo de ano de publicação
1.
Elife ; 122023 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-36799301

RESUMO

Mitochondrial dysfunction caused by aberrant Complex I assembly and reduced activity of the electron transport chain is pathogenic in many genetic and age-related diseases. Mice missing the Complex I subunit NADH dehydrogenase [ubiquinone] iron-sulfur protein 4 (NDUFS4) are a leading mammalian model of severe mitochondrial disease that exhibit many characteristic symptoms of Leigh Syndrome including oxidative stress, neuroinflammation, brain lesions, and premature death. NDUFS4 knockout mice have decreased expression of nearly every Complex I subunit. As Complex I normally contains at least 8 iron-sulfur clusters and more than 25 iron atoms, we asked whether a deficiency of Complex I may lead to iron perturbations, thereby accelerating disease progression. Consistent with this, iron supplementation accelerates symptoms of brain degeneration in these mice, while iron restriction delays the onset of these symptoms, reduces neuroinflammation, and increases survival. NDUFS4 knockout mice display signs of iron overload in the liver including increased expression of hepcidin and show changes in iron-responsive element-regulated proteins consistent with increased cellular iron that were prevented by iron restriction. These results suggest that perturbed iron homeostasis may contribute to pathology in Leigh Syndrome and possibly other mitochondrial disorders.


Iron is a mineral that contributes to many vital body functions. But as people age, it accumulates in many organs, including the liver and the brain. Excess iron accumulation is linked to age-related diseases like Parkinson's disease. Too much iron may contribute to harmful chemical reactions in the body. Usually, the body has systems in place to mitigate this harm, but these mechanisms may fail as people age. Uncontrolled iron accumulation may damage essential proteins, DNA and fats in the brain. These changes may kill brain cells causing neurodegenerative diseases like Parkinson's disease. Mitochondria, the cell's energy-producing factories, use and collect iron inside cells. As people age, mitochondria fail, which is also linked with age-related diseases. It has been unclear if mitochondrial failure may also contribute to iron accumulation and associated diseases like Parkinson's. Kelly et al. show that mitochondrial dysfunction causes iron accumulation and contributes to neurodegeneration in mice. In the experiments, Kelly et al. used mice with a mutation in a key-iron processing protein in mitochondria. These mice develop neurodegenerative symptoms and die early in life. Feeding the mice a high-iron diet accelerated the animals' symptoms. But providing them with an iron-restricted diet slowed their symptoms and extended their lives. Low-iron diets also slowed iron accumulation in the animal's liver and reduced brain inflammation. The experiments suggest that mitochondrial dysfunction contributes to both iron overload and brain degeneration. The next step for scientists is understanding the processes leading to mitochondrial dysfunction and iron accumulation. Then, scientists can determine if they can develop treatments targeting these processes. This research might lead to new treatments for Parkinson's disease or other age-related conditions caused by iron overload.


Assuntos
Doença de Leigh , Doenças Mitocondriais , Camundongos , Animais , Doença de Leigh/genética , Doença de Leigh/patologia , Ferro/metabolismo , Doenças Neuroinflamatórias , Doenças Mitocondriais/patologia , Mitocôndrias/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Camundongos Knockout , Mamíferos/metabolismo
2.
Nature ; 567(7748): 405-408, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30867598

RESUMO

Loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) compromise epithelial HCO3- and Cl- secretion, reduce airway surface liquid pH, and impair respiratory host defences in people with cystic fibrosis1-3. Here we report that apical addition of amphotericin B, a small molecule that forms unselective ion channels, restored HCO3- secretion and increased airway surface liquid pH in cultured airway epithelia from people with cystic fibrosis. These effects required the basolateral Na+, K+-ATPase, indicating that apical amphotericin B channels functionally interfaced with this driver of anion secretion. Amphotericin B also restored airway surface liquid pH, viscosity, and antibacterial activity in primary cultures of airway epithelia from people with cystic fibrosis caused by different mutations, including ones that do not yield CFTR, and increased airway surface liquid pH in CFTR-null pigs in vivo. Thus, unselective small-molecule ion channels can restore host defences in cystic fibrosis airway epithelia via a mechanism that is independent of CFTR and is therefore independent of genotype.


Assuntos
Fibrose Cística/metabolismo , Epitélio/metabolismo , Canais Iônicos/metabolismo , Mucosa Respiratória/metabolismo , Sistema Respiratório/metabolismo , Anfotericina B/farmacologia , Animais , Bicarbonatos/metabolismo , Células Cultivadas , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/deficiência , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Epitélio/efeitos dos fármacos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Masculino , Mucosa Respiratória/efeitos dos fármacos , Sistema Respiratório/efeitos dos fármacos , ATPase Trocadora de Sódio-Potássio/metabolismo , Suínos
3.
J Biol Chem ; 293(51): 19797-19811, 2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30366982

RESUMO

Erythropoietin (EPO) signaling is critical to many processes essential to terminal erythropoiesis. Despite the centrality of iron metabolism to erythropoiesis, the mechanisms by which EPO regulates iron status are not well-understood. To this end, here we profiled gene expression in EPO-treated 32D pro-B cells and developing fetal liver erythroid cells to identify additional iron regulatory genes. We determined that FAM210B, a mitochondrial inner-membrane protein, is essential for hemoglobinization, proliferation, and enucleation during terminal erythroid maturation. Fam210b deficiency led to defects in mitochondrial iron uptake, heme synthesis, and iron-sulfur cluster formation. These defects were corrected with a lipid-soluble, small-molecule iron transporter, hinokitiol, in Fam210b-deficient murine erythroid cells and zebrafish morphants. Genetic complementation experiments revealed that FAM210B is not a mitochondrial iron transporter but is required for adequate mitochondrial iron import to sustain heme synthesis and iron-sulfur cluster formation during erythroid differentiation. FAM210B was also required for maximal ferrochelatase activity in differentiating erythroid cells. We propose that FAM210B functions as an adaptor protein that facilitates the formation of an oligomeric mitochondrial iron transport complex, required for the increase in iron acquisition for heme synthesis during terminal erythropoiesis. Collectively, our results reveal a critical mechanism by which EPO signaling regulates terminal erythropoiesis and iron metabolism.


Assuntos
Células Eritroides/metabolismo , Eritropoetina/metabolismo , Ferroquelatase/metabolismo , Heme/biossíntese , Ferro/metabolismo , Proteínas de Membrana/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Animais , Células Eritroides/citologia , Eritropoese , Células HEK293 , Humanos , Proteínas de Membrana/química , Camundongos , Membranas Mitocondriais/metabolismo , Proteínas Mitocondriais/química , Transporte Proteico
4.
Science ; 356(6338): 608-616, 2017 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-28495746

RESUMO

Multiple human diseases ensue from a hereditary or acquired deficiency of iron-transporting protein function that diminishes transmembrane iron flux in distinct sites and directions. Because other iron-transport proteins remain active, labile iron gradients build up across the corresponding protein-deficient membranes. Here we report that a small-molecule natural product, hinokitiol, can harness such gradients to restore iron transport into, within, and/or out of cells. The same compound promotes gut iron absorption in DMT1-deficient rats and ferroportin-deficient mice, as well as hemoglobinization in DMT1- and mitoferrin-deficient zebrafish. These findings illuminate a general mechanistic framework for small molecule-mediated site- and direction-selective restoration of iron transport. They also suggest that small molecules that partially mimic the function of missing protein transporters of iron, and possibly other ions, may have potential in treating human diseases.


Assuntos
Ferro/metabolismo , Animais , Células CACO-2 , Absorção Gastrointestinal , Hemoglobinas/metabolismo , Humanos , Proteínas de Ligação ao Ferro/metabolismo , Monoterpenos/metabolismo , Ratos , Saccharomyces cerevisiae/metabolismo , Tropolona/análogos & derivados , Tropolona/metabolismo
5.
J Am Chem Soc ; 137(32): 10096-9, 2015 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-26230309

RESUMO

Deficiencies of protein ion channels underlie many currently incurable human diseases. Robust networks of pumps and channels are usually responsible for the directional movement of specific ions in organisms ranging from microbes to humans. We thus questioned whether minimally selective small molecule mimics of missing protein channels might be capable of collaborating with the corresponding protein ion pumps to restore physiology. Here we report vigorous and sustainable restoration of yeast cell growth by replacing missing protein ion transporters with imperfect small molecule mimics. We further provide evidence that this tolerance for imperfect mimicry is attributable to collaboration between the channel-forming small molecule and protein ion pumps. These results illuminate a mechanistic framework for pursuing small molecule replacements for deficient protein ion channels that underlie a range of challenging human diseases.


Assuntos
Anfotericina B/química , Anfotericina B/farmacologia , Proteínas de Transporte de Cátions/genética , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/fisiologia , Azóis/farmacologia , Proteínas de Transporte de Cátions/metabolismo , Canais Iônicos/química , Canais Iônicos/metabolismo , Isoindóis , Mimetismo Molecular , Mutação , Compostos Organosselênicos/farmacologia , ATPases Translocadoras de Prótons/metabolismo , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA