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1.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361060

RESUMO

Homeodomain-interacting protein kinase 2 (HIPK2) is a serine-threonine kinase that phosphorylates various transcriptional and chromatin regulators, thus modulating numerous important cellular processes, such as proliferation, apoptosis, DNA damage response, and oxidative stress. The role of HIPK2 in the pathogenesis of cancer and fibrosis is well established, and evidence of its involvement in the homeostasis of multiple organs has been recently emerging. We have previously demonstrated that Hipk2-null (Hipk2-KO) mice present cerebellar alterations associated with psychomotor abnormalities and that the double ablation of HIPK2 and its interactor HMGA1 causes perinatal death due to respiratory failure. To identify other alterations caused by the loss of HIPK2, we performed a systematic morphological analysis of Hipk2-KO mice. Post-mortem examinations and histological analysis revealed that Hipk2 ablation causes neuronal loss, neuronal morphological alterations, and satellitosis throughout the whole central nervous system (CNS); a myopathic phenotype characterized by variable fiber size, mitochondrial proliferation, sarcoplasmic inclusions, morphological alterations at neuromuscular junctions; and a cardiac phenotype characterized by fibrosis and cardiomyocyte hypertrophy. These data demonstrate the importance of HIPK2 in the physiology of skeletal and cardiac muscles and of different parts of the CNS, thus suggesting its potential relevance for different new aspects of human pathology.


Assuntos
Sistema Nervoso Central/patologia , Fibrose/patologia , Miocárdio/patologia , Neurônios/patologia , Proteínas Serina-Treonina Quinases/fisiologia , Animais , Sistema Nervoso Central/metabolismo , Feminino , Fibrose/metabolismo , Proteínas HMGA/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/metabolismo , Neurônios/metabolismo , Fenótipo , Fosforilação
2.
Proc Natl Acad Sci U S A ; 118(33)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34389665

RESUMO

Glycosylphosphatidylinositol-anchored proteins (GPI-APs) are lipid-associated luminal secretory cargoes selectively sorted to the apical surface of the epithelia where they reside and play diverse vital functions. Cholesterol-dependent clustering of GPI-APs in the Golgi is the key step driving their apical sorting and their further plasma membrane organization and activity; however, the specific machinery involved in this Golgi event is still poorly understood. In this study, we show that the formation of GPI-AP homoclusters (made of single GPI-AP species) in the Golgi relies directly on the levels of calcium within cisternae. We further demonstrate that the TGN calcium/manganese pump, SPCA1, which regulates the calcium concentration within the Golgi, and Cab45, a calcium-binding luminal Golgi resident protein, are essential for the formation of GPI-AP homoclusters in the Golgi and for their subsequent apical sorting. Down-regulation of SPCA1 or Cab45 in polarized epithelial cells impairs the oligomerization of GPI-APs in the Golgi complex and leads to their missorting to the basolateral surface. Overall, our data reveal an unexpected role for calcium in the mechanism of GPI-AP apical sorting in polarized epithelial cells and identify the molecular machinery involved in the clustering of GPI-APs in the Golgi.

3.
Biology (Basel) ; 10(7)2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209429

RESUMO

BACKGROUND: The presence of mitochondrial alterations in Down syndrome suggests that it might affect neuronal differentiation. We established a model of trisomic iPSCs, differentiating into neural precursor cells (NPCs) to monitor the occurrence of differentiation defects and mitochondrial dysfunction. METHODS: Isogenic trisomic and euploid iPSCs were differentiated into NPCs in monolayer cultures using the dual-SMAD inhibition protocol. Expression of pluripotency and neural differentiation genes was assessed by qRT-PCR and immunofluorescence. Meta-analysis of expression data was performed on iPSCs. Mitochondrial Ca2+, reactive oxygen species (ROS) and ATP production were investigated using fluorescent probes. Oxygen consumption rate (OCR) was determined by Seahorse Analyzer. RESULTS: NPCs at day 7 of induction uniformly expressed the differentiation markers PAX6, SOX2 and NESTIN but not the stemness marker OCT4. At day 21, trisomic NPCs expressed higher levels of typical glial differentiation genes. Expression profiles indicated that mitochondrial genes were dysregulated in trisomic iPSCs. Trisomic NPCs showed altered mitochondrial Ca2+, reduced OCR and ATP synthesis, and elevated ROS production. CONCLUSIONS: Human trisomic iPSCs can be rapidly and efficiently differentiated into NPC monolayers. The trisomic NPCs obtained exhibit greater glial-like differentiation potential than their euploid counterparts and manifest mitochondrial dysfunction as early as day 7 of neuronal differentiation.

4.
J Exp Clin Cancer Res ; 40(1): 22, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33413561

RESUMO

BACKGROUND: The programmed cell death-1 (PD-1) receptor and its ligands PD-L1 and PD-L2 are immune checkpoints that suppress anti-cancer immunity. Typically, cancer cells express the PD-Ls that bind PD-1 on immune cells, inhibiting their activity. Recently, PD-1 expression has also been found in cancer cells. Here, we analysed expression and functions of PD-1 in thyroid cancer (TC). METHODS: PD-1 expression was evaluated by immunohistochemistry on human TC samples and by RT-PCR, western blot and FACS on TC cell lines. Proliferation and migration of TC cells in culture were assessed by BrdU incorporation and Boyden chamber assays. Biochemical studies were performed by western blot, immunoprecipitation, pull-down and phosphatase assays. TC cell tumorigenicity was assessed by xenotransplants in nude mice. RESULTS: Human TC specimens (47%), but not normal thyroids, displayed PD-1 expression in epithelial cells, which significantly correlated with tumour stage and lymph-node metastasis. PD-1 was also constitutively expressed on TC cell lines. PD-1 overexpression/stimulation promoted TC cell proliferation and migration. Accordingly, PD-1 genetic/pharmacologic inhibition caused the opposite effects. Mechanistically, PD-1 recruited the SHP2 phosphatase to the plasma membrane and potentiated its phosphatase activity. SHP2 enhanced Ras activation by dephosphorylating its inhibitory tyrosine 32, thus triggering the MAPK cascade. SHP2, BRAF and MEK were necessary for PD-1-mediated biologic functions. PD-1 inhibition decreased, while PD-1 enforced expression facilitated, TC cell xenograft growth in mice by affecting tumour cell proliferation. CONCLUSIONS: PD-1 circuit blockade in TC, besides restoring anti-cancer immunity, could also directly impair TC cell growth by inhibiting the SHP2/Ras/MAPK signalling pathway.


Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Neoplasias da Glândula Tireoide/tratamento farmacológico , Proliferação de Células , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Transdução de Sinais , Neoplasias da Glândula Tireoide/patologia , Transfecção
6.
Int J Mol Sci ; 21(9)2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32365535

RESUMO

Mitochondria are organelles that mainly control energy conversion in the cell. In addition, they also participate in many relevant activities, such as the regulation of apoptosis and calcium levels, and other metabolic tasks, all closely linked to cell viability. Functionality of mitochondria appears to depend upon their network architecture that may dynamically pass from an interconnected structure with long tubular units, to a fragmented one with short separate fragments. A decline in mitochondrial quality, which presents itself as an altered structural organization and a function of mitochondria, has been observed in Down syndrome (DS), as well as in aging and in age-related pathologies. This review provides a basic overview of mitochondrial dynamics, from fission/fusion mechanisms to mitochondrial homeostasis. Molecular mechanisms determining the disruption of the mitochondrial phenotype in DS and aging are discussed. The impaired activity of the transcriptional co-activator PGC-1α/PPARGC1A and the hyperactivation of the mammalian target of rapamycin (mTOR) kinase are emerging as molecular underlying causes of these mitochondrial alterations. It is, therefore, likely that either stimulating the PGC-1α activity or inhibiting mTOR signaling could reverse mitochondrial dysfunction. Evidence is summarized suggesting that drugs targeting either these pathways or other factors affecting the mitochondrial network may represent therapeutic approaches to improve and/or prevent the effects of altered mitochondrial function. Overall, from all these studies it emerges that the implementation of such strategies may exert protective effects in DS and age-related diseases.


Assuntos
Envelhecimento/metabolismo , Síndrome de Down/etiologia , Síndrome de Down/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Dinâmica Mitocondrial , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Animais , Biomarcadores , Suscetibilidade a Doenças , Síndrome de Down/tratamento farmacológico , Homeostase , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Dinâmica Mitocondrial/efeitos dos fármacos , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos
7.
EMBO Rep ; 21(6): e48942, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32424995

RESUMO

Cultured mouse embryonic stem cells are a heterogeneous population with diverse differentiation potential. In particular, the subpopulation marked by Zscan4 expression has high stem cell potency and shares with 2 cell stage preimplantation embryos both genetic and epigenetic mechanisms that orchestrate zygotic genome activation. Although embryonic de novo genome activation is known to rely on metabolites, a more extensive metabolic characterization is missing. Here we analyze the Zscan4+ mouse stem cell metabolic phenotype associated with pluripotency maintenance and cell reprogramming. We show that Zscan4+ cells have an oxidative and adaptable metabolism, which, on one hand, fuels a high bioenergetic demand and, on the other hand, provides intermediate metabolites for epigenetic reprogramming. Our findings enhance our understanding of the metastable Zscan4+ stem cell state with potential applications in regenerative medicine.


Assuntos
Células-Tronco Embrionárias Murinas , Fatores de Transcrição , Animais , Blastocisto/metabolismo , Metaboloma , Camundongos , Células-Tronco Embrionárias Murinas/metabolismo , Estresse Oxidativo , Fatores de Transcrição/metabolismo
8.
Cells ; 9(4)2020 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-32235572

RESUMO

Despite initial chemotherapy response, ovarian cancer is the deadliest gynecologic cancer, due to frequent relapse and onset of drug resistance. To date, there is no affordable diagnostic/prognostic biomarker for early detection of the disease. However, it has been recently shown that high grade serous ovarian cancers show peculiar oxidative metabolism, which is in turn responsible for inflammatory response and drug resistance. The molecular chaperone TRAP1 plays pivotal roles in such metabolic adaptations, due to the involvement in the regulation of mitochondrial respiration. Here, we show that platinum-resistant ovarian cancer cells also show reduced cholesterol biosynthesis, and mostly rely on the uptake of exogenous cholesterol for their needs. Expression of FDPS and OSC, enzymes involved in cholesterol synthesis, are decreased both in drug-resistant cells and upon TRAP1 silencing, whereas the expression of LDL receptor, the main mediator of extracellular cholesterol uptake, is increased. Strikingly, treatment with statins to inhibit cholesterol synthesis reduces cisplatin-induced apoptosis, whereas silencing of LIPG, an enzyme involved in lipid metabolism, or withdrawal of lipids from the culture medium, increases sensitivity to the drug. These results suggest caveats for the use of statins in ovarian cancer patients and highlights the importance of lipid metabolism in ovarian cancer treatment.


Assuntos
Colesterol/metabolismo , Cisplatino/uso terapêutico , Homeostase , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Linhagem Celular Tumoral , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/patologia , Lipase/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Modelos Biológicos , Estresse Oxidativo/efeitos dos fármacos
9.
Biochem J ; 477(8): 1363-1366, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32322896

RESUMO

Cell-penetrating peptides (CPPs) are short peptides able to cross the cellular membranes without any interaction with specific receptors. Thanks to their ability to transport various cargo inside the cells are emerged as powerful therapeutic agents alternative to small molecules. In recent years, numerous preclinical studies provided promising results for the treatment of various human diseases. Several CPP-conjugated compounds are under clinical trials.


Assuntos
Peptídeos Penetradores de Células/metabolismo , Transporte Biológico , Membrana Celular/metabolismo , Peptídeos Penetradores de Células/administração & dosagem , Peptídeos Penetradores de Células/química , Tratamento Farmacológico , Humanos
10.
Cell Death Dis ; 10(10): 747, 2019 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-31582725

RESUMO

The serine-threonine kinase homeodomain-interacting protein kinase 2 (HIPK2) modulates important cellular functions during development, acting as a signal integrator of a wide variety of stress signals, and as a regulator of transcription factors and cofactors. We have previously demonstrated that HIPK2 binds and phosphorylates High-Mobility Group A1 (HMGA1), an architectural chromatinic protein ubiquitously expressed in embryonic tissues, decreasing its binding affinity to DNA. To better define the functional role of HIPK2 and HMGA1 interaction in vivo, we generated mice in which both genes are disrupted. About 50% of these Hmga1/Hipk2 double knock-out (DKO) mice die within 12 h of life (P1) for respiratory failure. The DKO mice present an altered lung morphology, likely owing to a drastic reduction in the expression of surfactant proteins, that are required for lung development. Consistently, we report that both HMGA1 and HIPK2 proteins positively regulate the transcriptional activity of the genes encoding the surfactant proteins. Moreover, these mice display an altered expression of thyroid differentiation markers, reasonably because of a drastic reduction in the expression of the thyroid-specific transcription factors PAX8 and FOXE1, which we demonstrate here to be positively regulated by HMGA1 and HIPK2. Therefore, these data indicate a critical role of HIPK2/HMGA1 cooperation in lung and thyroid development and function, suggesting the potential involvement of their impairment in the pathogenesis of human lung and thyroid diseases.


Assuntos
Proteína HMGA1a/genética , Proteínas Serina-Treonina Quinases/genética , Doenças Respiratórias/genética , Glândula Tireoide/anormalidades , Animais , Animais Recém-Nascidos , Desenvolvimento Embrionário , Deleção de Genes , Regulação da Expressão Gênica , Proteína HMGA1a/metabolismo , Células HeLa , Humanos , Pulmão/metabolismo , Pulmão/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Associadas a Surfactantes Pulmonares , Doenças Respiratórias/patologia , Glândula Tireoide/embriologia , Glândula Tireoide/patologia
11.
FEBS Lett ; 593(17): 2351-2365, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31400147

RESUMO

Glycosylphosphatidylinositol-anchored proteins (GPI-APs) are lipid APs attached to the extracellular leaflet of the plasma membrane (PM) via a glycolipid anchor. GPI-APs are commonly associated with cholesterol- and sphingolipid-enriched membrane microdomains. These microdomains help regulating various biological activities, by segregating different proteins and lipids in (nanoscale) membrane compartments. In fibroblasts, GPI-APs form actin- and cholesterol-dependent nanoclusters directly at the PM. In contrast, in polarized epithelial cells GPI-APs cluster in the Golgi apparatus, the major protein-sorting hub for the secretory pathway. Golgi clustering is required for the selective sorting of GPI-APs to the apical PM domain, but also regulates their organization and biological activities at the cell surface. In this review, we discuss recent advances in our understanding of the mechanism of GPI-AP sorting to the apical membrane. We focus on the roles of the protein moiety and lipids in the regulation of the clustering of GPI-APs in the Golgi apparatus.


Assuntos
Células Epiteliais/citologia , Complexo de Golgi/metabolismo , Proteínas de Membrana/metabolismo , Animais , Humanos , Transporte Proteico
12.
Front Neurosci ; 13: 673, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31316342

RESUMO

PARK20, an early onset autosomal recessive parkinsonism is due to mutations in the phosphatidylinositol-phosphatase Synaptojanin 1 (Synj1). We have recently shown that the early endosomal compartments are profoundly altered in PARK20 fibroblasts as well as the endosomal trafficking. Here, we report that PARK20 fibroblasts also display a drastic alteration of the architecture and function of the early secretory compartments. Our results show that the exit machinery from the Endoplasmic Reticulum (ER) and the ER-to-Golgi trafficking are markedly compromised in patient cells. As a consequence, PARK20 fibroblasts accumulate large amounts of cargo proteins within the ER, leading to the induction of ER stress. Interestingly, this stressful state is coupled to the activation of the PERK/eIF2α/ATF4/CHOP pathway of the Unfolded Protein Response (UPR). In addition, PARK20 fibroblasts reveal upregulation of oxidative stress markers and total ROS production with concomitant alteration of the morphology of the mitochondrial network. Interestingly, treatment of PARK20 cells with GSK2606414 (GSK), a specific inhibitor of PERK activity, restores the level of ROS, signaling a direct correlation between ER stress and the induction of oxidative stress in the PARK20 cells. All together, these findings suggest that dysfunction of early secretory pathway might contribute to the pathogenesis of the disease.

13.
Front Genet ; 10: 606, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31316549

RESUMO

Mitochondrial dysfunction plays a primary role in neurodevelopmental anomalies and neurodegeneration of Down syndrome (DS) subjects. For this reason, targeting mitochondrial key genes, such as PGC-1α/PPARGC1A, is emerging as a good therapeutic approach to attenuate cognitive disability in DS. After demonstrating the efficacy of the biguanide metformin (a PGC-1α activator) in a cell model of DS, we extended the study to other molecules that regulate the PGC-1α pathway acting on PPAR genes. We, therefore, treated trisomic fetal fibroblasts with different doses of pioglitazone (PGZ) and evaluated the effects on mitochondrial dynamics and function. Treatment with PGZ significantly increased mRNA and protein levels of PGC-1α. Mitochondrial network was fully restored by PGZ administration affecting the fission-fusion mitochondrial machinery. Specifically, optic atrophy 1 (OPA1) and mitofusin 1 (MFN1) were upregulated while dynamin-related protein 1 (DRP1) was downregulated. These effects, together with a significant increase of basal ATP content and oxygen consumption rate, and a significant decrease of reactive oxygen species (ROS) production, provide strong evidence of an overall improvement of mitochondria bioenergetics in trisomic cells. In conclusion, we demonstrate that PGZ is able to improve mitochondrial phenotype even at low concentrations (0.5 µM). We also speculate that a combination of drugs that target mitochondrial function might be advantageous, offering potentially higher efficacy and lower individual drug dosage.

14.
Redox Biol ; 24: 101228, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31153038

RESUMO

Thyroid hormone (TH) is a key metabolic regulator that acts by coordinating short- and long-term energy needs. Accordingly, significant metabolic changes are observed depending on thyroid status. Although it is established that hyperthyroidism augments basal energy consumption, thus resulting in an enhanced metabolic state, the net effects on cellular respiration and generation of reactive oxygen species (ROS) remain unclear. To elucidate the effects of augmented TH signal in muscle cells, we generated a doxycycline-inducible cell line in which the expression of the TH-activating enzyme, type 2 deiodinase (D2), is reversibly turned on by the "Tet-ON" system. Interestingly, increased intracellular TH caused a net shift from oxidative phosphorylation to glycolysis and a consequent increase in the extracellular acidification rate. As a result, mitochondrial ROS production, and both the basal and doxorubicin-induced production of cellular ROS were reduced. Importantly, the expression of a set of antioxidant genes was up-regulated, and, among them, the mitochondrial scavenger Sod2 was specifically induced at transcriptional level by D2-mediated TH activation. Finally, we observed that attenuation of oxidative stress and increased levels of SOD2 are key elements of the differentiating cascade triggered by TH and D2, thereby establishing that D2 is essential in coordinating metabolic reprogramming of myocytes during myogenic differentiation. In conclusion, our findings indicate that TH plays a key role in oxidative stress dynamics by regulating ROS generation. Our novel finding that TH and its intracellular metabolism act as mitochondrial detoxifying agents sheds new light on metabolic processes relevant to muscle physiology.


Assuntos
Iodeto Peroxidase/metabolismo , Mitocôndrias/metabolismo , Desenvolvimento Muscular , Oxirredução , Estresse Oxidativo , Hormônios Tireóideos/metabolismo , Animais , Antioxidantes/metabolismo , Glicólise , Masculino , Camundongos , Desenvolvimento Muscular/genética , Fosforilação Oxidativa , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
15.
Int J Mol Sci ; 20(11)2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31141937

RESUMO

Acute administration of a high level of extracellular citrate displays an anti-proliferative effect on both in vitro and in vivo models. However, the long-term effect of citrate treatment has not been investigated yet. Here, we address this question in PC3 cells, a prostate-cancer-derived cell line. Acute administration of high levels of extracellular citrate impaired cell adhesion and inhibited the proliferation of PC3 cells, but surviving cells adapted to grow in the chronic presence of 20 mM citrate. Citrate-resistant PC3 cells are significantly less glycolytic than control cells. Moreover, they overexpress short-form, citrate-insensitive phosphofructokinase 1 (PFK1) together with full-length PFK1. In addition, they show traits of mesenchymal-epithelial transition: an increase in E-cadherin and a decrease in vimentin. In comparison with PC3 cells, citrate-resistant cells display morphological changes that involve both microtubule and microfilament organization. This was accompanied by changes in homeostasis and the organization of intracellular organelles. Thus, the mitochondrial network appears fragmented, the Golgi complex is scattered, and the lysosomal compartment is enlarged. Interestingly, citrate-resistant cells produce less total ROS but accumulate more mitochondrial ROS than control cells. Consistently, in citrate-resistant cells, the autophagic pathway is upregulated, possibly sustaining their survival. In conclusion, chronic administration of citrate might select resistant cells, which could jeopardize the benefits of citrate anticancer treatment.


Assuntos
Citratos/farmacologia , Neoplasias da Próstata/metabolismo , Autofagia/efeitos dos fármacos , Caderinas/metabolismo , Proliferação de Células/efeitos dos fármacos , Glicólise , Humanos , Masculino , Microtúbulos/metabolismo , Células PC-3 , Fosfofrutoquinase-1/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Vimentina/metabolismo
16.
J Cell Biol ; 218(3): 1055-1065, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30659100

RESUMO

ER-TGN contact sites (ERTGoCS) have been visualized by electron microscopy, but their location in the crowded perinuclear area has hampered their analysis via optical microscopy as well as their mechanistic study. To overcome these limits we developed a FRET-based approach and screened several candidates to search for molecular determinants of the ERTGoCS. These included the ER membrane proteins VAPA and VAPB and lipid transfer proteins possessing dual (ER and TGN) targeting motifs that have been hypothesized to contribute to the maintenance of ERTGoCS, such as the ceramide transfer protein CERT and several members of the oxysterol binding proteins. We found that VAP proteins, OSBP1, ORP9, and ORP10 are required, with OSBP1 playing a redundant role with ORP9, which does not involve its lipid transfer activity, and ORP10 being required due to its ability to transfer phosphatidylserine to the TGN. Our results indicate that both structural tethers and a proper lipid composition are needed for ERTGoCS integrity.


Assuntos
Retículo Endoplasmático/metabolismo , Complexo de Golgi/metabolismo , Lipídeos de Membrana/metabolismo , Receptores de Esteroides/metabolismo , Motivos de Aminoácidos , Transporte Biológico Ativo/fisiologia , Retículo Endoplasmático/genética , Retículo Endoplasmático/ultraestrutura , Complexo de Golgi/genética , Complexo de Golgi/ultraestrutura , Células HeLa , Humanos , Lipídeos de Membrana/genética , Microscopia Eletrônica , Receptores de Esteroides/genética
17.
J Cell Physiol ; 234(6): 9233-9246, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30362565

RESUMO

Mitochondrial dysfunction seems to play a fundamental role in the pathogenesis of neurodegeneration in Huntington's disease (HD). We assessed possible neuroprotective actions of meldonium, a small molecule affecting mitochondrial fuel metabolism, in in vitro and in vivo HD models. We found that meldonium was able to prevent cytotoxicity induced by serum deprivation, to reduce the accumulation of mutated huntingtin (mHtt) aggregates, and to upregulate the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in mHTT-expressing cells. The PGC-1α increase was accompanied by the increment of mitochondrial mass and by the rebalancing of mitochondrial dynamics with a promotion of the mitochondrial fusion. Meldonium-induced PGC-1α significantly alleviated motor dysfunction and prolonged the survival of a transgenic HD Drosophila model in which mHtt expression in the nervous system led to progressive motor performance deficits. Our study strongly suggests that PGC-1α, as a master coregulator of mitochondrial biogenesis, energy homeostasis, and antioxidant defense, is a potential therapeutic target in HD.


Assuntos
Doença de Huntington/tratamento farmacológico , Metilidrazinas/uso terapêutico , Mitocôndrias/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Animais , Animais Geneticamente Modificados , Morte Celular/efeitos dos fármacos , Linhagem Celular , Meios de Cultura Livres de Soro , Modelos Animais de Doenças , Drosophila , Humanos , Proteína Huntingtina/genética , Doença de Huntington/patologia , Metilidrazinas/farmacologia , Modelos Biológicos , Mutação/genética , Agregados Proteicos/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Análise de Sobrevida , Regulação para Cima/efeitos dos fármacos
18.
Mol Med ; 24(1): 2, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30134785

RESUMO

Trisomy of chromosome 21 (TS21) is the most common autosomal aneuploidy compatible with postnatal survival with a prevalence of 1 in 700 newborns. Its phenotype is highly complex with constant features, such as mental retardation, dysmorphic traits and hypotonia, and variable features including heart defects, susceptibility to Alzheimer's disease (AD), type 2 diabetes, obesity and immune disorders. Overexpression of genes on chromosome-21 (Hsa21) is responsible for the pathogenesis of Down syndrome (DS) phenotypic features either in a direct or in an indirect manner since many Hsa21 genes can affect the expression of other genes mapping to different chromosomes. Many of these genes are involved in mitochondrial function and energy conversion, and play a central role in the mitochondrial dysfunction and chronic oxidative stress, consistently observed in DS subjects.Recent studies highlight the deep interconnections between mitochondrial dysfunction and DS phenotype. In this short review we first provide a basic overview of mitochondrial phenotype in DS cells and tissues. We then discuss how specific Hsa21 genes may be involved in determining the disruption of mitochondrial DS phenotype and biogenesis. Finally we briefly focus on drugs that affect mitochondrial function and mitochondrial network suggesting possible therapeutic approaches to improve and/or prevent some aspects of the DS phenotype.


Assuntos
Síndrome de Down/metabolismo , Mitocôndrias/metabolismo , Animais , Síndrome de Down/genética , Humanos
19.
Cell Physiol Biochem ; 47(5): 1951-1976, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29969760

RESUMO

A general hallmark of neurological diseases is the loss of redox homeostasis that triggers oxidative damages to biomolecules compromising neuronal function. Under physiological conditions the steady-state concentrations of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are finely regulated for proper cellular functions. Reduced surveillance of endogenous antioxidant defenses and/or increased ROS/RNS production leads to oxidative stress with consequent alteration of physiological processes. Neuronal cells are particularly susceptible to ROS/RNS due to their biochemical composition. Overwhelming evidences indicate that nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-linked pathways are involved in protective mechanisms against oxidative stress by regulating antioxidant and phase II detoxifying genes. As such, Nrf2 deregulation has been linked to both aging and pathogenesis of many human chronic diseases, including neurodegenerative ones such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Nrf2 activity is tightly regulated by a fine balance between positive and negative modulators. A better understanding of the regulatory mechanisms underlying Nrf2 activity could help to develop novel therapeutic interventions to prevent, slow down or possibly reverse various pathological states. To this end, microRNAs (miRs) are attractive candidates because they are linked to intracellular redox status being regulated and, post-transcriptionally, regulating key components of ROS/RNS pathways, including Nrf2.


Assuntos
Envelhecimento/metabolismo , MicroRNAs/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Doenças Neurodegenerativas/metabolismo , Estresse Oxidativo , Transdução de Sinais , Envelhecimento/genética , Envelhecimento/patologia , Animais , Humanos , MicroRNAs/genética , Fator 2 Relacionado a NF-E2/genética , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia
20.
Crit Rev Biochem Mol Biol ; 53(4): 403-419, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30040489

RESUMO

Glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-APs) are a class of proteins attached to the extracellular leaflet of the plasma membrane via a post-translational modification, the glycolipid anchor. The presence of both glycolipid anchor and protein portion confers them unique features. GPI-APs are expressed in all eukaryotes, from fungi to plants and animals. They display very diverse functions ranging from enzymatic activity, signaling, cell adhesion, cell wall metabolism, neuritogenesis, and immune response. Likewise other plasma membrane proteins, the spatio-temporal organization of GPI-APs is critical for their biological activities in physiological conditions. In this review, we will summarize the latest findings on plasma membrane organization of GPI-APs and the mechanism of its regulation in different cell types. We will also examine the involvement of specific GPI-APs namely the prion protein PrPC, the Folate Receptor alpha and the urokinase plasminogen activator receptor in human diseases focusing on neurodegenerative diseases and cancer.


Assuntos
Membrana Celular/metabolismo , Proteínas Ligadas por GPI/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Doenças Neurodegenerativas/metabolismo , Processamento de Proteína Pós-Traducional , Transdução de Sinais , Animais , Adesão Celular , Membrana Celular/genética , Membrana Celular/patologia , Proteínas Ligadas por GPI/genética , Humanos , Proteínas de Neoplasias/genética , Neoplasias/genética , Neoplasias/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Oligossacarídeos/genética , Oligossacarídeos/metabolismo
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