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1.
Biology (Basel) ; 10(7)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34356526

RESUMO

Our work evaluated cardiac function and mitochondrial bioenergetics parameters in hearts from male Wistar rats subjected to the UUO model during 28 days of progression. We measured markers of kidney damage and inflammation in plasma and renal fibrosis by histological analysis and Western blot. Cardiac function was evaluated by echocardiography and proteins involved in cardiac damage by Western blot. Oxygen consumption and transmembrane potential were monitored in cardiac mitochondria using high-resolution respirometry. We also determined the activity of ATP synthase and antioxidant enzymes such as glutathione peroxidase, glutathione reductase, and catalase. Our results show that, although renal dysfunction is established in animals subjected to ureteral obstruction, cardiac function is maintained along with mitochondrial function and antioxidant enzymes activity after 28 days of injury evolution. Our results suggest that renocardiac syndrome might develop but belatedly in obstruction-induced renal damage, opening the opportunity for treatment to prevent this condition.

2.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360637

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by increased activation of fibroblasts/myofibroblasts. Previous reports have shown that IPF fibroblasts are resistant to apoptosis, but the mechanisms remain unclear. Since inhibition of the mitochondrial permeability transition pore (mPTP) has been implicated in the resistance to apoptosis, in this study, we analyzed the role of mitochondrial function and the mPTP on the apoptosis resistance of IPF fibroblasts under basal conditions and after mitomycin C-induced apoptosis. We measured the release of cytochrome c, mPTP opening, mitochondrial calcium release, oxygen consumption, mitochondrial membrane potential, ADP/ATP ratio, ATP concentration, and mitochondrial morphology. We found that IPF fibroblasts were resistant to mitomycin C-induced apoptosis and that calcium, a well-established activator of mPTP, is decreased as well as the release of pro-apoptotic proteins such as cytochrome c. Likewise, IPF fibroblasts showed decreased mitochondrial function, while mPTP was less sensitive to ionomycin-induced opening. Although IPF fibroblasts did not present changes in the mitochondrial membrane potential, we found a fragmented mitochondrial network with scarce, thinned, and disordered mitochondria with reduced ATP levels. Our findings demonstrate that IPF fibroblasts are resistant to mitomycin C-induced apoptosis and that altered mPTP opening contributes to this resistance. In addition, IPF fibroblasts show mitochondrial dysfunction evidenced by a decrease in respiratory parameters.


Assuntos
Apoptose , Fibroblastos/metabolismo , Fibrose Pulmonar Idiopática/metabolismo , Mitocôndrias/metabolismo , Poro de Transição de Permeabilidade Mitocondrial/metabolismo , Trifosfato de Adenosina/metabolismo , Cálcio/metabolismo , Citocromos c/metabolismo , Fibroblastos/patologia , Humanos , Fibrose Pulmonar Idiopática/etiologia , Fibrose Pulmonar Idiopática/patologia , Ionomicina , Mitocôndrias/patologia , Mitomicina , Oxigênio/metabolismo , Cultura Primária de Células
3.
Cell Signal ; 87: 110123, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34438016

RESUMO

The fibrotic process could be easily defined as a pathological excess of extracellular matrix deposition, leading to disruption of tissue architecture and eventually loss of function; however, this process involves a complex network of several signal transduction pathways. Virtually almost all organs could be affected by fibrosis, the most affected are the liver, lung, skin, kidney, heart, and eyes; in all of them, the transforming growth factor-beta (TGF-ß) has a central role. The canonical and non-canonical signal pathways of TGF-ß impact the fibrotic process at the cellular and molecular levels, inducing the epithelial-mesenchymal transition (EMT) and the induction of profibrotic gene expression with the consequent increase in proteins such as alpha-smooth actin (α-SMA), fibronectin, collagen, and other extracellular matrix proteins. Recently, it has been reported that some molecules that have not been typically associated with the fibrotic process, such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4), mammalian target of rapamycin (mTOR), histone deacetylases (HDAC), and sphingosine-1 phosphate (S1P); are critical in its development. In this review, we describe and discuss the role of these new players of fibrosis and the convergence with TGF-ß signaling pathways, unveiling new insights into the panorama of fibrosis that could be useful for future therapeutic targets.

4.
Biomolecules ; 11(8)2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34439810

RESUMO

Mitochondria are essential organelles in physiology and kidney diseases, because they produce cellular energy required to perform their function. During mitochondrial metabolism, reactive oxygen species (ROS) are produced. ROS function as secondary messengers, inducing redox-sensitive post-translational modifications (PTM) in proteins and activating or deactivating different cell signaling pathways. However, in kidney diseases, ROS overproduction causes oxidative stress (OS), inducing mitochondrial dysfunction and altering its metabolism and dynamics. The latter processes are closely related to changes in the cell redox-sensitive signaling pathways, causing inflammation and apoptosis cell death. Although mitochondrial metabolism, ROS production, and OS have been studied in kidney diseases, the role of redox signaling pathways in mitochondria has not been addressed. This review focuses on altering the metabolism and dynamics of mitochondria through the dysregulation of redox-sensitive signaling pathways in kidney diseases.


Assuntos
Injúria Renal Aguda/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo , Processamento de Proteína Pós-Traducional , Espécies Reativas de Oxigênio/metabolismo , Insuficiência Renal Crônica/metabolismo , Injúria Renal Aguda/genética , Injúria Renal Aguda/patologia , Apoptose/genética , Ácidos Graxos/metabolismo , Humanos , Rim/metabolismo , Rim/patologia , Mitocôndrias/genética , Mitocôndrias/patologia , Dinâmica Mitocondrial , Mitofagia/genética , NADPH Oxidase 1/genética , NADPH Oxidase 1/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Fosforilação Oxidativa , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Transdução de Sinais , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
5.
Free Radic Biol Med ; 172: 358-371, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34175439

RESUMO

Renal fibrosis is a well-known mechanism that favors chronic kidney disease (CKD) development in obstructive nephropathy, a significant pathology worldwide. Fibrosis induction involves several pathways, and although mitochondrial alterations have recently emerged as a critical factor that triggers renal damage in the obstructed kidney, the temporal mitochondrial alterations during the fibrotic induction remain unexplored. Therefore, in this work, we evaluated the time course of mitochondrial mass and bioenergetics alterations induced by a unilateral ureteral obstruction (UUO), a widely used model to study the mechanism involved in kidney fibrosis induction and progression. Our results show a marked reduction in mitochondrial oxidative phosphorylation (OXPHOS) in the obstructed kidney on days 7 to 28 of obstruction without significant mitochondrial coupling changes. Besides, we observed that mitochondrial mass was reduced, probably due to decreased biogenesis and mitophagy induction. OXPHOS impairment was associated with decreased mitochondrial biogenesis markers, the peroxisome proliferator-activated receptor γ co-activator-1alpha (PGC-1α), and nuclear respiratory factor 1 (NRF1); and also, with the induction of mitophagy in a PTEN-induced kinase 1 (PINK1) and Parkin independent way. It is concluded that the impairment of OXPHOS capacity may be explained by the reduction in mitochondrial biogenesis and the induction of mitophagy during fibrotic progression.


Assuntos
Obstrução Ureteral , Animais , Fibrose , Mitocôndrias , Mitofagia , Biogênese de Organelas , Ratos
6.
Free Radic Biol Med ; 172: 65-81, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34077780

RESUMO

Unilateral ureteral obstruction (UUO) is an experimental rodent model that mimics renal fibrosis associated with obstructive nephropathy in an accelerated manner. After UUO, the activation of the renin-angiotensin system (RAS), nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) and mitochondrial dysfunction lead to reactive oxygen species (ROS) overproduction in the kidney. ROS are secondary messengers able to induce post-translational modifications (PTMs) in redox-sensitive proteins, which activate or deactivate signaling pathways. Therefore, in UUO, it has been proposed that ROS overproduction causes changes in said pathways promoting inflammation, oxidative stress, and apoptosis that contribute to fibrosis development. Furthermore, mitochondrial metabolism impairment has been associated with UUO, contributing to renal damage in this model. Although ROS production and oxidative stress have been studied in UUO, the development of renal fibrosis associated with redox signaling pathways has not been addressed. This review focuses on the current information about the activation and deactivation of signaling pathways sensitive to a redox state and their effect on mitochondrial metabolism in the fibrosis development in the UUO model.


Assuntos
Nefropatias , Obstrução Ureteral , Fibrose , Humanos , Rim/patologia , Nefropatias/patologia , Oxirredução , Estresse Oxidativo , Obstrução Ureteral/patologia
7.
Cell Rep ; 33(13): 108547, 2020 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-33378679

RESUMO

Mycobacterium tuberculosis (Mtb) regulates the macrophage metabolic state to thrive in the host, yet the responsible mechanisms remain elusive. Macrophage activation toward the microbicidal (M1) program depends on the HIF-1α-mediated metabolic shift from oxidative phosphorylation (OXPHOS) toward glycolysis. Here, we ask whether a tuberculosis (TB) microenvironment changes the M1 macrophage metabolic state. We expose M1 macrophages to the acellular fraction of tuberculous pleural effusions (TB-PEs) and find lower glycolytic activity, accompanied by elevated levels of OXPHOS and bacillary load, compared to controls. The eicosanoid fraction of TB-PE drives these metabolic alterations. HIF-1α stabilization reverts the effect of TB-PE by restoring M1 metabolism. Furthermore, Mtb-infected mice with stabilized HIF-1α display lower bacillary loads and a pronounced M1-like metabolic profile in alveolar macrophages (AMs). Collectively, we demonstrate that lipids from a TB-associated microenvironment alter the M1 macrophage metabolic reprogramming by hampering HIF-1α functions, thereby impairing control of Mtb infection.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Lipídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Mycobacterium tuberculosis/metabolismo , Tuberculose Pleural/metabolismo , Animais , Carga Bacteriana , Eicosanoides/farmacologia , Feminino , Glicólise/efeitos dos fármacos , Interações Hospedeiro-Patógeno , Humanos , Ativação de Macrófagos , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Derrame Pleural , Tuberculose Pleural/microbiologia
8.
Food Chem Toxicol ; 145: 111774, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32980475

RESUMO

Curcumin has protective effects in several acute kidney injury models, including that induced by potassium dichromate (K2Cr2O7). The protective effect of curcumin in this experimental model has been associated to the preservation of mitochondrial bioenergetics. This study is aimed at evaluating whether or not curcumin's protective effect in mitochondrial bioenergetics is related to the modulation of mitochondrial dynamics and biogenesis. Wistar rats were treated with a single subcutaneous dose of K2Cr2O7 (12.5 mg/kg) or received curcumin (400 mg/kg/day) by oral gavage 10 days before and one day after the K2Cr2O7 injection. K2Cr2O7 induced kidney dysfunction and increased mitochondrial hydrogen peroxide production, while decreasing the respiration directly attributable to oxidative phosphorylation and mitochondrial membrane potential. In mitochondria, K2Cr2O7 increased fission and reduced fusion. Structural analysis of mitochondria in the proximal tubular cells corroborated their fragmentation and loss of crests' integrity. Regarding mitochondrial biogenesis, K2Cr2O7 decreased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) levels. Conversely, curcumin treatment mitigated the aforementioned alterations and increased the expression of the mitochondrial transcription factor A (TFAM). Taken together, our results suggest that curcumin can protect against renal injury by modulating mitochondrial homeostasis, mitigating alterations in bioenergetics and dynamics, possibly by stimulating mitochondrial biogenesis.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Curcumina/administração & dosagem , Mitocôndrias/efeitos dos fármacos , Dicromato de Potássio/efeitos adversos , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/genética , Injúria Renal Aguda/metabolismo , Animais , Homeostase/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Mitocôndrias/genética , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Biogênese de Organelas , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Ratos , Ratos Wistar , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
9.
Biofactors ; 46(5): 716-733, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32905648

RESUMO

Obstructive nephropathy favors the progression to chronic kidney disease (CKD), a severe health problem worldwide. The unilateral ureteral obstruction (UUO) model is used to study the development of fibrosis. Impairment of renal mitochondria plays a crucial role in several types of CKD and has been strongly related to fibrosis onset. Nevertheless, in the UUO model, the impairment of mitochondria, their relationship with endoplasmic reticulum (ER) stress induction and the participation of both to induce the fibrotic process remain unclear. In this review, we summarize the current information about mitochondrial bioenergetics, redox dynamics, mitochondrial mass, and biogenesis alterations, as well as the relationship of these mitochondrial alterations with ER stress and their participation in fibrotic processes in UUO models. Early after obstruction, there is metabolic reprogramming related to mitochondrial fatty acid ß-oxidation impairment, triggering lipid deposition, oxidative stress, (calcium) Ca2+ dysregulation, and a reduction in mitochondrial mass and biogenesis. Mitochondria and the ER establish a pathological feedback loop that promotes the impairment of both organelles by ER stress pathways and Ca2+ levels dysregulation. Preserving mitochondrial and ER function can prevent or at least delay the fibrotic process and loss of renal function. However, deeper understanding is still necessary for future clinically-useful therapies.

10.
Int J Mol Sci ; 21(18)2020 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-32899919

RESUMO

Five-sixths nephrectomy (5/6Nx) model is widely used for studying the mechanisms involved in chronic kidney disease (CKD) progression, a kidney pathology that has increased dramatically in recent years. Mitochondrial impairment is a key mechanism that aggravates CKD progression; however, the information on mitochondrial bioenergetics and redox alterations along a time course in a 5/6Nx model is still limited and in some cases contradictory. Therefore, we performed for the first time a time-course study of mitochondrial alterations by high-resolution respirometry in the 5/6Nx model. Our results show a decrease in mitochondrial ß-oxidation at early times, as well as a permanent impairment in adenosine triphosphate (ATP) production in CI-linked respiration, a permanent oxidative state in mitochondria and decoupling of these organelles. These pathological alterations are linked to the early decrease in complex I and ATP synthase activities and to the further decrease in complex III activity. Therefore, our results may suggest that mitochondrial bioenergetics impairment is an early event in renal damage, whose persistence in time aggravates CKD development in the 5/6Nx model.


Assuntos
Mitocôndrias/metabolismo , Nefrectomia/efeitos adversos , Estresse Oxidativo/fisiologia , Insuficiência Renal Crônica , Animais , Progressão da Doença , Metabolismo Energético , Hemodinâmica/fisiologia , Rim/irrigação sanguínea , Rim/metabolismo , Rim/patologia , Rim/cirurgia , Masculino , Mitocôndrias/patologia , Nefrectomia/métodos , Oxirredução , Consumo de Oxigênio/fisiologia , Complicações Pós-Operatórias/metabolismo , Complicações Pós-Operatórias/patologia , Ratos , Ratos Wistar , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Fatores de Tempo
11.
Free Radic Biol Med ; 154: 18-32, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32360615

RESUMO

Recent studies suggest that mitochondrial bioenergetics and oxidative stress alterations may be common mechanisms involved in the progression of renal damage. However, the evolution of the mitochondrial alterations over time and the possible effects that their prevention could have in the progression of renal damage are not clear. Folic acid (FA)-induced kidney damage is a widely used experimental model to induce acute kidney injury (AKI), which can evolve to chronic kidney disease (CKD). Therefore, it has been extensively applied to study the mechanisms involved in AKI-to-CKD transition. We previously demonstrated that one day after FA administration, N-acetyl-cysteine (NAC) pre-administration prevented the development of AKI induced by FA. Such therapeutic effect was related to mitochondrial preservation. In the present study, we characterized the temporal course of mitochondrial bioenergetics and redox state alterations along the progression of renal damage induced by FA. Mitochondrial function was studied at different time points and showed a sustained impairment in oxidative phosphorylation capacity and a decrease in ß-oxidation, decoupling, mitochondrial membrane potential depolarization and a pro-oxidative state, attributed to the reduction in activity of complexes I and III and mitochondrial cristae effacement, thus favoring the transition from AKI to CKD. Furthermore, the mitochondrial protection by NAC administration before AKI prevented not only the long-term deterioration of mitochondrial function at the chronic stage, but also CKD development. Taken together, our results support the idea that the prevention of mitochondrial dysfunction during an AKI event can be a useful strategy to prevent the transition to CKD.


Assuntos
Injúria Renal Aguda , Insuficiência Renal Crônica , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/prevenção & controle , Progressão da Doença , Metabolismo Energético , Ácido Fólico , Humanos , Mitocôndrias/metabolismo , Oxirredução , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo
12.
Food Chem Toxicol ; 138: 111229, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32105807

RESUMO

Endoplasmic reticulum (ER) stress is a normal molecular process induced by the over-accumulation of misfolded or unfolded proteins. ER stress induces the unfolded protein response (UPR), which reduces global protein synthesis, increases ER capacity and protein degradation, to restart ER homeostasis, allowing cell survival. However, the over-induction of UPR can also trigger inflammatory processes, tissue damage and cell death. ER stress is involved in several pathologies, like endothelial dysfunction, diabetes and heart, liver, kidney or neurological diseases. Although the progression of these diseases is the result of several pathological mechanisms, oxidative stress has been widely related to these pathologies. Moreover, ER stress can establish a progressive pathological cycle with oxidative stress. Therefore, the use of natural antioxidants, able to modulate both oxidative and ER stress, can be a new strategy to mitigate these diseases. This review is focused on the effects of natural antioxidant compounds on ER stress in endothelial dysfunction, diabetes and heart, liver, kidney or neurological diseases.


Assuntos
Antioxidantes/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/efeitos dos fármacos , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Homeostase , Humanos , Transdução de Sinais/efeitos dos fármacos
13.
Biochem Biophys Res Commun ; 524(4): 1030-1036, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32063359

RESUMO

The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are encoded by a family of four genes (HCN1-4). All isoforms are expressed in the heart, HCN4 being the most abundant in the sinoatrial node (SAN). HCN channels are responsible for the "funny" current (If) associated with the generation and autonomic control of the diastolic depolarization phase of cardiac action potential. In this work we performed a proteomic analysis of HCN4 transfected in HEK293 cells. Most of the identified proteins in the HCN4 network belonged to mitochondria. The subcellular localization of HCN channels was predicted in plasma membrane, mitochondria and nucleus. Experimentally, HCN2 (full-length, truncated), HCN3 (full-length, truncated) and HCN4 (truncated) were detected in rat heart mitochondria by immunoblotting. If sensitive to ZD7288, was recorded by patch-clamp in mitoplasts from cardiomyocytes. Mitochondrial membrane potential (ΔΨm) assessment in H9c2 cells revealed that ZD7288 induced almost 50% higher hyperpolarization respect to control at 30 min. Furthermore, ZD7288 reduced oxygen consumption attributed to ATP synthesis in H9c2 cells. In conclusion, we identify for the first time functional HCN channels in mammalian cardiac mitochondria and demonstrate their impact on ΔΨm and respiration.


Assuntos
Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Potencial da Membrana Mitocondrial , Mitocôndrias Cardíacas/metabolismo , Consumo de Oxigênio , Animais , Linhagem Celular , Células HEK293 , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/análise , Camundongos Endogâmicos BALB C , Miócitos Cardíacos/metabolismo , Ratos Wistar
14.
Int J Mol Sci ; 20(20)2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31601020

RESUMO

Hyperpolarization-activated cationic HCN channels comprise four members (HCN1-4) that control dendritic integration, synaptic transmission and action potential firing. In the kidney, HCN1, HCN2 and HCN3 are differentially expressed and contribute to the transport of sodium, potassium (K+) and ammonium into the nephrons. HCN3 is regulated by K+ diets in the kidney. In this work we performed a proteomic analysis of HCN3 expressed in human embryonic kidney cells (HEK293 cells). More than 50% of the interacting proteins belonged to mitochondria. Therefore, we explored the presence of HCN channels in kidney mitochondria. By immunoblotting and immunogold electron microscopy HCN3 protein expression was found in rat kidney mitochondria; it was also confirmed in human kidney. Patch-clamp recordings of renal mitochondria and mitochondria from HEK293 cells overexpressing HCN1, HCN2 and HCN3 channels, stained with MitoTracker Green FM, indicated that only HCN3 could produce inwardly K+ currents that were inhibited by ZD7288, a specific blocker of HCN channels. Furthermore, ZD7288 caused inhibition of the oxygen consumption coupled to ATP synthesis and hyperpolarization of the inner mitochondrial membrane. In conclusion, we show for the first time that pacemaker HCN channels contribute to K+ transport in mitochondria facilitating the activity of the respiratory chain and ATP synthesis by controlling the inner mitochondrial membrane potential.


Assuntos
Rim/metabolismo , Mitocôndrias/metabolismo , Canais de Potássio/metabolismo , Potenciais de Ação , Respiração Celular , Cromatografia Líquida , Ativação do Canal Iônico , Mitocôndrias/genética , Nucleotídeos Cíclicos/metabolismo , Proteoma , Proteômica/métodos , Espectrometria de Massas em Tandem
15.
Biomolecules ; 9(8)2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398842

RESUMO

Head and neck squamous cell carcinoma (HNSCC) cells that are positive for human papillomavirus (HPV+) favor mitochondrial metabolism rather than glucose metabolism. However, the involvement of mitochondrial metabolism in HNSCC HPV+ cells is still unknown. The aim of this work was to evaluate the role of E6 oncoproteins from HPV16 and HPV18 in the mitochondrial metabolism in an HNSCC model. We found that E6 from both viral types abates the phosphorylation of protein kinase B-serine 473 (pAkt), which is associated with a shift in mitochondrial metabolism. E6 oncoproteins increased the levels of protein subunits of mitochondrial complexes (I to IV), as well as the ATP synthase and the protein levels of the voltage dependent anion channel (VDAC). Although E6 proteins increased the basal and leak respiration, the ATP-linked respiration was not affected, which resulted in mitochondrial decoupling. This increase in leak respiration was associated to the induction of oxidative stress (OS) in cells expressing E6, as it was observed by the fall in the glutathione/glutathione disulfide (GSH/GSSG) rate and the increase in reactive oxygen species (ROS), carbonylated proteins, and DNA damage. Taken together, our results suggest that E6 oncoproteins from HPV16 and HPV18 are inducers of mitochondrial metabolism.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Mitocôndrias/metabolismo , Proteínas Oncogênicas Virais/metabolismo , Papillomaviridae/química , Proteínas Repressoras/metabolismo , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Mitocôndrias/virologia , Papillomaviridae/metabolismo , Células Tumorais Cultivadas
16.
Medicina (Kaunas) ; 55(7)2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295875

RESUMO

Curcumin is a hydrophobic polyphenol compound extracted from the rhizome of turmeric. The protective effect of curcumin on kidney damage in multiple experimental models has been widely described. Its protective effect is mainly associated with its antioxidant and anti-inflammatory properties, as well as with mitochondrial function maintenance. On the other hand, occupational or environmental exposure to heavy metals is a serious public health problem. For a long time, heavy metals-induced nephrotoxicity was mainly associated with reactive oxygen species overproduction and loss of endogenous antioxidant activity. However, recent studies have shown that in addition to oxidative stress, heavy metals also suppress the autophagy flux, enhancing cell damage. Thus, natural compounds with the ability to modulate and restore autophagy flux represent a promising new therapeutic strategy. Furthermore, it has been reported in other renal damage models that curcumin's nephroprotective effects are related to its ability to regulate autophagic flow. The data indicate that curcumin modulates autophagy by classic signaling pathways (suppression of protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and/or by stimulation of adenosine monophosphate-activated protein kinase (AMPK) and extracellular signal-dependent kinase (ERK) pathways). Moreover, it allows lysosomal function preservation, which is crucial for the later stage of autophagy. However, future studies of autophagy modulation by curcumin in heavy metals-induced autophagy flux impairment are still needed.


Assuntos
Autofagia/fisiologia , Curcumina/farmacologia , Rim/fisiopatologia , Metais Pesados/efeitos adversos , Fatores de Proteção , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Arsênio/efeitos adversos , Cádmio/efeitos adversos , Cromo/efeitos adversos , Curcumina/uso terapêutico , Humanos , Rim/química , Rim/patologia , Chumbo/efeitos adversos , Mercúrio/efeitos adversos
17.
Antioxidants (Basel) ; 8(5)2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096625

RESUMO

Cis-dichlorodiammineplatinum II (CDDP) is a chemotherapeutic agent that induces nephrotoxicity by different mechanisms, including oxidative stress, mitochondrial dysfunction, autophagy, and endoplasmic reticulum stress. This study aimed to evaluate if the protective effects of the antioxidant alpha-mangostin (αM) in CDDP-induced damage in proximal tubule Lilly laboratory culture porcine kidney (LLC-PK1) cells, are related to mitochondrial function preservation. It was found that αM co-incubation prevented CDDP-induced cell death. Furthermore, αM prevented the CDDP-induced decrease in cell respiratory states, in the maximum capacity of the electron transfer system (E) and in the respiration associated to oxidative phosphorylation (OXPHOS). CDDP also decreased the protein levels of voltage dependence anion channel (VDAC) and mitochondrial complex subunits, which together with the reduction in E, the mitofusin 2 decrease and the mitochondrial network fragmentation observed by MitoTracker Green, suggest the mitochondrial morphology alteration and the decrease in mitochondrial mass induced by CDDP. CDDP also induced the reduction in mitochondrial biogenesis observed by transcription factor A, mitochondria (TFAM) decreased protein-level and the increase in mitophagy. All these changes were prevented by αM. Taken together, our results imply that αM's protective effects in CDDP-induced toxicity in LLC-PK1 cells are associated to mitochondrial function preservation.

18.
Biomolecules ; 9(4)2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30965656

RESUMO

Renal fibrosis is the common pathway for most forms of progressive renal disease. The Unilateral Ureteral Obstruction (UUO) model is used to cause renal fibrosis, where the primary feature of UUO is tubular injury as a result of obstructed urine flow. Furthermore, experimental UUO in rodents is believed to mimic human chronic obstructive nephropathy in an accelerated manner. Renal fibrosis is the common pathway for most forms of progressive renal disease. Removing the obstruction may not be sufficient to reverse fibrosis, so an accompanying treatment may be of benefit. In this review, we have done a revision on treatments shown to ameliorate fibrosis in the context of the UUO experimental model. The treatments inhibit the production of fibrotic and inflammatory proteins such as Transforming Growth Factor ß1 (TGF-ß1), Tumor Necrosis Factor α (TNF-α), collagen and fibronectin, Heat Shock Protein 47 (HSP47), suppress the proliferation of fibroblasts, prevent epithelial-to-mesenchymal transition, reduce oxidative stress, inhibit the action of the Nuclear Factor κB (NF-κB), reduce the phosphorylation of mothers against decapentaplegic homolog (SMAD) family members 2 and 3 (Smad2/3) or Mitogen-Activated Protein Kinases (MAPKs), inhibit the activation of the renin-angiotensin system. Summaries of the UUO experimental methods and alterations observed in the UUO experiments are included.


Assuntos
Fibrose/tratamento farmacológico , Modelos Biológicos , Obstrução Ureteral/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Fibrose/patologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/patologia , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Obstrução Ureteral/patologia
19.
Free Radic Biol Med ; 135: 60-67, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30818054

RESUMO

Food deprivation protects against ischemia-reperfusion (IR) injury through unknown mechanisms. In an experimental rat model of acute IR injury, we found that preoperative fasting for 3 days protects rats from tubular damage and renal functional decline by increasing antioxidant protection independently of the NF-E2-related factor 2 (Nrf2), and by maintaining mitochondrial morphology and function. In addition, further analysis revealed that fasting protects against tubulointerstitial fibrosis. In summary, our results point out to fasting as a robust nutritional intervention to limit oxidative stress and mitochondrial dysfunction in early acute kidney injury and also to promote long-term protection against fibrosis.


Assuntos
Injúria Renal Aguda/dietoterapia , Rim/metabolismo , Fator 2 Relacionado a NF-E2/genética , Traumatismo por Reperfusão/dietoterapia , Injúria Renal Aguda/genética , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Animais , Antioxidantes/metabolismo , Jejum/metabolismo , Fibrose/dietoterapia , Fibrose/metabolismo , Fibrose/patologia , Privação de Alimentos , Humanos , Rim/lesões , Rim/patologia , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Malondialdeído/metabolismo , Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/genética , Ratos , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
20.
Free Radic Biol Med ; 130: 379-396, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30439416

RESUMO

Folic acid (FA)-induced acute kidney injury (AKI) is a widely used model for studies of the renal damage and its progression to chronic state. However, the molecular mechanisms by which FA induces AKI remain poorly understood. Since renal function depends on mitochondrial homeostasis, it has been suggested that mitochondrial alterations contribute to AKI development. Additionally, N-acetyl-cysteine (NAC) can be a protective agent to prevent mitochondrial and renal dysfunction in this model, given its ability to increase mitochondrial glutathione (GSH) and to control the S-glutathionylation levels, a reversible post-translational modification that has emerged as a mechanism able to link mitochondrial energy metabolism and redox homeostasis. However, this hypothesis has not been explored. The present study demonstrates for the first time that, at 24 h, FA induced mitochondrial bioenergetics, redox state, dynamics and mitophagy alterations, which are involved in the mechanisms responsible for the AKI development. On the other hand, NAC preadministration was able to prevent mitochondrial bioenergetics, redox state and dynamics alterations as well as renal damage. The protective effects of NAC on mitochondria and renal function could be related to its observed capacity to preserve the S-glutathionylation process and GSH levels in mitochondria. Taken together, our results support the idea that these mitochondrial processes can be targets for the prevention of the renal damage and its progression in FA-induced AKI model.


Assuntos
Acetilcisteína/farmacologia , Injúria Renal Aguda/tratamento farmacológico , Glutationa/metabolismo , Mitocôndrias/efeitos dos fármacos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Animais , Modelos Animais de Doenças , Metabolismo Energético/genética , Ácido Fólico/toxicidade , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Dinâmica Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Ratos
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