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1.
Nat Commun ; 12(1): 4166, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230483

RESUMO

Classically considered a by-product of anaerobic metabolism, lactate is now viewed as a fundamental fuel for oxidative phosphorylation in mitochondria, and preferred over glucose by many tissues. Lactate is also a signaling molecule of increasing medical relevance. Lactate levels in the blood can increase in both normal and pathophysiological conditions (e.g., hypoxia, physical exercise, or sepsis), however the manner by which these changes are sensed and induce adaptive responses is unknown. Here we show that the carotid body (CB) is essential for lactate homeostasis and that CB glomus cells, the main oxygen sensing arterial chemoreceptors, are also lactate sensors. Lactate is transported into glomus cells, leading to a rapid increase in the cytosolic NADH/NAD+ ratio. This in turn activates membrane cation channels, leading to cell depolarization, action potential firing, and Ca2+ influx. Lactate also decreases intracellular pH and increases mitochondrial reactive oxygen species production, which further activates glomus cells. Lactate and hypoxia, although sensed by separate mechanisms, share the same final signaling pathway and jointly activate glomus cells to potentiate compensatory cardiorespiratory reflexes.


Assuntos
Artérias/metabolismo , Células Quimiorreceptoras/metabolismo , Ácido Láctico/metabolismo , Animais , Corpo Carotídeo/metabolismo , Homeostase , Concentração de Íons de Hidrogênio , Hipóxia/metabolismo , Canais Iônicos/metabolismo , Mitocôndrias/metabolismo , Oxigênio/metabolismo , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Reflexo , Transdução de Sinais
2.
Biomed Pharmacother ; 139: 111603, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243596

RESUMO

The HtrA protein family is composed by evolutionally-conserved serine proteases, which are homologous to the HtrA protein of the model bacterium Escherichia coli. They are widely distributed in organisms including humans, prokaryotes and eukaryotes. Moreover, HtrA family proteins are important regulators of a variety of human physiological processes, which contains the maintenance of mitochondrial homeostasis, cellular signal transduction and apoptosis regulation. The HtrA family has been found to be associated with cancer and could be used as a target for future cancer treatments. The purpose of this article is to review the relationship between these HtrA and cancer and to summarize the latest researches on HtrA and cancer.


Assuntos
Neoplasias/metabolismo , Serina Proteases/metabolismo , Animais , Apoptose/fisiologia , Homeostase/fisiologia , Humanos , Mitocôndrias/metabolismo , Transdução de Sinais/fisiologia
3.
FASEB J ; 35(8): e21764, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34245631

RESUMO

The size of the permeability transition pore (PTP) is accepted to be ≤1.5 kDa. However, different authors reported values from 650 to 4000 Da. The present study is focused on the variability of the average PTP size in and between mitochondrial samples, its reasons and relations with PTP dynamics. Measurement of PTP size by the standard method revealed its 500 Da-range variability between mitochondrial samples. Sequential measurements in the same sample showed that the PTP size tends to grow with time and Ca2+ concentration. Selective damage to the mitochondrial outer membrane (MOM) reduced the apparent PTP size by ~200-300 Da. Hypotonic and hypertonic osmotic shock and partial removal of the MOM with the preservation of the mitochondrial inner membrane intactness decreased the apparent PTP size by ~50%. We developed an approach to continuous monitoring of the PTP size that revealed the existence of stable PTP states with different pore sizes (~700, 900-1000, ~1350, 1700-1800, and 2100-2200 Da) and transitions between them. The transitions were accelerated by elevating the Ca2+ concentration, temperature, and osmotic pressure, which demonstrates an increased capability of PTP to accommodate to large molecules (plasticity). Cyclosporin A inhibited the transitions between states. The analysis of PTP size dynamics in osmotically shocked mitochondria and mitoplasts confirmed the importance of the MOM for the stabilization of PTP structure. Thus, this approach provides a new tool for PTP studies and the opportunity to reconcile data on the PTP size and mitochondrial megachannel conductance.


Assuntos
Cálcio/química , Mitocôndrias/química , Proteínas de Transporte da Membrana Mitocondrial/química , Membranas Mitocondriais/química , Humanos , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Membranas Mitocondriais/metabolismo
4.
Int J Mol Sci ; 22(13)2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34281248

RESUMO

Age-related macular degeneration (AMD), the main cause of vision loss in the elderly, is associated with oxidation in the retina cells promoting telomere attrition. Activation of telomerase was reported to improve macular functions in AMD patients. The catalytic subunit of human telomerase (hTERT) may directly interact with proteins important for senescence, DNA damage response, and autophagy, which are impaired in AMD. hTERT interaction with mTORC1 (mTOR (mechanistic target of rapamycin) complex 1) and PINK1 (PTEN-induced kinase 1) activates macroautophagy and mitophagy, respectively, and removes cellular debris accumulated over AMD progression. Ectopic expression of telomerase in retinal pigment epithelium (RPE) cells lengthened telomeres, reduced senescence, and extended their lifespan. These effects provide evidence for the potential of telomerase in AMD therapy. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) may be involved in AMD pathogenesis through decreasing oxidative stress and senescence, regulation of vascular endothelial growth factor (VEGF), and improving autophagy. PGC-1α and TERT form an inhibitory positive feedback loop. In conclusion, telomerase activation and its ectopic expression in RPE cells, as well as controlled clinical trials on the effects of telomerase activation in AMD patients, are justified and should be assisted by PGC-1α modulators to increase the therapeutic potential of telomerase in AMD.


Assuntos
Degeneração Macular/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Telomerase/metabolismo , Envelhecimento/metabolismo , Autofagia/fisiologia , Dano ao DNA/fisiologia , Reparo do DNA/fisiologia , Humanos , Degeneração Macular/fisiopatologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo/fisiologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/fisiologia , Fenótipo , Espécies Reativas de Oxigênio/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Transdução de Sinais , Telomerase/fisiologia , Telômero/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
5.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281274

RESUMO

It has been recognized that serotonin 2A receptor (5-HT2A) agonist 2,5-dimethoxy-4-iodo-amphetamine (DOI) impairs serotonergic homeostasis. However, the mechanism of DOI-induced serotonergic behaviors remains to be explored. Moreover, little is known about therapeutic interventions against serotonin syndrome, although evidence suggests that ginseng might possess modulating effects on the serotonin system. As ginsenoside Re (GRe) is well-known as a novel antioxidant in the nervous system, we investigated whether GRe modulates 5-HT2A receptor agonist DOI-induced serotonin impairments. We proposed that protein kinase Cδ (PKCδ) mediates serotonergic impairments. Treatment with GRe or 5-HT2A receptor antagonist MDL11939 significantly attenuated DOI-induced serotonergic behaviors (i.e., overall serotonergic syndrome behaviors, head twitch response, hyperthermia) by inhibiting mitochondrial translocation of PKCδ, reducing mitochondrial glutathione peroxidase activity, mitochondrial dysfunction, and mitochondrial oxidative stress in wild-type mice. These attenuations were in line with those observed upon PKCδ inhibition (i.e., pharmacologic inhibitor rottlerin or PKCδ knockout mice). Furthermore, GRe was not further implicated in attenuation mediated by PKCδ knockout in mice. Our results suggest that PKCδ is a therapeutic target for GRe against serotonergic behaviors induced by DOI.


Assuntos
Ginsenosídeos/farmacologia , Proteína Quinase C-delta/metabolismo , Antagonistas da Serotonina/farmacologia , Síndrome da Serotonina/prevenção & controle , Acetofenonas/farmacologia , Anfetaminas/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Benzopiranos/farmacologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/farmacologia , Proteína Quinase C-delta/deficiência , Proteína Quinase C-delta/genética , Inibidores de Proteínas Quinases/farmacologia , Serotonina/fisiologia , Agonistas do Receptor de Serotonina/farmacologia , Síndrome da Serotonina/induzido quimicamente , Síndrome da Serotonina/fisiopatologia
6.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281279

RESUMO

(1) Background: Autophagy, the major cytoplasmic process of substrate turnover, declines with age, contributing to proteostasis decline, accumulation of harmful protein aggregates, damaged mitochondria and to ROS production. Accordingly, abnormalities in the autophagic flux may contribute to many different pathophysiological conditions associated with ageing, including neurodegeneration. Recent data have shown that extra-virgin olive oil (EVOO) polyphenols stimulate cell defenses against plaque-induced neurodegeneration, mainly, through autophagy induction. (2) Methods: We carried out a set of in vitro experiments on SH-SY5Y human neuroblastoma cells exposed to toxic Aß1-42 oligomers to investigate the molecular mechanisms involved in autophagy activation by two olive oil polyphenols, oleuropein aglycone (OleA), arising from the hydrolysis of oleuropein (Ole), the main polyphenol found in olive leaves and drupes and its main metabolite, hydroxytyrosol (HT). (3) Results: Our data show that the mixture of the two polyphenols activates synergistically the autophagic flux preventing cell damage by Aß1-42 oligomers., in terms of ROS production, and impairment of mitochondria. (4) Conclusion: Our results support the idea that EVOO polyphenols act synergistically in autophagy modulation against neurodegeneration. These data confirm and provide the rationale to consider these molecules, alone or in combination, as promising candidates to contrast ageing-associated neurodegeneration.


Assuntos
Doença de Alzheimer/dietoterapia , Azeite de Oliva/farmacologia , Polifenóis/farmacologia , Acetatos/administração & dosagem , Acetatos/química , Acetatos/farmacologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Autofagia/efeitos dos fármacos , Linhagem Celular , Monoterpenos Ciclopentânicos/administração & dosagem , Monoterpenos Ciclopentânicos/química , Monoterpenos Ciclopentânicos/farmacologia , Dieta Mediterrânea , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Neurológicos , Degeneração Neural/induzido quimicamente , Degeneração Neural/patologia , Degeneração Neural/prevenção & controle , Neurônios/efeitos dos fármacos , Neurônios/patologia , Azeite de Oliva/administração & dosagem , Azeite de Oliva/química , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/toxicidade , Álcool Feniletílico/administração & dosagem , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , Polifenóis/administração & dosagem , Polifenóis/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Piranos/administração & dosagem , Piranos/química , Piranos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Ubiquitina/metabolismo
7.
Int J Mol Sci ; 22(13)2021 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-34199142

RESUMO

Metabolism is the central engine of living organisms as it provides energy and building blocks for many essential components of each cell, which are required for specific functions in different tissues. Mitochondria are the main site for energy production in living organisms and they also provide intermediate metabolites required for the synthesis of other biologically relevant molecules. Such cellular processes are finely tuned at different levels, including allosteric regulation, posttranslational modifications, and transcription of genes encoding key proteins in metabolic pathways. Peroxisome proliferator activated receptor γ coactivator 1 (PGC1) proteins are transcriptional coactivators involved in the regulation of many cellular processes, mostly ascribable to metabolic pathways. Here, we will discuss some aspects of the cellular processes regulated by PGC1s, bringing up some examples of their role in mitochondrial and cellular metabolism, and how metabolic regulation in mitochondria by members of the PGC1 family affects the immune system. We will analyze how PGC1 proteins are regulated at the transcriptional and posttranslational level and will also examine other regulators of mitochondrial metabolism and the related cellular functions, considering approaches to identify novel mitochondrial regulators and their role in physiology and disease. Finally, we will analyze possible therapeutical perspectives currently under assessment that are applicable to different disease states.


Assuntos
Metabolismo Energético , Mitocôndrias/genética , Mitocôndrias/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Animais , Gerenciamento Clínico , Suscetibilidade a Doenças , Regulação da Expressão Gênica , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Imunomodulação , Redes e Vias Metabólicas , Especificidade de Órgãos , Termogênese
8.
Int J Mol Sci ; 22(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200161

RESUMO

miRNA(miR)-124 is an important regulator of neurogenesis, but its upregulation in SOD1G93A motor neurons (mSOD1 MNs) was shown to associate with neurodegeneration and microglia activation. We used pre-miR-124 in wild-type (WT) MNs and anti-miR-124 in mSOD1 MNs to characterize the miR-124 pathological role. miR-124 overexpression in WT MNs produced a miRNA profile like that of mSOD1 MNs (high miR-125b; low miR-146a and miR-21), and similarly led to early apoptosis. Alterations in mSOD1 MNs were abrogated with anti-miR-124 and changes in their miRNAs mostly recapitulated by their secretome. Normalization of miR-124 levels in mSOD1 MNs prevented the dysregulation of neurite network, mitochondria dynamics, axonal transport, and synaptic signaling. Same alterations were observed in WT MNs after pre-miR-124 transfection. Secretome from mSOD1 MNs triggered spinal microglia activation, which was unno-ticed with that from anti-miR-124-modulated cells. Secretome from such modulated MNs, when added to SC organotypic cultures from mSOD1 mice in the early symptomatic stage, also coun-teracted the pathology associated to GFAP decrease, PSD-95 and CX3CL1-CX3CR1 signaling im-pairment, neuro-immune homeostatic imbalance, and enhanced miR-124 expression levels. Data suggest that miR-124 is implicated in MN degeneration and paracrine-mediated pathogenicity. We propose miR-124 as a new therapeutic target and a promising ALS biomarker in patient sub-populations.


Assuntos
Esclerose Amiotrófica Lateral/patologia , Biomarcadores/metabolismo , Modelos Animais de Doenças , MicroRNAs/metabolismo , Neurônios Motores/patologia , Superóxido Dismutase-1/fisiologia , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , MicroRNAs/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neurônios Motores/metabolismo , Transdução de Sinais
9.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200828

RESUMO

Mitochondria are dynamic organelles that undergo rounds of fission and fusion and exhibit a wide range of morphologies that contribute to the regulation of different signaling pathways and various cellular functions. It is important to understand the differences between mitochondrial structure in health and disease so that therapies can be developed to maintain the homeostatic balance of mitochondrial dynamics. Mitochondrial disorders are multisystemic and characterized by complex and variable clinical pathologies. The dynamics of mitochondria in mitochondrial disorders is thus worthy of investigation. Therefore, in this study, we performed a comprehensive analysis of mitochondrial dynamics in ten patient-derived fibroblasts containing different mutations and deletions associated with various mitochondrial disorders. Our results suggest that the most predominant morphological signature for mitochondria in the diseased state is fragmentation, with eight out of the ten cell lines exhibiting characteristics consistent with fragmented mitochondria. To our knowledge, this is the first comprehensive study that quantifies mitochondrial dynamics in cell lines with a wide array of developmental and mitochondrial disorders. A more thorough analysis of the correlations between mitochondrial dynamics, mitochondrial genome perturbations, and bioenergetic dysfunction will aid in identifying unique morphological signatures of various mitochondrial disorders in the future.


Assuntos
Deficiências do Desenvolvimento/patologia , Metabolismo Energético , Fibroblastos/patologia , Mitocôndrias/patologia , Doenças Mitocondriais/patologia , Dinâmica Mitocondrial , Mutação , Estudos de Casos e Controles , Deficiências do Desenvolvimento/etiologia , Fibroblastos/metabolismo , Homeostase , Humanos , Mitocôndrias/genética , Doenças Mitocondriais/etiologia
10.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201352

RESUMO

The VPS13 family of proteins have emerged as key players in intracellular lipid transport and human health. Humans have four different VPS13 orthologs, the dysfunction of which leads to different diseases. Yeast has a single VPS13 gene, which encodes a protein that localizes to multiple different membrane contact sites. The yeast vps13Δ mutant is pleiotropic, exhibiting defects in sporulation, protein trafficking, endoplasmic reticulum (ER)-phagy and mitochondrial function. Non-null alleles resulting from missense mutations can be useful reagents for understanding the multiple functions of a gene. The exceptionally large size of Vps13 makes the identification of key residues challenging. As a means to identify critical residues in yeast Vps13, amino acid substitution mutations from VPS13A, B, C and D, associated with human disease, were introduced at the cognate positions of yeast VPS13, some of which created separation-of-function alleles. Phenotypic analyses of these mutants have revealed that the promotion of ER-phagy is a fourth, genetically separable role of VPS13 and provide evidence that co-adaptors at the endosome mediate the activity of VPS13 in vacuolar sorting.


Assuntos
Mitocôndrias/metabolismo , Mutação , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Vacúolos/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Transporte Biológico , Membrana Celular/metabolismo , Retículo Endoplasmático/metabolismo , Humanos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Transporte Vesicular/genética
11.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202179

RESUMO

The progression of non-alcoholic fatty liver (NAFL) into non-alcoholic steatohepatitis implicates multiple mechanisms, chief of which is mitochondrial dysfunction. However, the sequence of events underlying mitochondrial failure are still poorly clarified. In this work, male C57BL/6J mice were fed with a high-fat plus high-sucrose diet for 16, 20, 22, and 24 weeks to induce NAFL. Up to the 20th week, an early mitochondrial remodeling with increased OXPHOS subunits levels and higher mitochondrial respiration occurred. Interestingly, a progressive loss of mitochondrial respiration along "Western diet" feeding was identified, accompanied by higher susceptibility to mitochondrial permeability transition pore opening. Importantly, our findings prove that mitochondrial alterations and subsequent impairment are independent of an excessive mitochondrial reactive oxygen species (ROS) generation, which was found to be progressively diminished along with disease progression. Instead, increased peroxisomal abundance and peroxisomal fatty acid oxidation-related pathway suggest that peroxisomes may contribute to hepatic ROS generation and oxidative damage, which may accelerate hepatic injury and disease progression. We show here for the first time the sequential events of mitochondrial alterations involved in non-alcoholic fatty liver disease (NAFLD) progression and demonstrate that mitochondrial ROS are not one of the first hits that cause NAFLD progression.


Assuntos
Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Antioxidantes/metabolismo , Autofagia , Ésteres do Colesterol/metabolismo , Biologia Computacional/métodos , Suscetibilidade a Doenças , Fibrose , Hepatócitos/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Masculino , Camundongos , Mitocôndrias/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Oxirredução , Estresse Oxidativo , Triglicerídeos/metabolismo
12.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202229

RESUMO

Alveolar epithelial cell (AEC) mitochondrial (mt) DNA damage and fibrotic monocyte-derived alveolar macrophages (Mo-AMs) are implicated in the pathobiology of pulmonary fibrosis. We showed that sirtuin 3 (SIRT3), a mitochondrial protein regulating cell fate and aging, is deficient in the AECs of idiopathic pulmonary fibrosis (IPF) patients and that asbestos- and bleomycin-induced lung fibrosis is augmented in Sirt3 knockout (Sirt3-/-) mice associated with AEC mtDNA damage and intrinsic apoptosis. We determined whether whole body transgenic SIRT3 overexpression (Sirt3Tg) protects mice from asbestos-induced pulmonary fibrosis by mitigating lung mtDNA damage and Mo-AM recruitment. Crocidolite asbestos (100 µg/50 µL) or control was instilled intratracheally in C57Bl6 (Wild-Type) mice or Sirt3Tg mice, and at 21 d lung fibrosis (histology, fibrosis score, Sircol assay) and lung Mo-AMs (flow cytometry) were assessed. Compared to controls, Sirt3Tg mice were protected from asbestos-induced pulmonary fibrosis and had diminished lung mtDNA damage and Mo-AM recruitment. Further, pharmacologic SIRT3 inducers (i.e., resveratrol, viniferin, and honokiol) each diminish oxidant-induced AEC mtDNA damage in vitro and, in the case of honokiol, protection occurs in a SIRT3-dependent manner. We reason that SIRT3 preservation of AEC mtDNA is a novel therapeutic focus for managing patients with IPF and other types of pulmonary fibrosis.


Assuntos
Asbestos/efeitos adversos , Dano ao DNA , Expressão Gênica , Fibrose Pulmonar Idiopática/etiologia , Mitocôndrias/genética , Monócitos/metabolismo , Sirtuína 3/genética , Animais , Biomarcadores , DNA Mitocondrial , Modelos Animais de Doenças , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Imuno-Histoquímica , Camundongos , Camundongos Transgênicos , Mitocôndrias/metabolismo , Monócitos/imunologia , Monócitos/patologia , Estresse Oxidativo , Sirtuína 3/metabolismo
13.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199378

RESUMO

Iron-sulfur clusters are essential to almost every life form and utilized for their unique structural and redox-targeted activities within cells during many cellular pathways. Although there are three different Fe-S cluster assembly pathways in prokaryotes (the NIF, SUF and ISC pathways) and two in eukaryotes (CIA and ISC pathways), the iron-sulfur cluster (ISC) pathway serves as the central mechanism for providing 2Fe-2S clusters, directly and indirectly, throughout the entire cell in eukaryotes. Proteins central to the eukaryotic ISC cluster assembly complex include the cysteine desulfurase, a cysteine desulfurase accessory protein, the acyl carrier protein, the scaffold protein and frataxin (in humans, NFS1, ISD11, ACP, ISCU and FXN, respectively). Recent molecular details of this complex (labeled NIAUF from the first letter from each ISC protein outlined earlier), which exists as a dimeric pentamer, have provided real structural insight into how these partner proteins arrange themselves around the cysteine desulfurase, the core dimer of the (NIAUF)2 complex. In this review, we focus on both frataxin and the scaffold within the human, fly and yeast model systems to provide a better understanding of the biophysical characteristics of each protein alone and within the FXN/ISCU complex as it exists within the larger NIAUF construct. These details support a complex dynamic interaction between the FXN and ISCU proteins when both are part of the NIAUF complex and this provides additional insight into the coordinated mechanism of Fe-S cluster assembly.


Assuntos
Proteínas de Ligação ao Ferro/genética , Proteínas Ferro-Enxofre/genética , Ferro/metabolismo , Enxofre/metabolismo , Liases de Carbono-Enxofre/genética , Humanos , Proteínas de Ligação ao Ferro/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Complexos Multiproteicos/genética , Complexos Multiproteicos/ultraestrutura , Ligação Proteica/genética
14.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199464

RESUMO

The influence of salt stress on gene expression, promoter methylation, and enzymatic activity of the mitochondrial and cytosolic forms of aconitase and fumarase has been investigated in maize (Zea mays L.) seedlings. The incubation of maize seedlings in 150-mM NaCl solution resulted in a several-fold increase of the mitochondrial activities of aconitase and fumarase that peaked at 6 h of NaCl treatment, while the cytosolic activity of aconitase and fumarase decreased. This corresponded to the decrease in promoter methylation of the genes Aco1 and Fum1 encoding the mitochondrial forms of these enzymes and the increase in promoter methylation of the genes Aco2 and Fum2 encoding the cytosolic forms. The pattern of expression of the genes encoding the mitochondrial forms of aconitase and fumarase corresponded to the profile of the increase of the stress marker gene ZmCOI6.1. It is concluded that the mitochondrial and cytosolic forms of aconitase and fumarase are regulated via the epigenetic mechanism of promoter methylation of their genes in the opposite ways in response to salt stress. The role of the mitochondrial isoforms of aconitase and fumarase in the elevation of respiration under salt stress is discussed.


Assuntos
Aconitato Hidratase/genética , Metilação de DNA/genética , Fumarato Hidratase/genética , Estresse Salino/genética , Citosol/enzimologia , Regulação da Expressão Gênica de Plantas/genética , Mitocôndrias/enzimologia , Regiões Promotoras Genéticas/genética , Zea mays/genética , Zea mays/crescimento & desenvolvimento
15.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199596

RESUMO

Peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α) regulates mitochondrial DNA replication and mitochondrial gene expression by interacting with several transcription factors. White adipose tissue (WAT) mainly comprises adipocytes that store triglycerides as an energy resource and secrete adipokines. The characteristics of WAT vary in response to systemic and chronic metabolic alterations, including obesity or caloric restriction. Despite a small amount of mitochondria in white adipocytes, accumulated evidence suggests that mitochondria are strongly related to adipocyte-specific functions, such as adipogenesis and lipogenesis, as well as oxidative metabolism for energy supply. Therefore, PGC-1α is expected to play an important role in WAT. In this review, we provide an overview of the involvement of mitochondria and PGC-1α with obesity- and caloric restriction-related physiological changes in adipocytes and WAT.


Assuntos
Tecido Adiposo Branco/metabolismo , Mitocôndrias/genética , Obesidade/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Adipócitos/metabolismo , Tecido Adiposo Branco/fisiologia , Restrição Calórica , Humanos , Lipogênese/genética , Mitocôndrias/metabolismo , Obesidade/patologia , Biogênese de Organelas
16.
Molecules ; 26(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199597

RESUMO

The disruption of iron homeostasis is an important factor in the loss of mitochondrial function in neural cells, leading to neurodegeneration. Here, we assessed the protective action of gossypitrin (Gos), a naturally occurring flavonoid, on iron-induced neuronal cell damage using mouse hippocampal HT-22 cells and mitochondria isolated from rat brains. Gos was able to rescue HT22 cells from the damage induced by 100 µM Fe(II)-citrate (EC50 8.6 µM). This protection was linked to the prevention of both iron-induced mitochondrial membrane potential dissipation and ATP depletion. In isolated mitochondria, Gos (50 µM) elicited an almost complete protection against iron-induced mitochondrial swelling, the loss of mitochondrial transmembrane potential and ATP depletion. Gos also prevented Fe(II)-citrate-induced mitochondrial lipid peroxidation with an IC50 value (12.45 µM) that was about nine time lower than that for the tert-butylhydroperoxide-induced oxidation. Furthermore, the flavonoid was effective in inhibiting the degradation of both 15 and 1.5 mM 2-deoxyribose. It also decreased Fe(II) concentration with time, while increasing O2 consumption rate, and impairing the reduction of Fe(III) by ascorbate. Gos-Fe(II) complexes were detected by UV-VIS and IR spectroscopies, with an apparent Gos-iron stoichiometry of 2:1. Results suggest that Gos does not generally act as a classical antioxidant, but it directly affects iron, by maintaining it in its ferric form after stimulating Fe(II) oxidation. Metal ions would therefore be unable to participate in a Fenton-type reaction and the lipid peroxidation propagation phase. Hence, Gos could be used to treat neuronal diseases associated with iron-induced oxidative stress and mitochondrial damage.


Assuntos
Flavonoides/farmacologia , Ferro/efeitos adversos , Mitocôndrias/metabolismo , Neurônios/citologia , Trifosfato de Adenosina/metabolismo , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ácido Cítrico/efeitos adversos , Compostos Ferrosos/efeitos adversos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos
17.
Ecotoxicol Environ Saf ; 221: 112449, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34214916

RESUMO

Dimethoxyethyl phthalate (DMEP) is an environmental endocrine disruptor. However, research into the underlying mechanisms of DMEP mitochondrial toxicity is still in its infancy. We therefore expect to understand whether DMEP induced mitochondrial damage in HepG2 cells and the associated signaling pathways. DMEP (0.125, 0.25, 0.5, 1 and 2 mM) exposure for 48 h induced a notable increment in reactive oxygen species (ROS), malondialdehyde (MDA), alanine aminotransferase (ALT), aspartate transaminase (AST) and 8-hydroxydeoxyguanosine (8-OHdG) in hepG2 cells, resulting in cellular oxidative stress. Low doses of DMEP upregulated nuclear factor E2-related factor 2 (Nrf2) and downstream protein haeme oxygenase-1 (HO-1) levels and high doses down-regulated their levels. Nrf2 levels increased after ROS scavenging by N-acetyl-L-cysteine (NAC), which indicated that the Nrf2 pathway may be affected by oxidative stress. We also found that DMEP decreased ATP content, mitochondrial copy number (mtDNA), translocase of the outer membrane subunit 20 (TOM20) expression, mitochondria-encoded genes CO1, CO2, CO3, ATP6, ATP8 expression, inhibited mitochondrial biogenesis pathway, down-regulated sirtuin 1(SIRT1), PPAR gamma co-activator 1 alpha (PGC-1α), Nuclear respiratory factor 1(Nrf1), Mitochondrial transcription factor A (TFAM) content and activated PINK1/Parkin autophagy pathway. DMEP also activated the mitochondrial apoptotic pathway, causing cytochrome c cytoplasmic translocation and caspase 3 cleavage. What's more, DMEP activated the Nuclear factor-κB (NF-κB) pathway and levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) were significantly upregulated, causing an inflammatory response. In summary, DMEP can cause inflammatory response and oxidative stress in HepG2 cells, inhibited the Nrf2 pathway and mitochondrial biogenesis, and induced autophagy and apoptosis. And oxidative stress at least partially affected the Nrf2 pathway and mitochondrial biogenesis SIRT1/PGC-1α pathway.


Assuntos
Disruptores Endócrinos/toxicidade , Mitocôndrias/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Ácidos Ftálicos/toxicidade , Sirtuína 1/metabolismo , Células Hep G2 , Humanos , Mitocôndrias/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
18.
Int J Mol Sci ; 22(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198557

RESUMO

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease of the motor system. It is characterized by the degeneration of both upper and lower motor neurons, which leads to muscle weakness and paralysis. ALS is incurable and has a bleak prognosis, with median survival of 3-5 years after the initial symptomatology. In ALS, motor neurons gradually degenerate and die. Many features of mitochondrial dysfunction are manifested in neurodegenerative diseases, including ALS. Mitochondria have shown to be an early target in ALS pathophysiology and contribute to disease progression. Disruption of their axonal transport, excessive generation of reactive oxygen species, disruption of the mitochondrial structure, dynamics, mitophagy, energy production, calcium buffering and apoptotic triggering have all been directly involved in disease pathogenesis and extensively reported in ALS patients and animal model systems. Alterations in energy production by motor neurons, which severely limit their survival capacity, are tightly linked to the redox status and mitochondria. The present review focuses on this link. Placing oxidative stress as a main pathophysiological mechanism, the molecular interactions and metabolic flows involved are analyzed. This leads to discussing potential therapeutic approaches targeting mitochondrial biology to slow disease progression.


Assuntos
Esclerose Amiotrófica Lateral/patologia , Esclerose Amiotrófica Lateral/fisiopatologia , Metabolismo Energético , Mitocôndrias/metabolismo , Estresse Oxidativo , Animais , Humanos , Neurônios Motores/patologia , Oxirredução
19.
Int J Mol Sci ; 22(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198873

RESUMO

Nicotinamide nucleotide transhydrogenase (NNT) is a proton pump in the inner mitochondrial membrane that generates reducing equivalents in the form of NAPDH, which can be used for anabolic pathways or to remove reactive oxygen species (ROS). A number of studies have linked NNT dysfunction to cardiomyopathies and increased risk of atherosclerosis; however, biallelic mutations in humans commonly cause a phenotype of adrenal insufficiency, with rare occurrences of cardiac dysfunction and testicular tumours. Here, we compare the transcriptomes of the hearts, adrenals and testes from three mouse models: the C57BL/6N, which expresses NNT; the C57BL/6J, which lacks NNT; and a third mouse, expressing the wild-type NNT sequence on the C57BL/6J background. We saw enrichment of oxidative phosphorylation genes in the C57BL/B6J in the heart and adrenal, possibly indicative of an evolved response in this substrain to loss of Nnt. However, differential gene expression was mainly driven by mouse background with some changes seen in all three tissues, perhaps reflecting underlying genetic differences between the C57BL/B6J and -6N substrains.


Assuntos
Aterosclerose/genética , Cardiomiopatias/genética , Miocárdio/metabolismo , NADP Trans-Hidrogenase Específica para A ou B/genética , Fosforilação Oxidativa , Glândulas Suprarrenais/metabolismo , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Cardiomiopatias/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/genética , Membranas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Fenótipo , Espécies Reativas de Oxigênio/metabolismo , Testículo/metabolismo
20.
Int J Mol Sci ; 22(11)2021 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-34204139

RESUMO

The prohibitin (PHB)-binding compound fluorizoline as well as PHB-downregulation activate the integrated stress response (ISR) in HEK293T and U2OS human cell lines. This activation is denoted by phosphorylation of eIF2α and increases in ATF4, ATF3, and CHOP protein levels. The blockage of the activation of the ISR by overexpression of GRP78, as well as an increase in IRE1 activity, indicate the presence of ER stress after fluorizoline treatment. The inhibition of the ER stress response in HEK293T and U2OS led to increased sensitivity to fluorizoline-induced apoptosis, indicating a pro-survival role of this pathway after fluorizoline treatment in these cell lines. Fluorizoline induced an increase in calcium concentration in the cytosol and the mitochondria. Finally, two different calcium chelators reduced fluorizoline-induced apoptosis in U2OS cells. Thus, we have found that fluorizoline causes increased ER stress and activation of the integrated stress response, which in HEK293T and U2OS cells are protective against fluorizoline-induced apoptosis.


Assuntos
Apoptose , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Tiazóis/farmacologia , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Linhagem Celular Tumoral , Respiração Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Células HEK293 , Homeostase/efeitos dos fármacos , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Repressoras/metabolismo , Transdução de Sinais/efeitos dos fármacos
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