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1.
Nat Cell Biol ; 26(9): 1447-1457, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38424270

RESUMO

Ferroptosis, an intricately regulated form of cell death characterized by uncontrolled lipid peroxidation, has garnered substantial interest since this term was first coined in 2012. Recent years have witnessed remarkable progress in elucidating the detailed molecular mechanisms that govern ferroptosis induction and defence, with particular emphasis on the roles of heterogeneity and plasticity. In this Review, we discuss the molecular ecosystem of ferroptosis, with implications that may inform and enable safe and effective therapeutic strategies across a broad spectrum of diseases.


Assuntos
Ferroptose , Peroxidação de Lipídeos , Ferroptose/genética , Humanos , Animais , Transdução de Sinais , Espécies Reativas de Oxigênio/metabolismo , Ferro/metabolismo
2.
Elife ; 122023 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-36951533

RESUMO

Reactive oxygen species (ROS) accumulation is a cardinal feature of skeletal muscle atrophy. ROS refers to a collection of radical molecules whose cellular signals are vast, and it is unclear which downstream consequences of ROS are responsible for the loss of muscle mass and strength. Here, we show that lipid hydroperoxides (LOOH) are increased with age and disuse, and the accumulation of LOOH by deletion of glutathione peroxidase 4 (GPx4) is sufficient to augment muscle atrophy. LOOH promoted atrophy in a lysosomal-dependent, proteasomal-independent manner. In young and old mice, genetic and pharmacological neutralization of LOOH or their secondary reactive lipid aldehydes robustly prevented muscle atrophy and weakness, indicating that LOOH-derived carbonyl stress mediates age- and disuse-induced muscle dysfunction. Our findings provide novel insights for the role of LOOH in sarcopenia including a therapeutic implication by pharmacological suppression.


Assuntos
Sarcopenia , Camundongos , Animais , Sarcopenia/patologia , Peróxidos Lipídicos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Músculo Esquelético/metabolismo , Estresse Oxidativo
3.
Cells ; 11(11)2022 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-35681465

RESUMO

Alzheimer's disease (AD) is the most common cause of dementia affecting millions of people around the globe. Impaired neurogenesis is reported in AD as well as in AD animal models, although the underlying mechanism remains unclear. Elevated lipid peroxidation products are well-documented in AD. In current study, the role of lipid peroxidation on neural stem cell (NSCs) function is tested. Neural stem cells (NSCs) from 5×FAD mice, a widely used AD model with impaired neurogenesis, were observed to have increased levels of lipid reactive oxygen species compared to NSCs from control WT mice. 5×FAD NSCs exhibited altered differentiation potential as revealed by their propensity to differentiate into astrocytic lineage instead of neuronal lineage compared to WT NSCs. In addition, 5×FAD NSCs showed a reduced level of Gpx4, a key enzyme in reducing hydroperoxides in membrane lipids, and this reduction appeared to be caused by enhanced autophagy-lysosomal degradation of Gpx4 protein. To test if increasing Gpx4 could restore differentiation potential, NSCs from 5×FAD and Gpx4 double transgenic mice, i.e., 5×FAD/GPX4 mice were studied. Remarkably, upon differentiation, neuronal linage cells increased significantly in 5×FAD/GPX4 cultures compared to 5×FAD cultures. Taken together, the findings suggest that deficiency of lipid peroxidation defense contributes to functional decline of NSCs in AD.


Assuntos
Doença de Alzheimer , Células-Tronco Neurais , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Doença de Alzheimer/metabolismo , Animais , Flavina-Adenina Dinucleotídeo/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Células-Tronco Neurais/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética
4.
ACR Open Rheumatol ; 4(5): 441-446, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35191223

RESUMO

OBJECTIVE: The study objective was to determine whether overexpression of the mitochondrial antioxidant peroxidase, peroxiredoxin 3 (Prx3), reduces the severity of osteoarthritis (OA) in mice. METHODS: Age-related OA (age 18 and 24 months) and OA induced by destabilization of the medial meniscus (DMM at age 6 months) were assessed in male mice that overexpress a human Prdx3 transgene encoding the Prx3 protein. Lox-stop-lox-Prdx3 (iPrdx3) mice were crossed with aggrecan-CreERT2 mice to produce iPrdx3AgCreERT2 or with Col2Cre to produce iPrdx3Col2Cre mice. Germline transgenics (Prdx3Tg) were also evaluated. Prx3 protein level was assessed by immunoblotting and functionally after induction of elevated mitochondrial hydrogen peroxide (H2 O2 ) using menadione. Histological sections of stifle joints were scored for cartilage damage (Articular Cartilage Structure score [ACS]), osteophytes, and synovial hyperplasia and were evaluated by histomorphometry. RESULTS: Overexpression of Prx3 maintained mitochondrial membrane integrity and inhibited p38 phosphorylation in the presence of elevated H2 O2 . ACS scores of 18-month-old iPrdx3AgCreERT2 mice (mean ± SD, 4.88 ± 5.05) were significantly lower than age-matched iPrdx3 controls (11.75 ± 6.34, P = 0.002) and trended lower in the 18-month Prdx3Tg group (P = 0.14), whereas no significant differences between experimental and control groups at 24 months of age or in OA induced by DMM surgery were noted. Osteophyte scores trended lower in the 18-month-old Prdx3Tg group (P = 0.09) and at 24 months in the iPrdx3Col2Cre mice (P = 0.05). There were no significant group differences in synovial hyperplasia or histomorphometric measures. CONCLUSION: Overexpression of the mitochondrial peroxidase Prx3 reduced the severity of age-related OA, but not at advanced ages and not in DMM-induced OA in younger mice.

5.
Aging Cell ; 21(3): e13569, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35199907

RESUMO

Age-related muscle atrophy and weakness, or sarcopenia, are significant contributors to compromised health and quality of life in the elderly. While the mechanisms driving this pathology are not fully defined, reactive oxygen species, neuromuscular junction (NMJ) disruption, and loss of innervation are important risk factors. The goal of this study is to determine the impact of mitochondrial hydrogen peroxide on neurogenic atrophy and contractile dysfunction. Mice with muscle-specific overexpression of the mitochondrial H2 O2  scavenger peroxiredoxin3 (mPRDX3) were crossed to Sod1KO mice, an established mouse model of sarcopenia, to determine whether reduced mitochondrial H2 O2 can prevent or delay the redox-dependent sarcopenia. Basal rates of H2 O2  generation were elevated in isolated muscle mitochondria from Sod1KO, but normalized by mPRDX3 overexpression. The mPRDX3 overexpression prevented the declines in maximum mitochondrial oxygen consumption rate and calcium retention capacity in Sod1KO. Muscle atrophy in Sod1KO was mitigated by ~20% by mPRDX3 overexpression, which was associated with an increase in myofiber cross-sectional area. With direct muscle stimulation, maximum isometric specific force was reduced by ~20% in Sod1KO mice, and mPRDX3 overexpression preserved specific force at wild-type levels. The force deficit with nerve stimulation was exacerbated in Sod1KO compared to direct muscle stimulation, suggesting NMJ disruption in Sod1KO. Notably, this defect was not resolved by overexpression of mPRDX3. Our findings demonstrate that muscle-specific PRDX3 overexpression reduces mitochondrial H2 O2  generation, improves mitochondrial function, and mitigates loss of muscle quantity and quality, despite persisting NMJ impairment in a murine model of redox-dependent sarcopenia.


Assuntos
Sarcopenia , Envelhecimento , Animais , Modelos Animais de Doenças , Peróxido de Hidrogênio/metabolismo , Camundongos , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Estresse Oxidativo , Peroxirredoxina III/metabolismo , Qualidade de Vida , Sarcopenia/patologia , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo
6.
Free Radic Biol Med ; 180: 1-12, 2022 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-34998934

RESUMO

Oxidative damage including lipid peroxidation is widely reported in Alzheimer's disease (AD) with the peroxidation of phospholipids in membranes being the driver of ferroptosis, an iron-dependent oxidative form of cell death. However, the importance of ferroptosis in AD remains unclear. This study tested whether ferroptosis inhibition ameliorates AD. 5xFAD mice, a widely used AD mouse model with cognitive impairment and robust neurodegeneration, exhibit markers of ferroptosis including increased lipid peroxidation, elevated lyso-phospholipids, and reduced level of Gpx4, the master defender against ferroptosis. To determine if enhanced defense against ferroptosis retards disease development, we generated 5xFAD mice that overexpress Gpx4, i.e., 5xFAD/GPX4 mice. Consistent with enhanced defense against ferroptosis, neurons from 5xFAD/GPX4 mice showed an augmented capacity to reduce lipid reactive oxygen species. In addition, compared with control 5xFAD mice, 5xFAD/GPX4 mice showed significantly improved learning and memory abilities and had reduced neurodegeneration. Moreover, 5xFAD/GPX4 mice exhibited attenuated markers of ferroptosis. Our results indicate that enhanced defense against ferroptosis is effective in ameliorating cognitive impairment and decreasing neurodegeneration of 5xFAD mice. The findings support the notion that ferroptosis is a key contributor to AD pathogenesis.


Assuntos
Disfunção Cognitiva , Ferroptose , Animais , Disfunção Cognitiva/genética , Ferroptose/genética , Peroxidação de Lipídeos , Camundongos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Espécies Reativas de Oxigênio/metabolismo
7.
Neurotox Res ; 40(2): 373-383, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35043381

RESUMO

The degeneration and death of motor neurons lead to motor neuron diseases such as amyotrophic lateral sclerosis (ALS). Although the exact mechanism by which motor neuron degeneration occurs is not well understood, emerging evidence implicates the involvement of ferroptosis, an iron-dependent oxidative mode of cell death. We reported previously that treating Gpx4NIKO mice with tamoxifen to ablate the ferroptosis regulator glutathione peroxidase 4 (GPX4) in neurons produces a severe paralytic model resembling an accelerated form of ALS that appears to be caused by ferroptotic cell death of spinal motor neurons. In this study, in support of the role of ferroptosis in this model, we found that the paralytic symptoms and spinal motor neuron death of Gpx4NIKO mice were attenuated by a chemical inhibitor of ferroptosis. In addition, we observed that the paralytic symptoms of Gpx4NIKO mice were malleable and could be tapered by lowering the dose of tamoxifen, allowing for the generation of a mild paralytic model without a rapid onset of death. We further used both models to evaluate mitochondrial reactive oxygen species (mtROS) in the ferroptosis of spinal motor neurons and showed that overexpression of peroxiredoxin 3, a mitochondrial antioxidant defense enzyme, ameliorated symptoms of the mild but not the severe model of the Gpx4NIKO mice. Our results thus indicate that the Gpx4NIKO mouse is a versatile model for testing interventions that target ferroptotic death of spinal motor neurons in vivo.


Assuntos
Esclerose Lateral Amiotrófica , Esclerose Lateral Amiotrófica/metabolismo , Animais , Morte Celular/fisiologia , Camundongos , Neurônios Motores/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Tamoxifeno/metabolismo , Tamoxifeno/farmacologia
8.
Gastroenterology ; 162(6): 1690-1704, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35031299

RESUMO

BACKGROUND & AIMS: Crohn's disease (CD) globally emerges with Westernization of lifestyle and nutritional habits. However, a specific dietary constituent that comprehensively evokes gut inflammation in human inflammatory bowel diseases remains elusive. We aimed to delineate how increased intake of polyunsaturated fatty acids (PUFAs) in a Western diet, known to impart risk for developing CD, affects gut inflammation and disease course. We hypothesized that the unfolded protein response and antioxidative activity of glutathione peroxidase 4 (GPX4), which are compromised in human CD epithelium, compensates for metabolic perturbation evoked by dietary PUFAs. METHODS: We phenotyped and mechanistically dissected enteritis evoked by a PUFA-enriched Western diet in 2 mouse models exhibiting endoplasmic reticulum (ER) stress consequent to intestinal epithelial cell (IEC)-specific deletion of X-box binding protein 1 (Xbp1) or Gpx4. We translated the findings to human CD epithelial organoids and correlated PUFA intake, as estimated by a dietary questionnaire or stool metabolomics, with clinical disease course in 2 independent CD cohorts. RESULTS: PUFA excess in a Western diet potently induced ER stress, driving enteritis in Xbp1-/-IEC and Gpx4+/-IEC mice. ω-3 and ω-6 PUFAs activated the epithelial endoplasmic reticulum sensor inositol-requiring enzyme 1α (IRE1α) by toll-like receptor 2 (TLR2) sensing of oxidation-specific epitopes. TLR2-controlled IRE1α activity governed PUFA-induced chemokine production and enteritis. In active human CD, ω-3 and ω-6 PUFAs instigated epithelial chemokine expression, and patients displayed a compatible inflammatory stress signature in the serum. Estimated PUFA intake correlated with clinical and biochemical disease activity in a cohort of 160 CD patients, which was similarly demonstrable in an independent metabolomic stool analysis from 199 CD patients. CONCLUSIONS: We provide evidence for the concept of PUFA-induced metabolic gut inflammation which may worsen the course of human CD. Our findings provide a basis for targeted nutritional therapy.


Assuntos
Doença de Crohn , Enterite , Ácidos Graxos Ômega-3 , Animais , Doença de Crohn/tratamento farmacológico , Endorribonucleases , Enterite/induzido quimicamente , Enterite/tratamento farmacológico , Ácidos Graxos Insaturados , Humanos , Inflamação/tratamento farmacológico , Camundongos , Proteínas Serina-Treonina Quinases , Receptor 2 Toll-Like
9.
Int J Obes (Lond) ; 46(5): 951-959, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35031697

RESUMO

OBJECTIVES: Metabolic inflammation is a hallmark of obesity and related disorders, afflicting substantial morbidity and mortality to individuals worldwide. White visceral and subcutaneous adipose tissue not only serves as energy storage but also controls metabolism. Adipose tissue inflammation, commonly observed in human obesity, is considered a critical driver of metabolic perturbation while molecular hubs are poorly explored. Metabolic stress evoked by e.g. long-chain fatty acids leads to oxidative perturbation of adipocytes and production of inflammatory cytokines, fuelling macrophage infiltration and systemic low-grade inflammation. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation, accumulation of oxygen-specific epitopes and cell death, collectively referred to as ferroptosis. Here, we explore the function of adipocyte GPX4 in mammalian metabolism. METHODS: We studied the regulation and function of GPX4 in differentiated mouse adipocytes derived from 3T3-L1 fibroblasts. We generated two conditional adipocyte-specific Gpx4 knockout mice by crossing Gpx4fl/fl mice with Adipoq-Cre+ (Gpx4-/-AT) or Fabp4-Cre+ (Gpx4+/-Fabp4) mice. Both models were metabolically characterized by a glucose tolerance test and insulin resistance test, and adipose tissue lipid peroxidation, inflammation and cell death were assessed by quantifying oxygen-specific epitopes, transcriptional analysis of chemokines, quantification of F4/80+ macrophages and TUNEL labelling. RESULTS: GPX4 expression was induced during and required for adipocyte differentiation. In mature adipocytes, impaired GPX4 activity spontaneously evoked lipid peroxidation and expression of inflammatory cytokines such as TNF-α, interleukin 1ß (IL-1ß), IL-6 and the IL-8 homologue CXCL1. Gpx4-/-AT mice spontaneously displayed adipocyte hypertrophy on a chow diet, which was paralleled by the accumulation of oxygen-specific epitopes and macrophage infiltration in adipose tissue. Furthermore, Gpx4-/-AT mice spontaneously developed glucose intolerance, hepatic insulin resistance and systemic low-grade inflammation, when compared to wildtype littermates, which was similarly recapitulated in Gpx4+/-Fabp4 mice. Gpx4-/-AT mice exhibited no signs of adipocyte death. CONCLUSION: Adipocyte GPX4 protects against spontaneous metabolic dysregulation and systemic low-grade inflammation independent from ferroptosis, which could be therapeutically exploited in the future.


Assuntos
Resistência à Insulina , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Animais , Citocinas/metabolismo , Dieta Hiperlipídica , Epitopos/metabolismo , Inflamação/metabolismo , Mamíferos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/metabolismo , Oxigênio/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase
10.
Orphanet J Rare Dis ; 16(1): 446, 2021 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-34688299

RESUMO

BACKGROUND: Extremely rare progressive diseases like Sedaghatian-type Spondylometaphyseal Dysplasia (SSMD) can be neonatally lethal and therefore go undiagnosed or are difficult to treat. Recent sequencing efforts have linked this disease to mutations in GPX4, with consequences in the resulting enzyme, glutathione peroxidase 4. This offers potential diagnostic and therapeutic avenues for those suffering from this disease, though the steps toward these treatments is often convoluted, expensive, and time-consuming. MAIN BODY: The CureGPX4 organization was developed to promote awareness of GPX4-related diseases like SSMD, as well as support research that could lead to essential therapeutics for patients. We provide an overview of the 21 published SSMD cases and have compiled additional sequencing data for four previously unpublished individuals to illustrate the genetic component of SSMD, and the role of sequencing data in diagnosis. We outline in detail the steps CureGPX4 has taken to reach milestones of team creation, disease understanding, drug repurposing, and design of future studies. CONCLUSION: The primary aim of this review is to provide a roadmap for therapy development for rare, ultra-rare, and difficult to diagnose diseases, as well as increase awareness of the genetic component of SSMD. This work will offer a better understanding of GPx4-related diseases, and help guide researchers, clinicians, and patients interested in other rare diseases find a path towards treatments.


Assuntos
Osteocondrodisplasias , Doenças Raras , Humanos , Doenças Raras/genética
11.
Sci Rep ; 11(1): 12890, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145375

RESUMO

Degeneration and death of motor neurons in Amyotrophic Lateral Sclerosis (ALS) are associated with increased lipid peroxidation. Lipid peroxidation is the driver of ferroptosis, an iron-dependent oxidative mode of cell death. However, the importance of ferroptosis in motor neuron degeneration of ALS remains unclear. Glutathione peroxidase 4 (Gpx4) is a key enzyme in suppressing ferroptosis by reducing phospholipid hydroperoxides in membranes. To assess the effect of increased protection against ferroptosis on motor neuron disease, we generated SOD1G93AGPX4 double transgenic mice by cross-breeding GPX4 transgenic mice with SOD1G93A mice, a widely used ALS mouse model. Compared with control SOD1G93A mice, both male and female SOD1G93AGPX4 mice had extended lifespans. SOD1G93AGPX4 mice also showed delayed disease onset and increased motor function, which were correlated with ameliorated spinal motor neuron degeneration and reduced lipid peroxidation. Moreover, cell toxicity induced by SOD1G93A was ameliorated by Gpx4 overexpression and by chemical inhibitors of ferroptosis in vitro. We further found that the anti-ferroptosis defense system in spinal cord tissues of symptomatic SOD1G93A mice and sporadic ALS patients might be compromised due to deficiency of Gpx4. Thus, our results suggest that ferroptosis plays a key role in motor neuron degeneration of ALS.


Assuntos
Ferroptose/genética , Expressão Gênica , Doença dos Neurônios Motores/etiologia , Neurônios Motores/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/etiologia , Esclerose Lateral Amiotrófica/metabolismo , Animais , Biomarcadores , Modelos Animais de Doenças , Ativação Enzimática , Técnicas de Silenciamento de Genes , Imuno-Histoquímica , Longevidade , Camundongos , Camundongos Transgênicos , Doença dos Neurônios Motores/diagnóstico , Doença dos Neurônios Motores/metabolismo , Mutação , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Medula Espinal/metabolismo , Medula Espinal/patologia , Superóxido Dismutase-1/genética
12.
Sci Rep ; 10(1): 13968, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32811851

RESUMO

Defects in neuromuscular innervation contribute significantly to the age-related decline in muscle mass and function (sarcopenia). Our previous studies demonstrated that denervation induces muscle mitochondrial hydroperoxide production (H2O2 and lipid hydroperoxides (LOOHs)). Here we define the relative contribution of mitochondrial electron transport chain (ETC) derived H2O2 versus cytosolic phospholipase A2 (cPLA2) derived LOOHs in neurogenic muscle atrophy. We show that denervation increases muscle cPLA2 protein content, activity, and metabolites downstream of cPLA2 including LOOHs. Increased scavenging of mitochondrial H2O2 does not protect against denervation atrophy, suggesting ETC generated H2O2 is not a critical player. In contrast, inhibition of cPLA2 in vivo mitigates LOOH production and muscle atrophy and maintains individual muscle fiber size while decreasing oxidative damage. Overall, we show that loss of innervation in several muscle atrophy models including aging induces generation of LOOHs produced by arachidonic acid metabolism in the cPLA2 pathway contributing to loss of muscle mass.


Assuntos
Peróxidos Lipídicos/metabolismo , Fosfolipases A2/metabolismo , Sarcopenia/terapia , Animais , Citosol/metabolismo , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Peróxido de Hidrogênio/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Estresse Oxidativo/efeitos dos fármacos , Sarcopenia/metabolismo
13.
Nat Commun ; 11(1): 1775, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286299

RESUMO

The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon that could be related to adoption of a Western life-style. Westernization of dietary habits is partly characterized by enrichment with the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), which entails risk for developing IBD. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation (LPO) and cell death termed ferroptosis. We report that small intestinal epithelial cells (IECs) in Crohn's disease (CD) exhibit impaired GPX4 activity and signs of LPO. PUFAs and specifically AA trigger a cytokine response of IECs which is restricted by GPX4. While GPX4 does not control AA metabolism, cytokine production is governed by similar mechanisms as ferroptosis. A PUFA-enriched Western diet triggers focal granuloma-like neutrophilic enteritis in mice that lack one allele of Gpx4 in IECs. Our study identifies dietary PUFAs as a trigger of GPX4-restricted mucosal inflammation phenocopying aspects of human CD.


Assuntos
Doença de Crohn/metabolismo , Gorduras na Dieta/efeitos adversos , Enterite/metabolismo , Ácidos Graxos Insaturados/metabolismo , Inflamação/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Adulto , Animais , Morte Celular/genética , Morte Celular/fisiologia , Doença de Crohn/genética , Enterite/etiologia , Enterite/genética , Ácidos Graxos Insaturados/genética , Feminino , Glutationa Peroxidase/metabolismo , Humanos , Inflamação/genética , Peroxidação de Lipídeos/genética , Peroxidação de Lipídeos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética
14.
Cell Host Microbe ; 24(1): 97-108.e4, 2018 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-29937272

RESUMO

Sepsis is a life-threatening condition caused by pathogen infection and associated with pyroptosis. Pyroptosis occurs upon activation of proinflammatory caspases and their subsequent cleavage of gasdermin D (GSDMD), resulting in GSDMD N-terminal fragments that form membrane pores to induce cell lysis. Here, we show that antioxidant defense enzyme glutathione peroxidase 4 (GPX4) and its ability to decrease lipid peroxidation, negatively regulate macrophage pyroptosis, and septic lethality in mice. Conditional Gpx4 knockout in myeloid lineage cells increases lipid peroxidation-dependent caspase-11 activation and GSDMD cleavage. The resultant N-terminal GSDMD fragments then trigger macrophage pyroptotic cell death in a phospholipase C gamma 1 (PLCG1)-dependent fashion. Administration of the antioxidant vitamin E that reduces lipid peroxidation, chemical inhibition of PLCG1, or genetic Caspase-11 deletion or Gsdmd inactivation prevents polymicrobial sepsis in Gpx4-/- mice. Collectively, this study suggests that lipid peroxidation drives GSDMD-mediated pyroptosis and hence constitutes a potential therapeutic target for lethal infection.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Coinfecção/metabolismo , Glutationa Peroxidase/metabolismo , Peroxidação de Lipídeos/genética , Piroptose/genética , Sepse/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Caspases/genética , Caspases/metabolismo , Caspases Iniciadoras , Modelos Animais de Doenças , Escherichia coli/efeitos dos fármacos , Escherichia coli/patogenicidade , Glutationa Peroxidase/genética , Células HL-60 , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Leucócitos Mononucleares/microbiologia , Peroxidação de Lipídeos/efeitos dos fármacos , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Ligação a Fosfato , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Piroptose/efeitos dos fármacos , Vitamina E/farmacologia
15.
Cell ; 171(2): 273-285, 2017 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-28985560

RESUMO

Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.


Assuntos
Morte Celular , Animais , Apoptose , Humanos , Ferro/metabolismo , Oxirredução , Espécies Reativas de Oxigênio/metabolismo
16.
Redox Biol ; 12: 8-17, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28212525

RESUMO

Synaptic loss and neuron death are the underlying cause of neurodegenerative diseases such as Alzheimer's disease (AD); however, the modalities of cell death in those diseases remain unclear. Ferroptosis, a newly identified oxidative cell death mechanism triggered by massive lipid peroxidation, is implicated in the degeneration of neurons populations such as spinal motor neurons and midbrain neurons. Here, we investigated whether neurons in forebrain regions (cerebral cortex and hippocampus) that are severely afflicted in AD patients might be vulnerable to ferroptosis. To this end, we generated Gpx4BIKO mouse, a mouse model with conditional deletion in forebrain neurons of glutathione peroxidase 4 (Gpx4), a key regulator of ferroptosis, and showed that treatment with tamoxifen led to deletion of Gpx4 primarily in forebrain neurons of adult Gpx4BIKO mice. Starting at 12 weeks after tamoxifen treatment, Gpx4BIKO mice exhibited significant deficits in spatial learning and memory function versus Control mice as determined by the Morris water maze task. Further examinations revealed that the cognitively impaired Gpx4BIKO mice exhibited hippocampal neurodegeneration. Notably, markers associated with ferroptosis, such as elevated lipid peroxidation, ERK activation and augmented neuroinflammation, were observed in Gpx4BIKO mice. We also showed that Gpx4BIKO mice fed a diet deficient in vitamin E, a lipid soluble antioxidant with anti-ferroptosis activity, had an expedited rate of hippocampal neurodegeneration and behavior dysfunction, and that treatment with a small-molecule ferroptosis inhibitor ameliorated neurodegeneration in those mice. Taken together, our results indicate that forebrain neurons are susceptible to ferroptosis, suggesting that ferroptosis may be an important neurodegenerative mechanism in diseases such as AD.


Assuntos
Disfunção Cognitiva/genética , Glutationa Peroxidase/genética , Doenças Neurodegenerativas/genética , Prosencéfalo/metabolismo , Animais , Morte Celular , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Glutationa Peroxidase/metabolismo , Peroxidação de Lipídeos , Aprendizagem em Labirinto , Camundongos , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Oxirredução , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Prosencéfalo/citologia , Tamoxifeno/efeitos adversos
17.
J Biol Chem ; 290(47): 28097-28106, 2015 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-26400084

RESUMO

Glutathione peroxidase 4 (GPX4), an antioxidant defense enzyme active in repairing oxidative damage to lipids, is a key inhibitor of ferroptosis, a non-apoptotic form of cell death involving lipid reactive oxygen species. Here we show that GPX4 is essential for motor neuron health and survival in vivo. Conditional ablation of Gpx4 in neurons of adult mice resulted in rapid onset and progression of paralysis and death. Pathological inspection revealed that the paralyzed mice had a dramatic degeneration of motor neurons in the spinal cord but had no overt neuron degeneration in the cerebral cortex. Consistent with the role of GPX4 as a ferroptosis inhibitor, spinal motor neuron degeneration induced by Gpx4 ablation exhibited features of ferroptosis, including no caspase-3 activation, no TUNEL staining, activation of ERKs, and elevated spinal inflammation. Supplementation with vitamin E, another inhibitor of ferroptosis, delayed the onset of paralysis and death induced by Gpx4 ablation. Also, lipid peroxidation and mitochondrial dysfunction appeared to be involved in ferroptosis of motor neurons induced by Gpx4 ablation. Taken together, the dramatic motor neuron degeneration and paralysis induced by Gpx4 ablation suggest that ferroptosis inhibition by GPX4 is essential for motor neuron health and survival in vivo.


Assuntos
Morte Celular , Glutationa Peroxidase/genética , Neurônios Motores/patologia , Paralisia/enzimologia , Animais , Glutationa Peroxidase/metabolismo , Camundongos , Camundongos Knockout , Neurônios Motores/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Espécies Reativas de Oxigênio/metabolismo , Medula Espinal/metabolismo , Medula Espinal/patologia
18.
Neurobiol Aging ; 36(9): 2533-43, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26119225

RESUMO

Exposure to environmental toxins such as pesticides is implicated in increasing Alzheimer's disease risk. In this study, we investigated the long-term effects of paraquat exposure on cognition of Alzheimer's disease animal model APP/PS1 mice and wild-type (WT) mice. Our results showed that APP/PS1 mice had exacerbated cognition impairment and elevated Aß levels at 5 months after paraquat exposure, and that WT mice had cognition impairment at 5 and 16 months after paraquat exposure. In addition, increased mitochondrial oxidative stress and augmented brain inflammation were observed in both paraquat-exposed APP/PS1 mice and WT mice. Interestingly, activation of NLRP3 inflammasome, which triggers inflammation in response to mitochondrial stress, was enhanced in paraquat-exposed mice. Moreover, transgenic mice overexpressing Prdx3, a key enzyme in detoxifying mitochondrial H2O2, had suppressed NLRP3 inflammasome activation, reduced brain inflammation, and attenuated cognition impairment after paraquat exposure. Together, our results indicate that NLRP3 inflammasome activation induced by mitochondrial reactive oxygen species plays a key role in mediating paraquat-induced long-term cognition decline by elevating brain inflammation.


Assuntos
Doença de Alzheimer/complicações , Proteínas de Transporte/metabolismo , Transtornos Cognitivos , Herbicidas/toxicidade , Mitocôndrias/efeitos dos fármacos , Paraquat/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/patologia , Modelos Animais de Doenças , Complexo I de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteínas do Tecido Nervoso/metabolismo , Estresse Oxidativo/genética , Presenilina-1/genética , Presenilina-1/metabolismo
19.
Neurobiol Aging ; 35(11): 2552-2561, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24906890

RESUMO

Increased mitochondrial hydrogen peroxide (H2O2) is associated with Alzheimer's disease and brain aging. Peroxiredoxin 3 (Prdx3) is the key mitochondrial antioxidant defense enzyme in detoxifying H2O2. To investigate the importance of mitochondrial H2O2 in age-associated cognitive decline, we compared cognition between aged (17-19 months) APP transgenic mice and APP/Prdx3 double transgenic mice (dTG) and between old (24 months) wild-type mice and Prdx3 transgenic mice (TG). Compared with aged APP mice, aged dTG mice showed improved cognition that was correlated with reduced brain amyloid beta levels and decreased amyloid beta production. Old TG mice also showed significantly increased cognitive ability compared with old wild-type mice. Both aged dTG mice and old TG mice had reduced mitochondrial oxidative stress and increased mitochondrial function. Moreover, CREB signaling, a signaling pathway important for cognition was enhanced in both aged dTG mice and old TG mice. Thus, our results indicate that mitochondrial H2O2 is a key culprit of age-associated cognitive impairment, and that a reduction of mitochondrial H2O2 could improve cognition by maintaining mitochondrial health and enhancing CREB signaling.


Assuntos
Envelhecimento/psicologia , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/genética , Cognição/fisiologia , Peróxido de Hidrogênio/metabolismo , Mitocôndrias/enzimologia , Mitocôndrias/metabolismo , Peroxirredoxina III/fisiologia , Doença de Alzheimer/etiologia , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Terapia de Alvo Molecular , Estresse Oxidativo , Transdução de Sinais/fisiologia
20.
Am J Physiol Endocrinol Metab ; 305(2): E254-62, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23695217

RESUMO

We have shown that oxidative stress is a mechanism of free fatty acid (FFA)-induced ß-cell dysfunction. Unsaturated fatty acids in membranes, including plasma and mitochondrial membranes, are substrates for lipid peroxidation, and lipid peroxidation products are known to cause impaired insulin secretion. Therefore, we hypothesized that mice overexpressing glutathione peroxidase-4 (GPx4), an enzyme that specifically reduces lipid peroxides, are protected from fat-induced ß-cell dysfunction. GPx4-overexpressing mice and their wild-type littermate controls were infused intravenously with saline or oleate for 48 h, after which reactive oxygen species (ROS) were imaged, using dihydrodichlorofluorescein diacetate in isolated islets, and ß-cell function was assessed ex vivo in isolated islets and in vivo during hyperglycemic clamps. Forty-eight-hour FFA elevation in wild-type mice increased ROS and the lipid peroxidation product malondialdehyde and impaired ß-cell function ex vivo in isolated islets and in vivo, as assessed by decreased disposition index. Also, islets of wild-type mice exposed to oleate for 48 h had increased ROS and lipid peroxides and decreased ß-cell function. In contrast, GPx4-overexpressing mice showed no FFA-induced increase in ROS and lipid peroxidation and were protected from the FFA-induced impairment of ß-cell function assessed in vitro, ex vivo and in vivo. These results implicate lipid peroxidation in FFA-induced ß-cell dysfunction.


Assuntos
Ácidos Graxos não Esterificados/toxicidade , Glutationa Peroxidase/biossíntese , Glutationa Peroxidase/fisiologia , Células Secretoras de Insulina/fisiologia , Animais , Glicemia/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Técnica Clamp de Glucose , Infusões Intravenosas , Insulina/sangue , Resistência à Insulina/fisiologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/ultraestrutura , Ilhotas Pancreáticas/enzimologia , Ilhotas Pancreáticas/fisiologia , Peroxidação de Lipídeos/fisiologia , Masculino , Lipídeos de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ácidos Oleicos/toxicidade , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Espécies Reativas de Oxigênio/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
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