Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
Mais filtros








Base de dados
Intervalo de ano de publicação
1.
Nature ; 628(8009): 844-853, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38570685

RESUMO

Mitochondria are critical modulators of antiviral tolerance through the release of mitochondrial RNA and DNA (mtDNA and mtRNA) fragments into the cytoplasm after infection, activating virus sensors and type-I interferon (IFN-I) response1-4. The relevance of these mechanisms for mitochondrial diseases remains understudied. Here we investigated mitochondrial recessive ataxia syndrome (MIRAS), which is caused by a common European founder mutation in DNA polymerase gamma (POLG1)5. Patients homozygous for the MIRAS variant p.W748S show exceptionally variable ages of onset and symptoms5, indicating that unknown modifying factors contribute to disease manifestation. We report that the mtDNA replicase POLG1 has a role in antiviral defence mechanisms to double-stranded DNA and positive-strand RNA virus infections (HSV-1, TBEV and SARS-CoV-2), and its p.W748S variant dampens innate immune responses. Our patient and knock-in mouse data show that p.W748S compromises mtDNA replisome stability, causing mtDNA depletion, aggravated by virus infection. Low mtDNA and mtRNA release into the cytoplasm and a slow IFN response in MIRAS offer viruses an early replicative advantage, leading to an augmented pro-inflammatory response, a subacute loss of GABAergic neurons and liver inflammation and necrosis. A population databank of around 300,000 Finnish individuals6 demonstrates enrichment of immunodeficient traits in carriers of the POLG1 p.W748S mutation. Our evidence suggests that POLG1 defects compromise antiviral tolerance, triggering epilepsy and liver disease. The finding has important implications for the mitochondrial disease spectrum, including epilepsy, ataxia and parkinsonism.


Assuntos
Alelos , DNA Polimerase gama , Vírus da Encefalite Transmitidos por Carrapatos , Herpesvirus Humano 1 , Tolerância Imunológica , SARS-CoV-2 , Animais , Feminino , Humanos , Masculino , Camundongos , Idade de Início , COVID-19/imunologia , COVID-19/virologia , COVID-19/genética , DNA Polimerase gama/genética , DNA Polimerase gama/imunologia , DNA Polimerase gama/metabolismo , DNA Mitocondrial/imunologia , DNA Mitocondrial/metabolismo , Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/genética , Encefalite Transmitida por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/virologia , Efeito Fundador , Técnicas de Introdução de Genes , Herpes Simples/genética , Herpes Simples/imunologia , Herpes Simples/virologia , Herpesvirus Humano 1/imunologia , Tolerância Imunológica/genética , Tolerância Imunológica/imunologia , Imunidade Inata/genética , Imunidade Inata/imunologia , Interferon Tipo I/imunologia , Doenças Mitocondriais/enzimologia , Doenças Mitocondriais/genética , Doenças Mitocondriais/imunologia , Mutação , RNA Mitocondrial/imunologia , RNA Mitocondrial/metabolismo , SARS-CoV-2/imunologia
2.
Front Immunol ; 12: 729763, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34512665

RESUMO

The immune response to viral infection involves the recognition of pathogen-derived nucleic acids by intracellular sensors, leading to type I interferon (IFN), and downstream IFN-stimulated gene, induction. Ineffective discrimination of self from non-self nucleic acid can lead to autoinflammation, a phenomenon implicated in an increasing number of disease states, and well highlighted by the group of rare genetic disorders referred to as the type I interferonopathies. To understand the pathogenesis of these monogenic disorders, and polyfactorial diseases associated with pathogenic IFN upregulation, such as systemic lupus erythematosus and dermatomyositis, it is important to define the self-derived nucleic acid species responsible for such abnormal IFN induction. Recently, attention has focused on mitochondria as a novel source of immunogenic self nucleic acid. Best appreciated for their function in oxidative phosphorylation, metabolism and apoptosis, mitochondria are double membrane-bound organelles that represent vestigial bacteria in the cytosol of eukaryotic cells, containing their own DNA and RNA enclosed within the inner mitochondrial membrane. There is increasing recognition that a loss of mitochondrial integrity and compartmentalization can allow the release of mitochondrial nucleic acid into the cytosol, leading to IFN induction. Here, we provide recent insights into the potential of mitochondrial-derived DNA and RNA to drive IFN production in Mendelian disease. Specifically, we summarize current understanding of how nucleic acids are detected as foreign when released into the cytosol, and then consider the findings implicating mitochondrial nucleic acid in type I interferonopathy disease states. Finally, we discuss the potential for IFN-driven pathology in primary mitochondrial disorders.


Assuntos
DNA Mitocondrial/imunologia , Interferons/metabolismo , Mitocôndrias/imunologia , Doenças Mitocondriais/imunologia , RNA Mitocondrial/imunologia , Animais , Autoimunidade , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Humanos , Imunidade Inata , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , RNA Mitocondrial/genética , RNA Mitocondrial/metabolismo , Transdução de Sinais , Regulação para Cima
3.
Int J Mol Sci ; 22(16)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34445229

RESUMO

Symbiosis between the mitochondrion and the ancestor of the eukaryotic cell allowed cellular complexity and supported life. Mitochondria have specialized in many key functions ensuring cell homeostasis and survival. Thus, proper communication between mitochondria and cell nucleus is paramount for cellular health. However, due to their archaebacterial origin, mitochondria possess a high immunogenic potential. Indeed, mitochondria have been identified as an intracellular source of molecules that can elicit cellular responses to pathogens. Compromised mitochondrial integrity leads to release of mitochondrial content into the cytosol, which triggers an unwanted cellular immune response. Mitochondrial nucleic acids (mtDNA and mtRNA) can interact with the same cytoplasmic sensors that are specialized in recognizing genetic material from pathogens. High-energy demanding cells, such as neurons, are highly affected by deficits in mitochondrial function. Notably, mitochondrial dysfunction, neurodegeneration, and chronic inflammation are concurrent events in many severe debilitating disorders. Interestingly in this context of pathology, increasing number of studies have detected immune-activating mtDNA and mtRNA that induce an aberrant production of pro-inflammatory cytokines and interferon effectors. Thus, this review provides new insights on mitochondria-driven inflammation as a potential therapeutic target for neurodegenerative and primary mitochondrial diseases.


Assuntos
Mitocôndrias/imunologia , Doenças Neurodegenerativas/imunologia , Animais , Citocinas/imunologia , DNA Mitocondrial/imunologia , Humanos , Mitocôndrias/patologia , Doenças Neurodegenerativas/patologia , RNA Mitocondrial/imunologia
4.
Lupus ; 29(12): 1623-1629, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32787553

RESUMO

BACKGROUND: Mitochondria are intracellular organelles of bacterial origin capable of stimulating the immune system when released into the extracellular milieu. We previously reported the expression of anti-mitochondrial antibodies (AMA) targeting whole organelles (AwMA), mitochondrial DNA (AmtDNA) or mitochondrial RNA (AmtRNA) in patients with systemic lupus erythematosus (SLE). Antiphospholipid syndrome (APS) is an autoimmune condition that may be independent of, or associated with, other diseases, usually SLE. This study aimed to detect AMA in patients with APS and to explore the association with clinical features of APS. METHODS: AwMA-, AmtDNA- and AmtRNA-IgG and -IgM were detected in a pilot study (healthy controls n = 30 and APS patients n = 24) by direct ELISA, and their levels were associated with demographic and disease characteristics. RESULTS: AmtDNA-IgM and AmtRNA-IgG and IgM were elevated in APS compared to healthy controls (p = 0.009, p = 0.0005 and p = 0.01, respectively). AwMA-IgG were increased in patients positive for lupus anticoagulant (median ± interquartile range = 0.36 ± 0.31 vs. 0.14 ± 0.08, p = 0.008), and optical density values for AwMA-IgM were correlated with titres of IgM against cardiolipin (rs = 0.51, p = 0.01). An increment of 0.1 unit of AmtDNA-IgM levels was associated with reduced prior reporting of arterial events (odds ratio = 0.86; 95% confidence interval 0.74-1.00; p = 0.047). CONCLUSION: Our pilot study suggests that AMA are represented within the autoantibody repertoire in APS and may display different associations with the clinical manifestations of the disease. Further studies should focus on reproducing these preliminary results by following AMA levels through time in larger prospective cohorts.


Assuntos
Síndrome Antifosfolipídica/imunologia , Autoanticorpos/imunologia , DNA Mitocondrial/imunologia , RNA Mitocondrial/imunologia , Adulto , Idoso , Autoanticorpos/sangue , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/genética , Mitocôndrias/imunologia , Projetos Piloto
5.
Neuron ; 107(5): 891-908.e8, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32681824

RESUMO

The mechanisms by which mutant huntingtin (mHTT) leads to neuronal cell death in Huntington's disease (HD) are not fully understood. To gain new molecular insights, we used single nuclear RNA sequencing (snRNA-seq) and translating ribosome affinity purification (TRAP) to conduct transcriptomic analyses of caudate/putamen (striatal) cell type-specific gene expression changes in human HD and mouse models of HD. In striatal spiny projection neurons, the most vulnerable cell type in HD, we observe a release of mitochondrial RNA (mtRNA) (a potent mitochondrial-derived innate immunogen) and a concomitant upregulation of innate immune signaling in spiny projection neurons. Further, we observe that the released mtRNAs can directly bind to the innate immune sensor protein kinase R (PKR). We highlight the importance of studying cell type-specific gene expression dysregulation in HD pathogenesis and reveal that the activation of innate immune signaling in the most vulnerable HD neurons provides a novel framework to understand the basis of mHTT toxicity and raises new therapeutic opportunities.


Assuntos
Proteína Huntingtina/imunologia , Doença de Huntington/imunologia , Imunidade Inata/imunologia , Neurônios/imunologia , RNA Mitocondrial/imunologia , Animais , Humanos , Proteína Huntingtina/genética , Doença de Huntington/genética , Doença de Huntington/patologia , Camundongos , Mutação , Neurônios/patologia , Transcriptoma
6.
Front Immunol ; 10: 1026, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31134086

RESUMO

The mitochondrion supplies energy to the cell and regulates apoptosis. Unlike other mammalian organelles, mitochondria are formed by binary fission and cannot be directly produced by the cell. They contain numerous copies of a compact circular genome that encodes RNA molecules and proteins involved in mitochondrial oxidative phosphorylation. Whereas, mitochondrial DNA (mtDNA) activates the innate immune system if present in the cytosol or the extracellular milieu, it is also the target of circulating autoantibodies in systemic lupus erythematosus (SLE). However, it is not known whether mitochondrial RNA is also recognized by autoantibodies in SLE. In the present study, we evaluated the presence of autoantibodies targeting mitochondrial RNA (AmtRNA) in SLE. We quantified AmtRNA in an inducible model of murine SLE. The AmtRNA were also determined in SLE patients and healthy volunteers. AmtRNA titers were measured in both our induced model of murine SLE and in human SLE, and biostatistical analyses were performed to determine whether the presence and/or levels of AmtRNA were associated with clinical features expressed by SLE patients. Both IgG and IgM classes of AmtRNA were increased in SLE patients (n = 86) compared to healthy controls (n = 30) (p < 0.0001 and p = 0.0493, respectively). AmtRNA IgG levels correlated with anti-mtDNA-IgG titers (rs = 0.54, p < 0.0001) as well as with both IgG and IgM against ß-2-glycoprotein I (anti-ß2GPI; rs = 0.22, p = 0.05), and AmtRNA-IgG antibodies were present at higher levels when patients were positive for autoantibodies to double-stranded-genomic DNA (p < 0.0001). AmtRNA-IgG were able to specifically discriminate SLE patients from healthy controls, and were negatively associated with plaque formation (p = 0.04) and lupus nephritis (p = 0.03). Conversely, AmtRNA-IgM titers correlated with those of anti-ß2GPI-IgM (rs = 0.48, p < 0.0001). AmtRNA-IgM were higher when patients were positive for anticardiolipin antibodies (aCL-IgG: p = 0.01; aCL-IgM: p = 0.002), but AmtRNA-IgM were not associated with any of the clinical manifestations assessed. These findings identify mtRNA as a novel mitochondrial antigen target in SLE, and support the concept that mitochondria may provide an important source of circulating autoantigens in SLE.


Assuntos
Anticorpos Antinucleares/imunologia , Autoanticorpos/imunologia , DNA/imunologia , Lúpus Eritematoso Sistêmico/imunologia , RNA Mitocondrial/imunologia , Animais , Anticorpos Anticardiolipina/sangue , Anticorpos Anticardiolipina/imunologia , Anticorpos Antinucleares/sangue , Autoanticorpos/sangue , Modelos Animais de Doenças , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mitocôndrias/genética , Mitocôndrias/imunologia
7.
Bioessays ; 41(7): e1900023, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31099409

RESUMO

Many innate immune response proteins recognize foreign nucleic acids from invading pathogens to initiate antiviral signaling. These proteins mostly rely on structural characteristics of the nucleic acids rather than their specific sequences to distinguish self and nonself. One feature utilized by RNA sensors is the extended stretch of double-stranded RNA (dsRNA) base pairs. However, the criteria for recognizing nonself dsRNAs are rather lenient, and hairpin structure of self-RNAs can also trigger an immune response. Consequently, aberrant activation of RNA sensors has been reported in numerous human diseases. Yet, in most cases, the activating antigens remain unknown. Recent studies have developed sequencing techniques tailored to specifically capture dsRNAs and identified that various noncoding elements in the nuclear and the mitochondrial genome can generate dsRNAs. Here, the identity of endogenous dsRNAs, their recognition by dsRNA sensors, and their implications in the pathogenesis of human diseases ranging from inflammatory to degenerative are presented.


Assuntos
Doenças Autoimunes/imunologia , Imunidade Inata/imunologia , RNA de Cadeia Dupla/imunologia , RNA Mitocondrial/imunologia , Doenças Autoimunes/genética , Humanos , Conformação de Ácido Nucleico , RNA de Cadeia Dupla/genética , RNA Mitocondrial/genética , Transdução de Sinais/imunologia
8.
RNA ; 25(6): 713-726, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30894411

RESUMO

Viral and cellular double-stranded RNA (dsRNA) is recognized by cytosolic innate immune sensors, including RIG-I-like receptors. Some cytoplasmic dsRNA is commonly present in cells, and one source is mitochondrial dsRNA, which results from bidirectional transcription of mitochondrial DNA (mtDNA). Here we demonstrate that Trp53 mutant mouse embryonic fibroblasts contain immune-stimulating endogenous dsRNA of mitochondrial origin. We show that the immune response induced by this dsRNA is mediated via RIG-I-like receptors and leads to the expression of type I interferon and proinflammatory cytokine genes. The mitochondrial dsRNA is cleaved by RNase L, which cleaves all cellular RNA including mitochondrial mRNAs, increasing activation of RIG-I-like receptors. When mitochondrial transcription is interrupted there is a subsequent decrease in this immune-stimulatory dsRNA. Our results reveal that the role of p53 in innate immunity is even more versatile and complex than previously anticipated. Our study, therefore, sheds new light on the role of endogenous RNA in diseases featuring aberrant immune responses.


Assuntos
Adenosina Desaminase/genética , Proteína DEAD-box 58/genética , Imunidade Inata/genética , RNA de Cadeia Dupla/genética , RNA Mitocondrial/genética , Proteína Supressora de Tumor p53/genética , Proteínas Adaptadoras de Transdução de Sinal , Adenosina Desaminase/deficiência , Adenosina Desaminase/imunologia , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Proteína DEAD-box 58/imunologia , Embrião de Mamíferos , Endorribonucleases/genética , Endorribonucleases/imunologia , Fibroblastos/citologia , Fibroblastos/imunologia , Fator Regulador 7 de Interferon/genética , Fator Regulador 7 de Interferon/imunologia , Helicase IFIH1 Induzida por Interferon/genética , Helicase IFIH1 Induzida por Interferon/imunologia , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas/genética , Proteínas/imunologia , RNA de Cadeia Dupla/imunologia , RNA Mitocondrial/imunologia , Proteínas de Ligação a RNA , Transcrição Gênica , Transfecção , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/imunologia
9.
Nature ; 560(7717): 238-242, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30046113

RESUMO

Mitochondria are descendants of endosymbiotic bacteria and retain essential prokaryotic features such as a compact circular genome. Consequently, in mammals, mitochondrial DNA is subjected to bidirectional transcription that generates overlapping transcripts, which are capable of forming long double-stranded RNA structures1,2. However, to our knowledge, mitochondrial double-stranded RNA has not been previously characterized in vivo. Here we describe the presence of a highly unstable native mitochondrial double-stranded RNA species at single-cell level and identify key roles for the degradosome components mitochondrial RNA helicase SUV3 and polynucleotide phosphorylase PNPase in restricting the levels of mitochondrial double-stranded RNA. Loss of either enzyme results in massive accumulation of mitochondrial double-stranded RNA that escapes into the cytoplasm in a PNPase-dependent manner. This process engages an MDA5-driven antiviral signalling pathway that triggers a type I interferon response. Consistent with these data, patients carrying hypomorphic mutations in the gene PNPT1, which encodes PNPase, display mitochondrial double-stranded RNA accumulation coupled with upregulation of interferon-stimulated genes and other markers of immune activation. The localization of PNPase to the mitochondrial inter-membrane space and matrix suggests that it has a dual role in preventing the formation and release of mitochondrial double-stranded RNA into the cytoplasm. This in turn prevents the activation of potent innate immune defence mechanisms that have evolved to protect vertebrates against microbial and viral attack.


Assuntos
Herpesvirus Humano 1/imunologia , RNA de Cadeia Dupla/imunologia , RNA Mitocondrial/imunologia , Animais , RNA Helicases DEAD-box/deficiência , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Endorribonucleases/metabolismo , Exorribonucleases/deficiência , Exorribonucleases/genética , Exorribonucleases/metabolismo , Regulação da Expressão Gênica/imunologia , Células HeLa , Herpesvirus Humano 1/genética , Humanos , Interferon Tipo I/antagonistas & inibidores , Interferon Tipo I/imunologia , Helicase IFIH1 Induzida por Interferon/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Complexos Multienzimáticos/metabolismo , Mutação , Polirribonucleotídeo Nucleotidiltransferase/metabolismo , RNA Helicases/metabolismo , Análise de Célula Única , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA