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1.
Brain ; 146(5): 1804-1811, 2023 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-36349561

RESUMO

Corpus callosum defects are frequent congenital cerebral disorders caused by mutations in more than 300 genes. These include genes implicated in corpus callosum development or function, as well as genes essential for mitochondrial physiology. However, in utero corpus callosum anomalies rarely raise a suspicion of mitochondrial disease and are characterized by a very large clinical heterogeneity. Here, we report a detailed pathological and neuro-histopathological investigation of nine foetuses from four unrelated families with prenatal onset of corpus callosum anomalies, sometimes associated with other cerebral or extra-cerebral defects. Next generation sequencing allowed the identification of novel pathogenic variants in three different nuclear genes previously reported in mitochondrial diseases: TIMMDC1, encoding a Complex I assembly factor never involved before in corpus callosum defect; MRPS22, a protein of the small mitoribosomal subunit; and EARS2, the mitochondrial tRNA-glutamyl synthetase. The present report describes the antenatal histopathological findings in mitochondrial diseases and expands the genetic spectrum of antenatal corpus callosum anomalies establishing OXPHOS function as an important factor for corpus callosum biogenesis. We propose that, when observed, antenatal corpus callosum anomalies should raise suspicion of mitochondrial disease and prenatal genetic counselling should be considered.


Assuntos
Corpo Caloso , Doenças Mitocondriais , Humanos , Feminino , Gravidez , Corpo Caloso/patologia , Agenesia do Corpo Caloso/genética , Agenesia do Corpo Caloso/patologia , Doenças Mitocondriais/genética , Mitocôndrias/patologia , Mutação , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial
2.
Hum Mutat ; 40(7): 893-898, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30981218

RESUMO

Leigh syndrome is a mitochondrial disease caused by pathogenic variants in over 85 genes. Whole exome sequencing of a patient with Leigh-like syndrome identified homozygous protein-truncating variants in two genes associated with Leigh syndrome; a reported pathogenic variant in PDHX (NP_003468.2:p.(Arg446*)), and an uncharacterized variant in complex I (CI) assembly factor TIMMDC1 (NP_057673.2:p.(Arg225*)). The TIMMDC1 variant was predicted to truncate 61 amino acids at the C-terminus and functional studies demonstrated a hypomorphic impact of the variant on CI assembly. However, the mutant protein could still rescue CI assembly in TIMMDC1 knockout cells and the patient's clinical phenotype was not clearly distinct from that of other patients with the same PDHX defect. Our data suggest that the hypomorphic effect of the TIMMDC1 protein-truncating variant does not constitute a dual diagnosis in this individual. We recommend cautious assessment of variants in the C-terminus of TIMMDC1 and emphasize the need to consider the caveats detailed within the American College of Medical Genetics and Genomics (ACMG) criteria when assessing variants.


Assuntos
Doença de Leigh/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Deleção de Sequência , Diagnóstico Precoce , Técnicas de Inativação de Genes , Células HEK293 , Homozigoto , Humanos , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Complexo Piruvato Desidrogenase/genética , Sequenciamento do Exoma
3.
Biochem Biophys Res Commun ; 508(3): 749-755, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30528236

RESUMO

BACKGROUND: Long noncoding RNAs (lncRNAs) have been revealed to participate in cellular biological processes in multiple diseases, including asthma. Nevertheless, the role of lncRNA TCF7 (lncTCF7) in airway smooth muscle cells (ASMCs) is still covered. METHODS: The expression of lncTCF7 and TIMMDC1 in ASMCs from 12 asthma patients and 12 healthy controls were detected using qRT-PCR. Then MTT assay, EdU assay and transwell assay were conducted respectively to assess the impact of lncTCF7 on ASMCs viability, proliferation and migration. Besides, western blotting was performed to determine the protein levels of TIMMDC1 and AKT/p-AKT. RESULTS: We discovered that lncTCF7 and TIMMDC1 were upregulated in asthma groups and lncTCF7 improved ASMCs viability/proliferation and migration. In addition, lncTCF7 regulated TIMMDC1 expression indeed and PDGF-BB treated ASMCs exhibited elevated levels of lncTCF7 and TIMMDC1. Moreover, lncTCF7 suppression diminished both the mRNA and protein levels of TIMMDC1 and markedly reduced p-AKT level which could be enhanced under TIMMDC1 overexpression. Finally, both TIMMDC1 overexpression and AKT activator could restored the inhibitory impacts of lncTCF7 silence on PDGF-BB treated ASMCs. CONCLUSION: Our study uncovered that lncTCF7 facilitated human ASMCs growth and migration via targeting TIMMDC1 thus activating AKT signaling, providing a novel possible target for asthma therapy.


Assuntos
Asma/genética , Asma/patologia , Movimento Celular , Pulmão/patologia , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Miócitos de Músculo Liso/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/metabolismo , Becaplermina/farmacologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Progressão da Doença , Humanos , Proteínas de Transporte da Membrana Mitocondrial/genética , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , RNA Longo não Codificante/genética , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
4.
Cell Rep ; 35(2): 108963, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33852835

RESUMO

The assembly pathways of mitochondrial respirasome (supercomplex I+III2+IV) are not fully understood. Here, we show that an early sub-complex I assembly, rather than holo-complex I, is sufficient to initiate mitochondrial respirasome assembly. We find that a distal part of the membrane arm of complex I (PD-a module) is a scaffold for the incorporation of complexes III and IV to form a respirasome subcomplex. Depletion of PD-a, rather than other complex I modules, decreases the steady-state levels of complexes III and IV. Both HEK293T cells lacking TIMMDC1 and patient-derived cells with disease-causing mutations in TIMMDC1 showed accumulation of this respirasome subcomplex. This suggests that TIMMDC1, previously known as a complex-I assembly factor, may function as a respirasome assembly factor. Collectively, we provide a detailed, cooperative assembly model in which most complex-I subunits are added to the respirasome subcomplex in the lateral stages of respirasome assembly.


Assuntos
Complexo III da Cadeia de Transporte de Elétrons/genética , Complexo IV da Cadeia de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/genética , Mitocôndrias/genética , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial/genética , Animais , Linfócitos B , Linhagem Celular Transformada , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Complexo I de Transporte de Elétrons/metabolismo , Complexo III da Cadeia de Transporte de Elétrons/antagonistas & inibidores , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/antagonistas & inibidores , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Embrião não Mamífero , Regulação da Expressão Gênica no Desenvolvimento , Células HEK293 , Humanos , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial/deficiência , Morfolinos/genética , Morfolinos/metabolismo , Hipotonia Muscular/genética , Hipotonia Muscular/metabolismo , Hipotonia Muscular/patologia , Fosforilação Oxidativa , Peixe-Zebra
5.
Eur J Med Genet ; 64(1): 104120, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33278652

RESUMO

Complex I deficiency is the most common pediatric mitochondrial disease. It can cause a wide range of clinical disorders, including Leigh syndrome. TIMMDC1 encodes an assembly protein of complex I and has been recently associated with early onset mitochondrial disease in three unrelated families. In all three families the same homozygous deep intronic variant was identified leading to inclusion of a new exon resulting in a frameshift and premature stop codon (c.596 + 2146A > G, p.Gly199_Thr200ins5*). Herein, we describe two brothers of Dutch descent, presenting in infancy with hypotonia and respiratory insufficiency and a rapidly progressive and fatal disease course. Laboratory findings and metabolic investigations revealed no specific abnormalities, notably no raised plasma lactate. MRI showed transient lesions in the basal ganglia of brother 1. A muscle biopsy demonstrated complex I deficiency in brother 2. Exome sequencing yielded a novel heterozygous TIMMDC1 variant: c.385C > T, p.(Arg129*). Targeted sequencing revealed the previously published deep intronic variant c.596 + 2146A > G, p.(Gly199_Thr200ins5*) on the second allele which is not detected by exome sequencing. In summary, we present the fourth family with TIMMDC1-related disease, with a novel nonsense variant. This report illustrates the importance of considering mitochondrial disease even when laboratory findings are normal, and the added value of targeted sequencing of introns.


Assuntos
Doenças Mitocondriais/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Fenótipo , Gânglios da Base/diagnóstico por imagem , Códon sem Sentido , Diagnóstico Tardio , Heterozigoto , Humanos , Lactente , Íntrons , Ácido Láctico/sangue , Masculino , Doenças Mitocondriais/diagnóstico , Proteínas de Transporte da Membrana Mitocondrial/deficiência , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Linhagem
6.
Cell Metab ; 33(3): 531-546.e9, 2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33545050

RESUMO

The haploinsufficiency of C9orf72 is implicated in the most common forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the full spectrum of C9orf72 functions remains to be established. Here, we report that C9orf72 is a mitochondrial inner-membrane-associated protein regulating cellular energy homeostasis via its critical role in the control of oxidative phosphorylation (OXPHOS). The translocation of C9orf72 from the cytosol to the inter-membrane space is mediated by the redox-sensitive AIFM1/CHCHD4 pathway. In mitochondria, C9orf72 specifically stabilizes translocase of inner mitochondrial membrane domain containing 1 (TIMMDC1), a crucial factor for the assembly of OXPHOS complex I. C9orf72 directly recruits the prohibitin complex to inhibit the m-AAA protease-dependent degradation of TIMMDC1. The mitochondrial complex I function is impaired in C9orf72-linked ALS/FTD patient-derived neurons. These results reveal a previously unknown function of C9orf72 in mitochondria and suggest that defective energy metabolism may underlie the pathogenesis of relevant diseases.


Assuntos
Proteína C9orf72/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Metabolismo Energético/fisiologia , Proteases Dependentes de ATP/metabolismo , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Animais , Fator de Indução de Apoptose/antagonistas & inibidores , Fator de Indução de Apoptose/genética , Fator de Indução de Apoptose/metabolismo , Proteína C9orf72/antagonistas & inibidores , Proteína C9orf72/genética , Linhagem Celular , Sobrevivência Celular , Complexo I de Transporte de Elétrons/química , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial/antagonistas & inibidores , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial/genética , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Fosforilação Oxidativa , Interferência de RNA , RNA Interferente Pequeno/metabolismo
7.
Int J Biol Sci ; 14(10): 1256-1267, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30123074

RESUMO

TIMMDC1 (C3orf1), a predicted 4-pass membrane protein, which locates in the mitochondrial inner membrane, has been demonstrated to have association with multiple member of mitochondrial complex I assembly factors and core mitochondrial complex I subunits. The expression level of TIMMDC1 in highly-metastatic tumor cells is higher than that in lowly- metastatic tumor cells. However, the role of TIMMDC1 in human gastric cancer progression is unclear. In this study, human gastric cancer cells SGC-7901 and BGC-823 cells were used, and TIMMDC1 was knockdown with small interfering RNA. The data showed that TIMMDC1 knockdown caused inhibitory effects on the cell proliferation in vitro and tumor progression in vivo. Knockdown of TIMMDC1 significantly and exclusively reduced the activity of mitochondrial complex I but not complex II~ IV, and caused an obvious inhibition in mitochondrial respiration and ATP-linked oxygen consumption. Besides, the glycolysis pathway was also attenuated by TIMMDC1 knockdown, and the ATP content in the group of shTIMMDC1 cells was significantly lower than that in the shCont cells. The expression levels of phosphoylated AKT(Ser473) and GSK-3ß (Ser9), as well as the downstream protein ß-catenin and c-Myc were also markedly reduced in the group of shTIMMDC1 cells. Taken together, these findings suggest that TIMMDC1 may play an important role in human gastric cancer development, and its underlying mechanism is not only associated with mitochondrial complex I inhibition and reduced mitochondrial respiration, but is also associated with reduced glycolysis activity and the AKT/GSK3ß/ß-catenin signaling pathways.


Assuntos
Glicogênio Sintase Quinase 3 beta/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/metabolismo , beta Catenina/metabolismo , Animais , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/fisiologia , Regulação Neoplásica da Expressão Gênica/genética , Glicogênio Sintase Quinase 3 beta/genética , Glicólise/genética , Glicólise/fisiologia , Humanos , Masculino , Camundongos , Camundongos Nus , Proteínas de Transporte da Membrana Mitocondrial/genética , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Proteínas Proto-Oncogênicas c-akt/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Neoplasias Gástricas/genética , Cicatrização/genética , Cicatrização/fisiologia , beta Catenina/genética
8.
Biol Direct ; 11(1): 54, 2016 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-27760563

RESUMO

BACKGROUND: The Tim17 family of proteins plays a fundamental role in the biogenesis of mitochondria. Three Tim17 family proteins, Tim17, Tim22, and Tim23, are the central components of the widely conserved multi-subunit protein translocases, TIM23 and TIM22, which mediate protein transport across and into the inner mitochondrial membrane, respectively. In addition, several Tim17 family proteins occupy the inner and outer membranes of plastids. RESULTS: We have performed comprehensive sequence analyses on 5631 proteomes from all domains of life deposited in the Uniprot database. The analyses showed that the Tim17 family of proteins is much more diverse than previously thought and involves at least ten functionally and phylogenetically distinct groups of proteins. As previously shown, mitochondrial inner membrane accommodates prototypical Tim17, Tim22 and Tim23 and two Tim17 proteins, TIMMDC1 and NDUFA11, which participate in the assembly of complex I of the respiratory chain. In addition, we have identified Romo1/Mgr2 as Tim17 family member. The protein has been shown to control lateral release of substrates fromTIM23 complex in yeast and to participate in the production of reactive oxygen species in mammalian cells. Two peroxisomal proteins, Pmp24 and Tmem135, of so far unknown function also belong to Tim17 protein family. Additionally, a new group of Tim17 family proteins carrying a C-terminal coiled-coil domain has been identified predominantly in fungi. CONCLUSIONS: We have mapped the distribution of Tim17 family members in the eukaryotic supergroups and found that the mitochondrial Tim17, Tim22 and Tim23 proteins, as well as the peroxisomal Tim17 family proteins, were all likely to be present in the last eukaryotic common ancestor (LECA). Thus, kinetoplastid mitochondria previously identified as carrying a single Tim17protein family homologue are likely to be the outcome of a secondary reduction. The eukaryotic cell has modified mitochondrial Tim17 family proteins to mediate different functions in multiple cellular compartments including mitochondria, plastids and peroxisomes. Concerning the origin of Tim17 protein family, our analyses do not support the affiliation of the protein family and the component of bacterial amino acid permease. Thus, it is likely that Tim17 protein family is exclusive to eukaryotes. REVIEWERS: The article was reviewed by Michael Gray, Martijn Huynen and Kira Makarova.


Assuntos
Evolução Molecular , Proteínas de Transporte da Membrana Mitocondrial/genética , Sequência de Aminoácidos , Proteínas de Transporte da Membrana Mitocondrial/química , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Filogenia , Alinhamento de Sequência
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