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1.
J Clin Invest ; 130(1): 108-125, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31550240

RESUMO

Inherited optic neuropathies include complex phenotypes, mostly driven by mitochondrial dysfunction. We report an optic atrophy spectrum disorder, including retinal macular dystrophy and kidney insufficiency leading to transplantation, associated with mitochondrial DNA (mtDNA) depletion without accumulation of multiple deletions. By whole-exome sequencing, we identified mutations affecting the mitochondrial single-strand binding protein (SSBP1) in 4 families with dominant and 1 with recessive inheritance. We show that SSBP1 mutations in patient-derived fibroblasts variably affect the amount of SSBP1 protein and alter multimer formation, but not the binding to ssDNA. SSBP1 mutations impaired mtDNA, nucleoids, and 7S-DNA amounts as well as mtDNA replication, affecting replisome machinery. The variable mtDNA depletion in cells was reflected in severity of mitochondrial dysfunction, including respiratory efficiency, OXPHOS subunits, and complex amount and assembly. mtDNA depletion and cytochrome c oxidase-negative cells were found ex vivo in biopsies of affected tissues, such as kidney and skeletal muscle. Reduced efficiency of mtDNA replication was also reproduced in vitro, confirming the pathogenic mechanism. Furthermore, ssbp1 suppression in zebrafish induced signs of nephropathy and reduced optic nerve size, the latter phenotype complemented by WT mRNA but not by SSBP1 mutant transcripts. This previously unrecognized disease of mtDNA maintenance implicates SSBP1 mutations as a cause of human pathology.

2.
Neuropediatrics ; 50(2): 71-79, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30572371

RESUMO

Among 131 children admitted to our institution for early phase rehabilitation after freshwater near-drowning (ND) between the year 1986 and 2000, 87 were in unresponsive wakefulness syndrome (UWS) for at least 4 weeks after the accidents. An anonymous questionnaire was sent to the families after 0.5 to 15.0 years (median: 4.6) and 48 mothers and 51 fathers of 55 of these 87 children were interviewed after 6.6 to 23.8 years (median: 13.8) of ND. At the time of the interviews, 8/55 children were able to perform daily living activities independently, 36/55 children were not able to do so (many of them suffered from chronic medical conditions like spasticity or disorders of swallowing), and 11/55 children had died. Health-related quality of life (HRQoL) was, however, similar to the normal population for mothers, and even higher for fathers. Furthermore, the ND accident had apparently not lead to a higher rate of separations of parents but had increased their likelihood to have further children. Feelings of guilt were highly prevalent (23/47 mothers, 20/47 fathers), and correlated with lower HRQoL of the respective parent. We found correlations between duty of supervision and feelings of guilt and between outcome and HRQoL for only the fathers. In conclusion, we found that after 4 weeks in UWS, the long-term neurological outcome of pediatric ND victims is often but not always poor. Despite often severe disabilities or death of the child during long-term care, parents surprisingly report little impact on their HRQoL, on the stability of their partnership or on their wish to have further children. Our findings may help parents and physicians to choose the best treatment for a child in UWS due to different etiologies striking the balance between rehabilitation and palliative care.


Assuntos
Afogamento Iminente/psicologia , Pais/psicologia , Estado Vegetativo Persistente/psicologia , Qualidade de Vida/psicologia , Inquéritos e Questionários , Vigília , Criança , Pré-Escolar , Feminino , Culpa , Humanos , Lactente , Masculino , Afogamento Iminente/diagnóstico , Estado Vegetativo Persistente/diagnóstico , Fatores de Tempo , Resultado do Tratamento
3.
Am J Hum Genet ; 103(4): 592-601, 2018 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-30245030

RESUMO

Isolated complex I deficiency is a common biochemical phenotype observed in pediatric mitochondrial disease and often arises as a consequence of pathogenic variants affecting one of the ∼65 genes encoding the complex I structural subunits or assembly factors. Such genetic heterogeneity means that application of next-generation sequencing technologies to undiagnosed cohorts has been a catalyst for genetic diagnosis and gene-disease associations. We describe the clinical and molecular genetic investigations of four unrelated children who presented with neuroradiological findings and/or elevated lactate levels, highly suggestive of an underlying mitochondrial diagnosis. Next-generation sequencing identified bi-allelic variants in NDUFA6, encoding a 15 kDa LYR-motif-containing complex I subunit that forms part of the Q-module. Functional investigations using subjects' fibroblast cell lines demonstrated complex I assembly defects, which were characterized in detail by mass-spectrometry-based complexome profiling. This confirmed a marked reduction in incorporated NDUFA6 and a concomitant reduction in other Q-module subunits, including NDUFAB1, NDUFA7, and NDUFA12. Lentiviral transduction of subjects' fibroblasts showed normalization of complex I. These data also support supercomplex formation, whereby the ∼830 kDa complex I intermediate (consisting of the P- and Q-modules) is in complex with assembled complex III and IV holoenzymes despite lacking the N-module. Interestingly, RNA-sequencing data provided evidence that the consensus RefSeq accession number does not correspond to the predominant transcript in clinically relevant tissues, prompting revision of the NDUFA6 RefSeq transcript and highlighting not only the importance of thorough variant interpretation but also the assessment of appropriate transcripts for analysis.


Assuntos
Complexo I de Transporte de Elétrons/deficiência , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Mutação/genética , Alelos , Sequência de Aminoácidos , Complexo I de Transporte de Elétrons/genética , Feminino , Fibroblastos/patologia , Heterogeneidade Genética , Humanos , Lactente , Masculino , Mitocôndrias/genética , Fenótipo , Alinhamento de Sequência
4.
Congenit Heart Dis ; 13(5): 671-677, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30133155

RESUMO

OBJECTIVE: In general, a mitochondrial disorder is diagnosed on the basis of symptom combinations and confirmed by genetic findings. However, patients carrying the m.3243A>G mutation in the mitochondrial tRNA leucine 1 (MT-TL1) do not always meet all the proposed criteria for the most frequently encountered mitochondrial syndrome "MELAS," an acronym for Mitochondrial Encephalomyopathy, Lactic Acidosis, and at least one Stroke-like episode. We here present various phenotypic characteristics of the mitochondrial mutation m.3243A>G with particular focus on cardiac manifestations. METHODS AND RESULTS: We followed nine patients (1 month to 68 years old; median 42 years; four female and five male) from nine different families with this m.3243A>G mutation in the MT-TL1. The classical "MELAS" criteria are met by only three of these patients. Electrocardiography (ECG) shows preexcitation pattern with short PR intervals and delta waves (Wolff-Parkinson-White) in three patients and sick sinus syndrome plus atrioventricular block I in one patient. Hypertrophic cardiomyopathy was found in eight patients with moderate to severe regurgitation of various valves. CONCLUSION: Cardiac manifestation can encompass hypertrophic or dilated cardiomyopathy, as well as preexcitation syndromes or conduction delay. In general, the clinical presentation to meet the "MELAS" criteria varies due to heteroplasmy. Thus, cardiologists should screen patients with unexplained cardiac features in the context of deafness, short stature and learning disabilities for mtDNA mutations, especially the m.3243A>G mutation. A clear diagnosis is essential as a basis for prognostic advice concerning the disease course and clinical impact on family testing.


Assuntos
DNA Mitocondrial/genética , Ventrículos do Coração/diagnóstico por imagem , Síndrome MELAS/genética , Mutação , Adolescente , Adulto , Idoso , Cardiologistas , Criança , Pré-Escolar , Análise Mutacional de DNA , Ecocardiografia , Eletrocardiografia , Feminino , Humanos , Lactente , Recém-Nascido , Síndrome MELAS/diagnóstico , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
5.
Orphanet J Rare Dis ; 13(1): 120, 2018 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-30025539

RESUMO

BACKGROUND: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. RESULTS: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and severe developmental delays in four patients. More than 70% of the patients were able to perform the same activities of daily living when compared to peers. CONCLUSIONS: Our data show that riboflavin treatment improves complex I activity in the majority of patient-derived fibroblasts tested. This effect was also reported for most of the treated patients and is mirrored in the survival data. In the patient group with disease-onset below 1 year of age, we observed a statistically-significant better survival for patients treated with riboflavin.


Assuntos
Acidose/genética , Acidose/metabolismo , Acil-CoA Desidrogenase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/metabolismo , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Debilidade Muscular/genética , Debilidade Muscular/metabolismo , Riboflavina/uso terapêutico , Acidose/patologia , Atividades Cotidianas , Acil-CoA Desidrogenase/genética , Acil-CoA Desidrogenase/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Cardiomiopatia Hipertrófica/patologia , Complexo I de Transporte de Elétrons/metabolismo , Feminino , Humanos , Masculino , Doenças Mitocondriais/patologia , Debilidade Muscular/tratamento farmacológico , Debilidade Muscular/patologia , Prognóstico
6.
Cells ; 7(5)2018 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-29747424

RESUMO

The papillary thyroid carcinoma (PTC) is the most common malignant tumor of the thyroid gland, with disruptive mutations in mitochondrial complex I subunits reported at very low frequency. Furthermore, metabolic diversity of PTC has been postulated owing to variable messenger RNA (mRNA) expression of genes encoding subunits of the oxidative phosphorylation (OXHPOS) complexes. The aim of the present study was to evaluate the metabolic diversity of the OXPHOS system at the protein level by using immunohistochemical staining. Analysis of 18 human PTCs revealed elevated mitochondrial biogenesis but significantly lower levels of OXPHOS complex I in the tumor tissue (p < 0.0001) compared to the adjacent normal tissue. In contrast, OXPHOS complexes II⁻V were increased in the majority of PTCs. In three PTCs, we found pathologic mutations within mitochondrially encoded complex I subunits. Our data indicate that PTCs are characterized by an oncocytic metabolic signature that is in low complex I is combined with elevated mitochondrial mass and high complex II⁻V levels, which might be an important factor for tumor formation.

7.
Am J Hum Genet ; 102(4): 685-695, 2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29576219

RESUMO

Biogenesis of the mitochondrial oxidative phosphorylation system, which produces the bulk of ATP for almost all eukaryotic cells, depends on the translation of 13 mtDNA-encoded polypeptides by mitochondria-specific ribosomes in the mitochondrial matrix. These mitoribosomes are dual-origin ribonucleoprotein complexes, which contain mtDNA-encoded rRNAs and tRNAs and ∼80 nucleus-encoded proteins. An increasing number of gene mutations that impair mitoribosomal function and result in multiple OXPHOS deficiencies are being linked to human mitochondrial diseases. Using exome sequencing in two unrelated subjects presenting with sensorineural hearing impairment, mild developmental delay, hypoglycemia, and a combined OXPHOS deficiency, we identified mutations in the gene encoding the mitochondrial ribosomal protein S2, which has not previously been implicated in disease. Characterization of subjects' fibroblasts revealed a decrease in the steady-state amounts of mutant MRPS2, and this decrease was shown by complexome profiling to prevent the assembly of the small mitoribosomal subunit. In turn, mitochondrial translation was inhibited, resulting in a combined OXPHOS deficiency detectable in subjects' muscle and liver biopsies as well as in cultured skin fibroblasts. Reintroduction of wild-type MRPS2 restored mitochondrial translation and OXPHOS assembly. The combination of lactic acidemia, hypoglycemia, and sensorineural hearing loss, especially in the presence of a combined OXPHOS deficiency, should raise suspicion for a ribosomal-subunit-related mitochondrial defect, and clinical recognition could allow for a targeted diagnostic approach. The identification of MRPS2 as an additional gene related to mitochondrial disease further expands the genetic and phenotypic spectra of OXPHOS deficiencies caused by impaired mitochondrial translation.


Assuntos
Alelos , Perda Auditiva Neurossensorial/genética , Hipoglicemia/genética , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Mutação/genética , Proteínas Ribossômicas/genética , Sequência de Aminoácidos , Pré-Escolar , Análise Mutacional de DNA , DNA Mitocondrial/genética , Feminino , Fibroblastos/metabolismo , Perda Auditiva Neurossensorial/complicações , Humanos , Hipoglicemia/complicações , Lactente , Recém-Nascido , Masculino , Doenças Mitocondriais/complicações , Proteínas Mitocondriais/química , Fosforilação Oxidativa , Subunidades Proteicas/genética , RNA Ribossômico/genética , Proteínas Ribossômicas/química
8.
Am J Hum Genet ; 102(3): 460-467, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29429571

RESUMO

Respiratory chain complex I deficiency is the most frequently identified biochemical defect in childhood mitochondrial diseases. Clinical symptoms range from fatal infantile lactic acidosis to Leigh syndrome and other encephalomyopathies or cardiomyopathies. To date, disease-causing variants in genes coding for 27 complex I subunits, including 7 mitochondrial DNA genes, and in 11 genes encoding complex I assembly factors have been reported. Here, we describe rare biallelic variants in NDUFB8 encoding a complex I accessory subunit revealed by whole-exome sequencing in two individuals from two families. Both presented with a progressive course of disease with encephalo(cardio)myopathic features including muscular hypotonia, cardiac hypertrophy, respiratory failure, failure to thrive, and developmental delay. Blood lactate was elevated. Neuroimaging disclosed progressive changes in the basal ganglia and either brain stem or internal capsule. Biochemical analyses showed an isolated decrease in complex I enzymatic activity in muscle and fibroblasts. Complementation studies by expression of wild-type NDUFB8 in cells from affected individuals restored mitochondrial function, confirming NDUFB8 variants as the cause of complex I deficiency. Hereby we establish NDUFB8 as a relevant gene in childhood-onset mitochondrial disease.


Assuntos
Encefalopatias/genética , Complexo I de Transporte de Elétrons/deficiência , Doença de Leigh/genética , Doenças Mitocondriais/genética , Mutação/genética , Sequência de Aminoácidos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Complexo I de Transporte de Elétrons/química , Complexo I de Transporte de Elétrons/genética , Feminino , Fibroblastos/enzimologia , Fibroblastos/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Fosforilação Oxidativa , Linhagem , Porinas/metabolismo
9.
Nature ; 554(7690): 128-132, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29364879

RESUMO

Folates enable the activation and transfer of one-carbon units for the biosynthesis of purines, thymidine and methionine. Antifolates are important immunosuppressive and anticancer agents. In proliferating lymphocytes and human cancers, mitochondrial folate enzymes are particularly strongly upregulated. This in part reflects the need for mitochondria to generate one-carbon units and export them to the cytosol for anabolic metabolism. The full range of uses of folate-bound one-carbon units in the mitochondrial compartment itself, however, has not been thoroughly explored. Here we show that loss of the catalytic activity of the mitochondrial folate enzyme serine hydroxymethyltransferase 2 (SHMT2), but not of other folate enzymes, leads to defective oxidative phosphorylation in human cells due to impaired mitochondrial translation. We find that SHMT2, presumably by generating mitochondrial 5,10-methylenetetrahydrofolate, provides methyl donors to produce the taurinomethyluridine base at the wobble position of select mitochondrial tRNAs. Mitochondrial ribosome profiling in SHMT2-knockout human cells reveals that the lack of this modified base causes defective translation, with preferential mitochondrial ribosome stalling at certain lysine (AAG) and leucine (UUG) codons. This results in the impaired expression of respiratory chain enzymes. Stalling at these specific codons also occurs in certain inborn errors of mitochondrial metabolism. Disruption of whole-cell folate metabolism, by either folate deficiency or antifolate treatment, also impairs the respiratory chain. In summary, mammalian mitochondria use folate-bound one-carbon units to methylate tRNA, and this modification is required for mitochondrial translation and thus oxidative phosphorylation.


Assuntos
Ácido Fólico/metabolismo , Mitocôndrias/metabolismo , Biossíntese de Proteínas , RNA de Transferência/química , RNA de Transferência/metabolismo , Aminoidrolases/metabolismo , Biocatálise , Proteínas de Transporte/metabolismo , Códon/genética , Transporte de Elétrons , Antagonistas do Ácido Fólico/farmacologia , Proteínas de Ligação ao GTP/metabolismo , Glicina Hidroximetiltransferase/deficiência , Glicina Hidroximetiltransferase/metabolismo , Guanosina/metabolismo , Células HCT116 , Células HEK293 , Humanos , Leucina/genética , Lisina/genética , Metilação/efeitos dos fármacos , Metilenotetra-Hidrofolato Desidrogenase (NADP)/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/enzimologia , Enzimas Multifuncionais/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , RNA de Transferência/genética , Ribossomos/metabolismo , Sarcosina/metabolismo , Tetra-Hidrofolatos/metabolismo , Nucleotídeos de Timina/biossíntese
10.
Exp Dermatol ; 27(2): 204-207, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29131438

RESUMO

The Warburg theory of cancer postulates that an important driver of tumorigenesis is insufficient respiration due to mitochondrial defects, and concomitant enhancement of lactate production due to increased aerobic glycolysis. We analysed 48 melanoma samples by immunohistochemistry and found that 38% of melanomas are characterized by areas of isolated or combined deficiencies of complexes of the oxidative phosphorylation (OXPHOS) system, whereby the incidence of OXPHOS-deficient areas is associated with an increased Breslow index; 62% of melanomas showed high expression of all OXPHOS complexes. Expression of carbonic anhydrase IX was low, indicating that melanomas generally are well-oxygenated. Expression of HIF-1α and MCT4 was high, which might be a consequence of increased lactate dehydrogenase A levels in melanomas. Our data indicate that there are two types of melanomas: one that features a classic Warburg effect, whereas the other one, despite being glycolytic, maintains a high level of OXPHOS complexes.


Assuntos
Melanoma/metabolismo , Neoplasias Cutâneas/metabolismo , Antígenos de Neoplasias/metabolismo , Anidrase Carbônica IX/metabolismo , Perfilação da Expressão Gênica , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glicólise , Humanos , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Imuno-Histoquímica , Melanócitos , Mitocôndrias/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/metabolismo , Fosforilação Oxidativa , Oxigênio/química , Fenótipo , Fosforilação
11.
Ann Neurol ; 82(6): 1004-1015, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29205472

RESUMO

OBJECTIVE: 3-Methylglutaconic aciduria, dystonia-deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1. METHODS: This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported. RESULTS: Sixty-seven individuals (39 previously unreported) from 59 families were included (age range = 5 days-33.4 years, median age = 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in >40% of all cases. Starting at a median age of 6 months, muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset = 15 months) and dystonia (82%, 18 months). The majority of affected individuals never learned to walk (68%). Seventy-nine percent suffered hearing loss, 58% never learned to speak, and nearly all had significant intellectual disability (88%). Magnetic resonance imaging features were accordingly homogenous, with bilateral basal ganglia involvement (98%); the characteristic "putaminal eye" was seen in 53%. The urinary marker 3-methylglutaconic aciduria was present in virtually all patients (98%). Supportive treatment focused on spasticity and drooling, and was effective in the individuals treated; hearing aids or cochlear implants did not improve communication skills. INTERPRETATION: MEGDHEL syndrome is a progressive deafness-dystonia syndrome with frequent and reversible neonatal liver involvement and a strikingly homogenous course of disease. Ann Neurol 2017;82:1004-1015.


Assuntos
Hidrolases de Éster Carboxílico/genética , Transtornos da Surdocegueira/diagnóstico por imagem , Transtornos da Surdocegueira/genética , Progressão da Doença , Distonia/diagnóstico por imagem , Distonia/genética , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/genética , Mutação/genética , Atrofia Óptica/diagnóstico por imagem , Atrofia Óptica/genética , Adolescente , Adulto , Sequência de Aminoácidos , Criança , Pré-Escolar , Estudos de Coortes , Transtornos da Surdocegueira/terapia , Distonia/terapia , Feminino , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/terapia , Masculino , Atrofia Óptica/terapia , Adulto Jovem
12.
Oncotarget ; 8(39): 64728-64744, 2017 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-29029389

RESUMO

Neuroblastoma (NB) is a pediatric malignancy characterized by a marked reduction in aerobic energy metabolism. Recent preclinical data indicate that targeting this metabolic phenotype by a ketogenic diet (KD), especially in combination with calorie restriction, slows tumor growth and enhances metronomic cyclophosphamide (CP) therapy of NB xenografts. Because calorie restriction would be contraindicated in most cancer patients, the aim of the present study was to optimize the KD such that the tumors are sensitized to CP without the need of calorie restriction. In a NB xenograft model, metronomic CP was combined with KDs of different triglyceride compositions and fed to CD1-nu mice ad libitum. Metronomic CP in combination with a KD containing 8-carbon medium-chain triglycerides exerted a robust anti-tumor effect, suppressing growth and causing a significant reduction of tumor blood-vessel density and intratumoral hemorrhage, accompanied by activation of AMP-activated protein kinase in NB cells. Furthermore, the KDs caused a significant reduction in the serum levels of essential amino acids, but increased those of serine, glutamine and glycine. Our data suggest that targeting energy metabolism by a modified KD may be considered as part of a multimodal treatment regimen to improve the efficacy of classic anti-NB therapy.

13.
Hum Mutat ; 38(12): 1649-1659, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28940506

RESUMO

F-box and leucine-rich repeat protein 4 (FBXL4) is a mitochondrial protein whose exact function is not yet known. However, cellular studies have suggested that it plays significant roles in mitochondrial bioenergetics, mitochondrial DNA (mtDNA) maintenance, and mitochondrial dynamics. Biallelic pathogenic variants in FBXL4 are associated with an encephalopathic mtDNA maintenance defect syndrome that is a multisystem disease characterized by lactic acidemia, developmental delay, and hypotonia. Other features are feeding difficulties, growth failure, microcephaly, hyperammonemia, seizures, hypertrophic cardiomyopathy, elevated liver transaminases, recurrent infections, variable distinctive facial features, white matter abnormalities and cerebral atrophy found in neuroimaging, combined deficiencies of multiple electron transport complexes, and mtDNA depletion. Since its initial description in 2013, 36 different pathogenic variants in FBXL4 were reported in 50 affected individuals. In this report, we present 37 additional affected individuals and 11 previously unreported pathogenic variants. We summarize the clinical features of all 87 individuals with FBXL4-related mtDNA maintenance defect, review FBXL4 structure and function, map the 47 pathogenic variants onto the gene structure to assess the variants distribution, and investigate the genotype-phenotype correlation. Finally, we provide future directions to understand the disease mechanism and identify treatment strategies.


Assuntos
DNA Mitocondrial/genética , Proteínas F-Box/genética , Estudos de Associação Genética , Encefalomiopatias Mitocondriais/genética , Ubiquitina-Proteína Ligases/genética , Acidose Láctica/genética , Cardiomiopatia Hipertrófica/genética , Predisposição Genética para Doença , Humanos , Estimativa de Kaplan-Meier , Mitocôndrias/genética , Encefalomiopatias Mitocondriais/epidemiologia , Encefalomiopatias Mitocondriais/patologia , Proteínas Mitocondriais/genética , Hipotonia Muscular/genética , Mutação , Fosforilação Oxidativa , Proteoma/genética
14.
Hum Mutat ; 38(12): 1786-1795, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28905505

RESUMO

Mitochondrial protein synthesis involves an intricate interplay between mitochondrial DNA encoded RNAs and nuclear DNA encoded proteins, such as ribosomal proteins and aminoacyl-tRNA synthases. Eukaryotic cells contain 17 mitochondria-specific aminoacyl-tRNA synthases. WARS2 encodes mitochondrial tryptophanyl-tRNA synthase (mtTrpRS), a homodimeric class Ic enzyme (mitochondrial tryptophan-tRNA ligase; EC 6.1.1.2). Here, we report six individuals from five families presenting with either severe neonatal onset lactic acidosis, encephalomyopathy and early death or a later onset, more attenuated course of disease with predominating intellectual disability. Respiratory chain enzymes were usually normal in muscle and fibroblasts, while a severe combined respiratory chain deficiency was found in the liver of a severely affected individual. Exome sequencing revealed rare biallelic variants in WARS2 in all affected individuals. An increase of uncharged mitochondrial tRNATrp and a decrease of mtTrpRS protein content were found in fibroblasts of affected individuals. We hereby define the clinical, neuroradiological, and metabolic phenotype of WARS2 defects. This confidently implicates that mutations in WARS2 cause mitochondrial disease with a broad spectrum of clinical presentation.


Assuntos
Aminoacil-tRNA Sintetases/genética , Variação Genética , Deficiência Intelectual/genética , Doenças Mitocondriais/genética , Encefalomiopatias Mitocondriais/genética , Sequência de Aminoácidos , Aminoacil-tRNA Sintetases/metabolismo , Exoma/genética , Feminino , Humanos , Recém-Nascido , Deficiência Intelectual/enzimologia , Masculino , Doenças Mitocondriais/enzimologia , Encefalomiopatias Mitocondriais/enzimologia , Encefalomiopatias Mitocondriais/patologia , Modelos Moleculares , Mutação , Linhagem , Fenótipo , Gravidez , Alinhamento de Sequência , Sequenciamento Completo do Exoma
15.
Oncotarget ; 8(34): 57201-57215, 2017 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-28915665

RESUMO

The ketogenic diet (KD), a high-fat low-carbohydrate diet, has shown some efficacy in the treatment of certain types of tumors such as brain tumors and neuroblastoma. These tumors are characterized by the Warburg effect. Because renal cell carcinoma (RCC) presents similar energetic features as neuroblastoma, KD might also be effective in the treatment of RCC. To test this, we established xenografts with RCC 786-O cells in CD-1 nu/nu mice and then randomized them to a control diet or to KDs with different triglyceride contents. Although the KDs tended to reduce tumor growth, mouse survival was dramatically reduced due to massive weight loss. A possible explanation comes from observations of human RCC patients, who often experience secondary non-metastatic hepatic dysfunction due to secretion of high levels of inflammatory cytokines by the RCCs. Measurement of the mRNA levels of tumor necrosis factor alpha (TNFα) and interleukin-6 revealed high expression in the RCC xenografts compared to the original 786-O cells. The expression of TNFα, interleukin-6 and C-reactive protein were all increased in the livers of tumor-bearing mice, and KD significantly boosted their expression. KDs did not cause weight loss or liver inflammation in healthy mice, suggesting that KDs are per se safe, but might be contraindicated in the treatment of RCC patients presenting with Stauffer's syndrome, because they potentially worsen the associated hepatic dysfunction.

16.
Am J Hum Genet ; 101(4): 525-538, 2017 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-28942965

RESUMO

Complement component 1 Q subcomponent-binding protein (C1QBP; also known as p32) is a multi-compartmental protein whose precise function remains unknown. It is an evolutionary conserved multifunctional protein localized primarily in the mitochondrial matrix and has roles in inflammation and infection processes, mitochondrial ribosome biogenesis, and regulation of apoptosis and nuclear transcription. It has an N-terminal mitochondrial targeting peptide that is proteolytically processed after import into the mitochondrial matrix, where it forms a homotrimeric complex organized in a doughnut-shaped structure. Although C1QBP has been reported to exert pleiotropic effects on many cellular processes, we report here four individuals from unrelated families where biallelic mutations in C1QBP cause a defect in mitochondrial energy metabolism. Infants presented with cardiomyopathy accompanied by multisystemic involvement (liver, kidney, and brain), and children and adults presented with myopathy and progressive external ophthalmoplegia. Multiple mitochondrial respiratory-chain defects, associated with the accumulation of multiple deletions of mitochondrial DNA in the later-onset myopathic cases, were identified in all affected individuals. Steady-state C1QBP levels were decreased in all individuals' samples, leading to combined respiratory-chain enzyme deficiency of complexes I, III, and IV. C1qbp-/- mouse embryonic fibroblasts (MEFs) resembled the human disease phenotype by showing multiple defects in oxidative phosphorylation (OXPHOS). Complementation with wild-type, but not mutagenized, C1qbp restored OXPHOS protein levels and mitochondrial enzyme activities in C1qbp-/- MEFs. C1QBP deficiency represents an important mitochondrial disorder associated with a clinical spectrum ranging from infantile lactic acidosis to childhood (cardio)myopathy and late-onset progressive external ophthalmoplegia.


Assuntos
Cardiomiopatias/genética , Proteínas de Transporte/genética , Transporte de Elétrons/fisiologia , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Mutação , Adulto , Idade de Início , Idoso , Alelos , Sequência de Aminoácidos , Animais , Cardiomiopatias/complicações , Cardiomiopatias/patologia , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Células Cultivadas , Pré-Escolar , Estudos de Coortes , DNA Mitocondrial , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/patologia , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Recém-Nascido , Masculino , Camundongos , Pessoa de Meia-Idade , Doenças Mitocondriais/complicações , Doenças Mitocondriais/patologia , Proteínas Mitocondriais/química , Proteínas Mitocondriais/metabolismo , Fosforilação Oxidativa , Linhagem , Conformação Proteica , Homologia de Sequência , Índice de Gravidade de Doença , Adulto Jovem
17.
Oxid Med Cell Longev ; 2017: 7202589, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28804536

RESUMO

Vertebrate respiratory chain complex III consists of eleven subunits. Mutations in five subunits either mitochondrial (MT-CYB) or nuclear (CYC1, UQCRC2, UQCRB, and UQCRQ) encoded have been reported. Defects in five further factors for assembly (TTC19, UQCC2, and UQCC3) or iron-sulphur cluster loading (BCS1L and LYRM7) cause complex III deficiency. Here, we report a second patient with UQCC2 deficiency. This girl was born prematurely; pregnancy was complicated by intrauterine growth retardation and oligohydramnios. She presented with respiratory distress syndrome, developed epileptic seizures progressing to status epilepticus, and died at day 33. She had profound lactic acidosis and elevated urinary pyruvate. Exome sequencing revealed two homozygous missense variants in UQCC2, leading to a severe reduction of UQCC2 protein. Deficiency of complexes I and III was found enzymatically and on the protein level. A review of the literature on genetically distinct complex III defects revealed that, except TTC19 deficiency, the biochemical pattern was very often a combined respiratory chain deficiency. Besides complex III, typically, complex I was decreased, in some cases complex IV. In accordance with previous observations, the presence of assembled complex III is required for the stability or assembly of complexes I and IV, which might be related to respirasome/supercomplex formation.


Assuntos
Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Fibroblastos/metabolismo , Encefalomiopatias Mitocondriais/metabolismo , ATPases Associadas a Diversas Atividades Celulares/genética , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Western Blotting , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Complexo III da Cadeia de Transporte de Elétrons/genética , Eletroforese em Gel de Poliacrilamida , Feminino , Humanos , Recém-Nascido , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Encefalomiopatias Mitocondriais/genética , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo
18.
Mitochondrion ; 37: 55-61, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28694194

RESUMO

LYRM7 is involved in the last steps of mitochondrial complex III assembly where it acts as a chaperone for the Rieske iron­sulfur (Fe-S) protein in the mitochondrial matrix. Using exome sequencing, we identified homozygosity for a splice site destroying 4 base pair deletion in LYRM7 in a child with recurrent lactic acidotic crises and distinct early-onset leukencephalopathy. Sanger sequencing showed variant segregation in similarly affected family members. Functional analyses revealed a reduced amount of the Rieske Fe-S protein, which was restored after re-expression of LYRM7. Our data provide further evidence for the importance of LYRM7 for mitochondrial function and emphasize the importance of whole exome sequencing in the diagnosis of rare mitochondrial diseases.


Assuntos
Complexo III da Cadeia de Transporte de Elétrons/deficiência , Mitocôndrias/enzimologia , Mitocôndrias/metabolismo , Doenças Mitocondriais/genética , Doenças Mitocondriais/patologia , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Acidose Láctica/complicações , Acidose Láctica/genética , Acidose Láctica/patologia , Pré-Escolar , Complexo III da Cadeia de Transporte de Elétrons/análise , Feminino , Humanos , Lactente , Leucoencefalopatias/complicações , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Deleção de Sequência
19.
Oxid Med Cell Longev ; 2017: 1320241, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28744336

RESUMO

Switching of cellular energy production from oxidative phosphorylation (OXPHOS) by mitochondria to aerobic glycolysis occurs in many types of tumors. However, the significance of this switching for the development of gastric carcinoma and what connection it may have to Helicobacter pylori infection of the gut, a primary cause of gastric cancer, are poorly understood. Therefore, we investigated the expression of OXPHOS complexes in two types of human gastric carcinomas ("intestinal" and "diffuse"), bacterial gastritis with and without metaplasia, and chemically induced gastritis by using immunohistochemistry. Furthermore, we analyzed the effect of HP infection on several key mitochondrial proteins. Complex I expression was significantly reduced in intestinal type (but not diffuse) gastric carcinomas compared to adjacent control tissue, and the reduction was independent of HP infection. Significantly, higher complex I and complex II expression was present in large tumors. Furthermore, higher complex II and complex III protein levels were also obvious in grade 3 versus grade 2. No differences of OXPHOS complexes and markers of mitochondrial biogenesis were found between bacterially caused and chemically induced gastritis. Thus, intestinal gastric carcinomas, but not precancerous stages, are frequently characterized by loss of complex I, and this pathophysiology occurs independently of HP infection.


Assuntos
Complexo I de Transporte de Elétrons/biossíntese , Gastrite/enzimologia , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Infecções por Helicobacter/enzimologia , Helicobacter pylori , Proteínas de Neoplasias/biossíntese , Fosforilação Oxidativa , Neoplasias Gástricas/enzimologia , Feminino , Gastrite/patologia , Infecções por Helicobacter/patologia , Humanos , Masculino , Neoplasias Gástricas/patologia
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