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1.
Int J Mol Sci ; 24(16)2023 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-37628761

RESUMO

Leber's hereditary optic neuropathy (LHON) is a disease that affects the optical nerve, causing visual loss. The diagnosis of LHON is mostly defined by the identification of three pathogenic variants in the mitochondrial DNA. Idebenone is widely used to treat LHON patients, but only some of them are responders to treatment. In our study, we assessed the maximal respiration rate (MRR) and other respiratory parameters in eight fibroblast lines from subjects carrying LHON pathogenic variants. We measured also the effects of idebenone treatment on cell growth and mtDNA amounts. Results showed that LHON fibroblasts had significantly reduced respiratory parameters in untreated conditions, but no significant gain in MRR after idebenone supplementation. No major toxicity toward mitochondrial function and no relevant compensatory effect in terms of mtDNA quantity were found for the treatment at the tested conditions. Our findings confirmed that fibroblasts from subjects harboring LHON pathogenic variants displayed impaired respiration, regardless of the disease penetrance and severity. Testing responsiveness to idebenone treatment in cultured cells did not fully recapitulate in vivo data. The in-depth evaluation of cellular respiration in fibroblasts is a good approach to evaluating novel mtDNA variants associated with LHON but needs further evaluation as a potential biomarker for disease prognosis and treatment responsiveness.


Assuntos
Atrofia Óptica Hereditária de Leber , Humanos , Atrofia Óptica Hereditária de Leber/tratamento farmacológico , Atrofia Óptica Hereditária de Leber/genética , DNA Mitocondrial/genética , Mitocôndrias/genética , Fibroblastos
2.
Hum Mutat ; 41(10): 1745-1750, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32652806

RESUMO

Biallelic mutations in the C1QBP gene have been associated with mitochondrial cardiomyopathy and combined respiratory-chain deficiencies, with variable onset (including intrauterine or neonatal forms), phenotypes, and severity. We studied two unrelated adult patients from consanguineous families, presenting with progressive external ophthalmoplegia (PEO), mitochondrial myopathy, and without any heart involvement. Muscle biopsies from both patients showed typical mitochondrial alterations and the presence of multiple mitochondrial DNA deletions, whereas biochemical defects of the respiratory chain were present only in one subject. Using next-generation sequencing approaches, we identified homozygous mutations in C1QBP. Immunoblot analyses in patients' muscle samples revealed a strong reduction in the amount of the C1QBP protein and varied impairment of respiratory chain complexes, correlating with disease severity. Despite the original study indicated C1QBP mutations as causative for mitochondrial cardiomyopathy, our data indicate that mutations in C1QBP have to be considered in subjects with PEO phenotype or primary mitochondrial myopathy and without cardiomyopathy.


Assuntos
Proteínas de Transporte , Miopatias Mitocondriais , Proteínas Mitocondriais , Oftalmoplegia Externa Progressiva Crônica , Oftalmoplegia , Proteínas de Transporte/genética , DNA Mitocondrial/genética , Homozigoto , Humanos , Miopatias Mitocondriais/genética , Proteínas Mitocondriais/genética , Mutação , Oftalmoplegia/genética , Oftalmoplegia Externa Progressiva Crônica/genética , Oftalmoplegia Externa Progressiva Crônica/patologia
3.
Scand J Clin Lab Invest ; 78(1-2): 18-24, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29168398

RESUMO

Obesity is independently associated with disturbances in lipid and lipoprotein metabolism, oxidative stress, and is a well-established independent risk factor for cardiovascular diseases (CVD). Human paraoxonase 1 (PON1) is a pleotropic high-density lipoprotein (HDL)-associated enzyme with antioxidant and anti-inflammatory proprieties that have been suggested to contribute to the athero-protective function of the lipoprotein. The aim of this study was to investigate whether obesity is associated with PON1 activity and whether this association is influenced by oxidative stress, inflammation and HDL cholesterol (HDL-C) concentration. The promiscuous activities, arylesterase and paraoxonase, and the putative physiological activity, lactonase, of PON1 were assessed in the serum of 214 obese and severely obese, 101 overweight and 129 normal-weight women. Levels of high-sensitivity C-reactive protein (hs-CRP), hydroperoxides (by-products of lipid oxidative damage) and lipid profiles were also evaluated. Arylesterase activity was the only activity that significantly differed across the groups (ANOVA, p < .01), with the greatest decrease observed in individuals with body mass index (BMI) > 40 kg/m2 compared to controls (p < .001). This activity was also inversely, although weakly (r = -0.160, p < .001) correlated with the BMI, and the association was independent of age and levels of oxidative stress and inflammation, but not of HDL-C concentration. In conclusion, our results suggest that the apparent obesity-associated decrement of PON1 activity might simply reflect the decrease in concentration of its plasmatic carrier.


Assuntos
Arildialquilfosfatase/sangue , Hidrolases de Éster Carboxílico/sangue , Obesidade/sangue , Obesidade/enzimologia , Antropometria , Índice de Massa Corporal , Feminino , Humanos , Pessoa de Meia-Idade , Análise de Regressão
4.
Stem Cell Res ; 77: 103406, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38552355

RESUMO

Leber hereditary optic neuropathy (LHON) is one of the most common mitochondrial illness, causing retinal ganglion cell degeneration and central vision loss. It stems from point mutations in mitochondrial DNA (mtDNA), with key mutations being m.3460G > A, m.11778G > A, and m.14484 T > C. Fibroblasts from identical twins, sharing m.14484 T > C and m.10680G > A variants each with 70 % heteroplasmy, were used to generate iPSC lines. Remarkably, one twin, a LHON patient, displayed symptoms, while the other, a carrier, remained asymptomatic. These iPSCs offer a valuable tool for studying factors influencing disease penetrance and unravelling the role of m.10680G > A, which is still debated.


Assuntos
DNA Mitocondrial , Células-Tronco Pluripotentes Induzidas , Atrofia Óptica Hereditária de Leber , Gêmeos Monozigóticos , Humanos , Atrofia Óptica Hereditária de Leber/genética , Atrofia Óptica Hereditária de Leber/patologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , DNA Mitocondrial/genética , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/genética , Feminino , Mutação Puntual , Adulto
5.
EMBO Mol Med ; 12(11): e12619, 2020 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-32969598

RESUMO

Leigh syndrome is a progressive neurodegenerative disorder, most commonly observed in paediatric mitochondrial disease, and is often associated with pathogenic variants in complex I structural subunits or assembly factors resulting in isolated respiratory chain complex I deficiency. Clinical heterogeneity has been reported, but key diagnostic findings are developmental regression, elevated lactate and characteristic neuroimaging abnormalities. Here, we describe three affected children from two unrelated families who presented with Leigh syndrome due to homozygous variants (c.346_*7del and c.173A>T p.His58Leu) in NDUFC2, encoding a complex I subunit. Biochemical and functional investigation of subjects' fibroblasts confirmed a severe defect in complex I activity, subunit expression and assembly. Lentiviral transduction of subjects' fibroblasts with wild-type NDUFC2 cDNA increased complex I assembly supporting the association of the identified NDUFC2 variants with mitochondrial pathology. Complexome profiling confirmed a loss of NDUFC2 and defective complex I assembly, revealing aberrant assembly intermediates suggestive of stalled biogenesis of the complex I holoenzyme and indicating a crucial role for NDUFC2 in the assembly of the membrane arm of complex I, particularly the ND2 module.


Assuntos
Doença de Leigh , Doenças Mitocondriais , Alelos , Criança , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismo , Humanos , Doença de Leigh/genética , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Mutação
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