RESUMO
AIM: Hereditary hemochromatosis (HH) is a group of inherited disorders that causes a slow and progressive iron deposition in diverse organs, particularly in the liver. Iron overload induces oxidative stress and tissue damage. Coenzyme Q10 (CoQ10) is a cofactor in the electron-transport chain of the mitochondria, but it is also a potent endogenous antioxidant. CoQ10 interest has recently grown since various studies show that CoQ10 supplementation may provide protective and safe benefits in mitochondrial diseases and oxidative stress disorders. In the present study we sought to determine CoQ10 plasma level in patients recently diagnosed with HH and to correlate it with biochemical, genetic, and histological features of the disease. METHODS: Plasma levels of CoQ10, iron, ferritin, transferrin and vitamins (A, C and E), liver tests (transaminases, alkaline phosphatase and bilirubin), and histology, as well as three HFE gene mutations (H63D, S654C and C282Y), were assessed in thirty-eight patients (32 males, 6 females) newly diagnosed with HH without treatment and in twenty-five age-matched normolipidemic healthy subjects with no HFE gene mutations (22 males, 3 females) and without clinical or biochemical signs of iron overload or liver diseases. RESULTS: Patients with HH showed a significant decrease in CoQ10 levels respect to control subjects (0.31⯱â¯0.03 µM vs 0.70⯱â¯0.06 µM, pâ¯<â¯0.001, respectively) independently of the genetic mutation, cirrhosis, transferrin saturation, ferritin level or markers of hepatic dysfunction. Although a decreasing trend in CoQ10 levels was observed in patients with elevated iron levels, no correlation was found between both parameters in patients with HH. Vitamins C and A levels showed no changes in HH patients. Vitamin E was significantly decreased in HH patients (21.1⯱â¯1.3 µM vs 29.9⯱â¯2.5 µM, pâ¯<â¯0.001, respectively), but no correlation was observed with CoQ10 levels. CONCLUSION: The decrease in CoQ10 levels found in HH patients suggests that CoQ10 supplementation could be a safe intervention strategy complementary to the traditional therapy to ameliorate oxidative stress and further tissue damage induced by iron overload.
Assuntos
Ataxia , Hemocromatose , Doenças Mitocondriais , Debilidade Muscular , Ubiquinona/deficiência , Ataxia/epidemiologia , Estudos de Casos e Controles , Feminino , Hemocromatose/sangue , Hemocromatose/epidemiologia , Hemocromatose/genética , Humanos , Masculino , Doenças Mitocondriais/epidemiologia , Debilidade Muscular/epidemiologia , Ubiquinona/análogos & derivados , Ubiquinona/sangueRESUMO
Oxidative stress (OS) and mitochondrial dysfunction (MD) have been extensively studied and defined as therapeutic targets in Down syndrome (DS). Though originally associated to individual genes located in supernumerary chromosome 21, OS and MD metabolic compromises appear to be linked to whole genome functionally defined transcriptional fingerprints that further exacerbate the contribution of critical genes in DS-AD pathology. As the main ROS generator, mitochondrial complex double-membrane organization, tightly regulated fission/fusion dynamics, and involvement in critical pathways, makes it particularly vulnerable to functional alterations. Consequently, mitochondrial network morphology depends on its metabolic state and has been used as an indicator of cellular homeostasis. Initial qualitative categorization, suitable for sparse arranged fragments analysis, were proven to be ineffective to measure network connectivity and replaced by innovative tools that involve the transformation of raw images to linear skeletons. These manipulations allowed the development of a new generation of structural parameters, such as mean degree value (MDV). Alterations in DS mitochondrial networks include increased frequency of aberrant morphologies, shorter mitochondrial fragments, and significantly lower mitochondrial network connectivity. Similar structural and functional mitochondrial defects are common to other neurodegenerative diseases, such as Parkinson disease and Prion disease, and to a progeroid syndrome like HGPS. Therapeutic interventions aimed to either increase mitochondrial biogenesis or diminish OS using mitochondrial-targeted antioxidants, successfully restored mitochondrial activity and structural organization, confirming the strong correlation between network form and function.
Assuntos
Síndrome de Down/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doenças Mitocondriais/metabolismo , Estresse Oxidativo/fisiologia , Animais , Síndrome de Down/epidemiologia , Síndrome de Down/genética , Humanos , Mitocôndrias/genética , Doenças Mitocondriais/epidemiologia , Doenças Mitocondriais/genéticaRESUMO
OBJECTIVE: To determine the frequency, type, and severity of cardiac involvement in pediatric patients with oxidative phosphorylation (OXPHOS) disorders. STUDY DESIGN: Retrospective review of clinical and laboratory records of all patients with definitive OXPHOS disorders diagnosed and treated at the Royal Children's Hospital in Melbourne between 1984 and 2005. RESULTS: Of a total of 89 patients (male:female ratio 1.5:1) 29 (33%) had cardiac involvement: 9 as presenting symptoms, 9 developing on follow-up, and 11 with subclinical cardiac findings. Leigh or Leigh-like syndrome and complex I and combined complex I, III, and IV deficiencies were the most common clinical and laboratory diagnoses, respectively. Clinically symptomatic patients had hypertrophic cardiomyopathy (5 patients), dilated cardiomyopathy (4 patients), combined ventricular hypertrophy and systolic dysfunction (3 patients), and left ventricular noncompaction (3 patients) at first assessment. A change in the type of cardiomyopathy was noted on follow-up in 2 patients. Conduction and rhythm abnormalities were present in 7 symptomatic patients. CONCLUSIONS: Cardiac assessment in children with OXPHOS disorders may reveal subclinical abnormalities of cardiac function. Patients who present with primary cardiac features have a poor prognosis. OXPHOS disorders should be considered in the differential diagnosis of children presenting with otherwise unexplained cardiomyopathy.
Assuntos
Cardiopatias/epidemiologia , Doenças Mitocondriais/epidemiologia , Adolescente , Idade de Início , Causalidade , Criança , Pré-Escolar , Estudos de Coortes , Comorbidade , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Doenças Mitocondriais/classificação , Prevalência , Estudos Retrospectivos , Distribuição por Sexo , Análise de Sobrevida , Vitória/epidemiologiaRESUMO
In 1992-1994, a disorder known as the epidemic neuropathy afflicted more than 50,000 Cubans. Three different forms of the illness were identified: epidemic optic neuropathy, peripheral neuropathy and mixed optic and peripheral neuropathy. The causes are still unknown. Skeletal muscle biopsy samples were analyzed by standard histological techniques and by biochemical assays. Elevated activities of citrate synthase, a non-respiratory-chain mitochondrial matrix enzyme, suggested possible mitochondrial proliferation in 7 of the 8 patients. Nicotinamide adenine dinucleotide phosphate (NADP(+)) levels were higher in the patients than in the controls (p = 0.04). Levels of nicotinamide adenine dinucleotide (NAD) and the reduced compounds NADH and NADPH were comparable in patients and controls. Elevations of succinate dehydrogenase and citrate synthase activities and high NADP(+) levels suggest that alterations of mitochondrial functions may be associated with this disorder.