RESUMEN
Mitochondrial impairment is hypothesized to be involved in chronic fatigue syndrome (CFS) and schizophrenia. We performed a clinical, genetic and functional mitochondrial study in a family consisting of a female presenting schizophrenia in addition to CFS symptoms and her mother and older sister, both presenting with CFS. The three family members showed higher blood lactate levels, higher mitochondrial mass, lower mtDNA content and overall lower mitochondrial enzymatic activities and lower oxygen consumption capacities than healthy women. This family presented mtDNA depletion; however, no mutation was identified neither in the mtDNA nor in the nuclear genes related with mtDNA depletion, even though C16179A and T16519A variants should be further studied.
Asunto(s)
Salud de la Familia , Síndrome de Fatiga Crónica/complicaciones , Síndrome de Fatiga Crónica/patología , Mitocondrias/patología , Trastornos Psicóticos/complicaciones , Trastornos Psicóticos/patología , Adulto , Anciano , Respiración de la Célula , ADN Mitocondrial/análisis , Enzimas/análisis , Femenino , Humanos , Ácido Láctico/sangre , Persona de Mediana Edad , Mitocondrias/enzimología , Oxígeno/metabolismoRESUMEN
BACKGROUND: Antiretroviral (ARV)-associated mitochondrial toxicity in HIV/ARV-exposed healthy infants is a concern. Clinically relevant toxicity is rare. Hyperlactatemia is common but nonspecific, both increased and decreased mitochondrial DNA (mtDNA) level has been reported. Mitochondrial function has scarcely been investigated. METHODS: In a prospective observational study of 133 HIV/ARV-exposed infants, mtDNA content was measured with quantitative real-time polymerase chain reaction, and mitochondrial respiratory chain enzymatic activity of complex IV (CIV) and mitochondrial mass (MM) were assessed spectrophotometrically from cryopreserved peripheral blood mononuclear cells obtained at 6 weeks and 3, 6 and 12 months of age and compared with a control group. RESULTS: Most mothers (88%) received combined ARV therapy during pregnancy, and 92% of infants received zidovudine monotherapy. No infant had clinical evidence of mitochondrial disease during follow-up. Nonsignificant higher MM and lower mtDNA levels (normalized by MM) were observed over time in HIV/ARV-exposed infants. MM-normalized CIV activity was consistently lower in HIV/ARV-exposed children than in controls over time (0.09 vs. 0.35, 0.12 vs. 0.38, 0.13 vs. 0.24 and 0.14 vs. 0.24 nmol/min/mg at 6 weeks and 3, 6 and 12 months; P = 0.014, P < 0.0001, P = 0.065 and P = 0.011, respectively) and showed a linear trend toward normalization with age (P < 0.01). In HIV/ARV-exposed infants, an inverse correlation between CIV activity and mtDNA levels was observed until 6 months of age (r = -0.327, P = 0.016; r = -0.311, P = 0.040 and r = -0.275, P = 0.046). CONCLUSIONS: Mitochondrial-encoded CIV activity was consistently lower among HIV/ARV-exposed healthy infants and inversely correlated with mtDNA levels, suggesting upregulation of the latter.
Asunto(s)
Antirretrovirales/efectos adversos , ADN Mitocondrial/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Mitocondrias/efectos de los fármacos , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Antirretrovirales/uso terapéutico , ADN Mitocondrial/análisis , ADN Mitocondrial/genética , Femenino , Humanos , Lactante , Recién Nacido , Mitocondrias/enzimología , Mitocondrias/fisiología , Embarazo , Estudios ProspectivosRESUMEN
BACKGROUND: Mitochondrial consequences from foetal exposure to HIV infection and antiretrovirals could be further investigated. OBJECTIVE: The main objective of this study was to evaluate maternofoetal mitochondrial disturbances in HIV infection and antiretroviral administration in human pregnancies as the aetiopathogenic basis of suboptimal perinatal-clinical features. DESIGN: Cross-sectional, prospective, observational, exploratory and controlled study. METHODS: Clinical/epidemiological data of 35 HIV-infected pregnant women and 17 controls were collected. Mitochondrial DNA (mtDNA) and RNA (mtRNA) content (real time-PCR), enzymatic activities and content (spectrophotometry) were measured in leucocytes. Genetic-functional, maternofoetal and molecular-clinical correlations were assessed. RESULTS: Birth weight was lower in infants from HIV-infected mothers compared with controls. MtDNA values were slightly decreased in HIV cases, although not reaching statistical significance. MtRNA values were lower in HIV-infected mothers. Similarly, binary complex II+III enzymatic activity decreased to 50% in both HIV-infected mothers (44.45â±â3.77%) and their infants (48.79â±â3.41%) (Pâ=â0.001 and Pâ<â0.001). Global CI+III+IV enzymatic activity was lower in HIV-infected mothers and infants (90.43â±â2.39% and 51.16â±â9.30%) (Pâ<â0.005 and Pâ<â0.05). MtDNA content correlated with function in mothers and infants. Maternofoetal parameters correlated at genetic and functional levels. CONCLUSION: HAART toxicity caused mitochondrial damage in HIV-infected pregnant women and their newborns, being present at a genetic and functional level with a maternofoetal correlation.
Asunto(s)
Fármacos Anti-VIH/efectos adversos , Terapia Antirretroviral Altamente Activa/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Mitocondrias/efectos de los fármacos , Complicaciones Infecciosas del Embarazo/virología , Adulto , Fármacos Anti-VIH/uso terapéutico , Estudios Transversales , ADN Mitocondrial/genética , Femenino , Infecciones por VIH/transmisión , Humanos , Lactante , Recién Nacido , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Leucocitos Mononucleares/citología , Masculino , Mitocondrias/genética , Embarazo , Estudios Prospectivos , ARN/genética , ARN MitocondrialRESUMEN
Mitochondrial toxicity in perinatally human immunodeficiency virus (HIV)-infected pediatric patients has been scarcely investigated. Limited data are available about HIV or antiretroviral (ARV)-mediated mitochondrial damage in this population group, specifically, regarding oxygen consumption and apoptosis approach. We aimed to elucidate whether a given mitochondrial DNA depletion is reflected at downstream levels, to gain insight on the pathology of HIV and highly active antiretroviral therapy (HAART) in perinatally HIV-infected pediatric patients. We studied 10 healthy control participants and 20 perinatally HIV-infected pediatric patients (10 under ARV treatment and 10 off treatment). We determined mitochondrial mass, subunits II and IV of complex IV, global and specific mitochondrial enzymatic and oxidative activities, and apoptosis from peripheral blood mononuclear cells. Global oxygen consumption was significantly compromised in HIV-infected untreated patients, compared to the control group (0.76 ± 0.01 versus 1.59 ± 0.15; P = 0.014). Apoptosis showed a trend to increase in untreated patients as well. The overall complex (C) CI-III-IV activity of the mitochondrial respiratory chain (MRC) was significantly decreased in HIV-infected treated patients with respect to the control group (1.52 ± 0.38 versus 6.38 ± 1.53; P = 0.02). No statistically significant differences were found between untreated and HAART-treated patients. These findings suggest the pathogenic role of both HIV and HAART in mitochondrial dysfunction in vertical infection. The abnormalities in mitochondrial genome may be downstream reflected through a global alteration of the MRC. Mitochondrial impairment associated with HIV and HAART was generalized, rather than localized, in this series of perinatally HIV-infected patients.
Asunto(s)
Terapia Antirretroviral Altamente Activa/efectos adversos , Apoptosis/fisiología , Transporte de Electrón/fisiología , Infecciones por VIH/tratamiento farmacológico , Mitocondrias/efectos de los fármacos , Adolescente , Niño , Citrato (si)-Sintasa/metabolismo , Estudios Transversales , Transporte de Electrón/efectos de los fármacos , Citometría de Flujo , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Oxidación-Reducción , Consumo de Oxígeno/fisiología , España , Espectrofotometría , Estadísticas no ParamétricasRESUMEN
BACKGROUND: Highly active antiretroviral therapy (HAART) and HIV-related mitochondrial toxicity lead to several adverse effects and have become a major issue, especially in children. The main goal in the treatment of HIV-infected children is to maximize cost-effectiveness while minimizing toxicity. We aimed to study the evolution of mitochondrial parameters over time in children receiving different types antiretroviral regimens. METHODS: We followed-up 28 HIV-infected children receiving HAART including either first-generation nucleoside reverse transcriptase inhibitors (1gNRTIs; didanosine, zidovudine, or stavudine; n = 15) or second-generation NRTIs (2gNRTIs; the remaining drugs; n = 13) for a period of 2 years for their immunovirological and mitochondrial status, and compared these subjects with a group of untreated HIV-infected patients (n = 10) and uninfected controls (n = 27). We measured T-lymphocyte CD4+ content (flow cytometry), viral load (real-time polymerase chain reaction), and lactate levels (spectrophotometry); we assessed mtDNA content (real-time polymerase chain reaction), mitochondrial protein levels (Western blot), oxidative stress, mitochondrial mass, and electron transport chain function (spectrophotometry) in peripheral blood mononuclear cells. RESULTS: At the second time point, lactate levels were significantly higher in children on 1gNRTIs compared with those receiving 2gNRTIs (1.28 ± 0.08 vs. 1.00 ± 0.07 mmol/L, respectively; P = 0.022). MtDNA content was similar among all HIV-infected groups and significantly lower than in healthy controls at baseline. Oxidative stress tended to increase over time in all the groups, with no differences among them. However, a significant decrease in cytochrome c oxidase activity was found over time in HIV-infected patients; this decline was greater in the 1gNRTIs group. CONCLUSIONS: HIV infection and the use of 1gNRTIs caused greater mitochondrial damage than 2gNRTIs over time. The higher lactate levels and the significant decrease observed in cytochrome c oxidase activity argue against the use of 1gNRTIs in HIV-infected children when an alternative is available, in accordance with international recommendations.