Organization of the respiratory supercomplexes in cells with defective complex III: Structural features and metabolic consequences

The mitochondrial respiratory chain encompasses four oligomeric enzymatic complexes (complex I, II, III and IV) which, together with the redox carrier ubiquinone and cytochrome c, catalyze electron transport coupled to proton extrusion from the inner membrane. The protonmotive force is utilized by complex V for ATP synthesis in the process of oxidative phosphorylation. Respiratory complexes are known to coexist in the membrane as single functional entities and as supramolecular aggregates or supercomplexes (SCs). Understanding the assembly features of SCs has relevant biomedical implications because defects in a single protein can derange the overall SC organization and compromise the energetic function, causing severe mitochondrial disorders. Here we describe in detail the main types of SCs, all characterized by the presence of complex III. We show that the genetic alterations that hinder the assembly of Complex III, not just the activity, cause a rearrangement of the architecture of the SC that can help to preserve a minimal energetic function. Finally, the major metabolic disturbances associated with severe SCs perturbation due to defective complex III are discussed along with interventions that may circumvent these deficiencies

Application Of Continuous Positive Airway Pressure In The Delivery Room: A Multicenter Randomized Clinical Trial.

This study evaluated whether the use of continuous positive airway pressure (CPAP) in the delivery room alters the need for mechanical ventilation and surfactant during the first 5 days of life and modifies the incidence of respiratory morbidity and mortality during the hospital stay. The study was a multicenter randomized clinical trial conducted in five public university hospitals in Brazil, from June 2008 to December 2009. Participants were 197 infants with birth weight of 1000-1500 g and without major birth defects. They were treated according to the guidelines of the American Academy of Pediatrics (APP). Infants not intubated or extubated less than 15 min after birth were randomized for two treatments, routine or CPAP, and were followed until hospital discharge. The routine (n=99) and CPAP (n=98) infants studied presented no statistically significant differences regarding birth characteristics, complications during the prenatal period, the need for mechanical ventilation during the first 5 days of life (19.2 vs 23.4%, P=0.50), use of surfactant (18.2 vs 17.3% P=0.92), or respiratory morbidity and mortality until discharge. The CPAP group required a greater number of doses of surfactant (1.5 vs 1.0, P=0.02). When CPAP was applied to the routine group, it was installed within a median time of 30 min. We found that CPAP applied less than 15 min after birth was not able to reduce the need for ventilator support and was associated with a higher number of doses of surfactant when compared to CPAP applied as clinically indicated within a median time of 30 min.47259-6

Quality of life of asthmatic children and adolescents: relation to maternal coping

OBJECTIVE: To evaluate the quality of life of asthmatic children and adolescents, its relation with sociodemographic and clinical variables, and maternal coping strategies. METHODS: Cross-sectional study in which children and adolescents with asthma answered a quality of life questionnaire, and their mothers did the same with a coping scale. RESULTS: Out of the 42 children and adolescents investigated, 74% were classified as having mild/severe persistent asthma; 19%, mild persistent asthma; and 7%, intermittent asthma. A total of 69% of the participants showed impaired quality of life with mean scores ranging between 4.7 and 3.5, with greater harm in the domain of symptoms (score=3.6). There was a significant association between maternal schooling and the general index of quality of life, whereas maternal coping strategies were not associated with the severity of asthma. A large number of strategies used by mothers to cope with their children's crises were related to the management of stressors or to religious practices, and the latter presented negative correlation with the children's quality of life general index, showing that mothers whose children had worse quality of life used more religious coping. CONCLUSIONS: Asthmatic children, particularly those with moderate/severe persistent asthma, showed significant alterations as to quality of life. The high percentage of mothers using religious strategies, particularly in face of more severe clinical conditions, seem to indicate that they feel powerless to act, thus requiring concrete and useful orientation to low income families.OBJETIVO: Avaliar a qualidade de vida de crianças e adolescentes asmáticos, sua relação com variáveis sociodemográficas e clínicas e estratégias de enfrentamento materno. MÉTODOS: Estudo transversal no qual crianças e adolescentes com asma responderam a um questionário de qualidade de vida, e suas mães a uma escala de enfrentamento. RESULTADOS: Foram estudadas 42 crianças e adolescentes com idades entre 7 e 15 anos, sendo 74% classificados como tendo um quadro de asma persistente moderada/grave, 19% como persistente leve e 7% asma intermitente; 69% dos entrevistados apresentaram prejuízo na qualidade de vida, com escores médios variando de 4,7 a 3,5 e maior prejuízo no domínio sintomas (escore=3,6). Houve associação significativa entre escolaridade materna e índice geral de qualidade de vida, mas não entre gravidade da asma e tipo de enfrentamento materno. Grande parte das estratégias utilizadas pelas mães para enfrentar as crises do filho estava direcionada ao manejo de estressores ou práticas religiosas, estas com correlação negativa com o índice geral de qualidade de vida da criança, sinalizando que mães cujos filhos tinham pior qualidade de vida usavam mais enfrentamentos religiosos. CONCLUSÕES: Crianças asmáticas, especialmente com asma persistente moderada/grave, apresentaram alterações significativas em sua qualidade de vida. A alta porcentagem de uso de estratégias religiosas por parte das mães, especialmente frente a quadros mais graves, parece indicar que elas se sentem impotentes para atuar, necessitando de orientações concretas e factíveis para uma população de baixa renda.OBJETIVO: Evaluar la calidad de vida de niños y adolescentes asmáticos, su relación con variables sociodemográficas, clínicas y estratégicas de enfrentamiento materno. MÉTODOS: Estudio transversal en el que niños y adolescentes con asma contestaron un cuestionario de calidad de vida (PAQLQ-A) y sus madres a una escala de enfrentamiento (EMEP). RESULTADOS: Se estudiaron 42 niños y adolescentes con edad de 7-15 años y, entre ellos, el 74% fueron clasificados como teniendo un cuadro de asma persistente moderada/grave, el 19% como persistente y el 7% asma intermitente; el 69% de los entrevistados presentaron perjuicio en la calidad de vida, con escores medianos variando de 4,7 a 3,5 y mayor perjuicio en el dominio de síntomas (escore=3,6). Hubo asociación significativa entre escolaridad materna e índice general de calidad de vida, pero no hubo asociación entre gravedad del asma y tipo de enfrentamiento materno. Gran parte de las estrategias utilizadas por las madres para enfrentar las crisis de los hijos estaba dirigida al manejo de estresores o prácticas religiosas. Estas últimas con correlación negativa con el índice general de calidad de vida del niño, señalizando que madres cuyos hijos tenían peor calidad de vida usaban más enfrentamientos religiosos. CONCLUSIONES: Niños asmáticos, especialmente con asma persistente moderada/grave, presentaron alteraciones significativas en su calidad de vida. El alto porcentaje de uso de estrategias religiosas por parte de las madres, especialmente frente a cuadros más graves, parece indicar que ellas se sienten impotentes para actuar, necesitando de orientaciones concretas y factibles para una población de bajos ingresos.14515

OPA1 mutations induce mitochondrial DNA instability and optic atrophy ‘plus’ phenotypes

Mutations in OPA1, a dynamin-related GTPase involved in mitochondrial fusion, cristae organization and control of apoptosis, have been linked to non-syndromic optic neuropathy transmitted as an autosomal-dominant trait (DOA). We here report on eight patients from six independent families showing that mutations in the OPA1 gene can also be responsible for a syndromic form of DOA associated with sensorineural deafness, ataxia, axonal sensory-motor polyneuropathy, chronic progressive external ophthalmoplegia and mitochondrial myopathy with cytochrome c oxidase negative and Ragged Red Fibres. Most remarkably, we demonstrate that these patients all harboured multiple deletions of mitochondrial DNA (mtDNA) in their skeletal muscle, thus revealing an unrecognized role of the OPA1 protein in mtDNA stability. The five OPA1 mutations associated with these DOA ‘plus’ phenotypes were all mis-sense point mutations affecting highly conserved amino acid positions and the nuclear genes previously known to induce mtDNA multiple deletions such as POLG1, PEO1 (Twinkle) and SLC25A4 (ANT1) were ruled out. Our results show that certain OPA1 mutations exert a dominant negative effect responsible for multi-systemic disease, closely related to classical mitochondrial cytopathies, by a mechanism involving mtDNA instability

OPA1 links human mitochondrial genome maintenance to mtDNA replication and distribution

Eukaryotic cells harbor a small multiploid mitochondrial genome, organized in nucleoids spread within the mitochondrial network. Maintenance and distribution of mitochondrial DNA (mtDNA) are essential for energy metabolism, mitochondrial lineage in primordial germ cells, and to prevent mtDNA instability, which leads to many debilitating human diseases. Mounting evidence suggests that the actors of the mitochondrial network dynamics, among which is the intramitochondrial dynamin OPA1, might be involved in these processes. Here, using siRNAs specific to OPA1 alternate spliced exons, we evidenced that silencing of the OPA1 variants including exon 4b leads to mtDNA depletion, secondary to inhibition of mtDNA replication, and to marked alteration of mtDNA distribution in nucleoid and nucleoid distribution throughout the mitochondrial network. We demonstrate that a small hydrophobic 10-kDa peptide generated by cleavage of the OPA1-exon4b isoform is responsible for this process and show that this peptide is embedded in the inner membrane and colocalizes and coimmunoprecipitates with nucleoid components. We propose a novel synthetic model in which a peptide, including two trans-membrane domains derived from the N terminus of the OPA1-exon4b isoform in vertebrates or from its ortholog in lower eukaryotes, might contribute to nucleoid attachment to the inner mitochondrial membrane and promotes mtDNA replication and distribution. Thus, this study places OPA1 as a direct actor in the maintenance of mitochondrial genome integrity

Factors Associated with Height Catch-Up and Catch-Down Growth Among Schoolchildren

In developed countries, children with intrauterine growth restriction (IUGR) or born preterm (PT) tend to achieve catch-up growth. There is little information about height catch-up in developing countries and about height catch-down in both developed and developing countries. We studied the effect of IUGR and PT birth on height catch-up and catch-down growth of children from two cohorts of liveborn singletons. Data from 1,463 children was collected at birth and at school age in Ribeirão Preto (RP), a more developed city, and in São Luís (SL), a less developed city. A change in z-score between schoolchild height z-score and birth length z-score≥0.67 was considered catch-up; a change in z-score≤−0.67 indicated catch-down growth. The explanatory variables were: appropriate weight for gestational age/PT birth in four categories: term children without IUGR (normal), IUGR only (term with IUGR), PT only (preterm without IUGR) and preterm with IUGR; infant's sex; maternal parity, age, schooling and marital status; occupation of family head; family income and neonatal ponderal index (PI). The risk ratio for catch-up and catch-down was estimated by multinomial logistic regression for each city. In RP, preterms without IUGR (RR = 4.13) and thin children (PI<10th percentile, RR = 14.39) had a higher risk of catch-down; catch-up was higher among terms with IUGR (RR = 5.53), preterms with IUGR (RR = 5.36) and children born to primiparous mothers (RR = 1.83). In SL, catch-down was higher among preterms without IUGR (RR = 5.19), girls (RR = 1.52) and children from low-income families (RR = 2.74); the lowest risk of catch-down (RR = 0.27) and the highest risk of catch-up (RR = 3.77) were observed among terms with IUGR. In both cities, terms with IUGR presented height catch-up growth whereas preterms with IUGR only had height catch-up growth in the more affluent setting. Preterms without IUGR presented height catch-down growth, suggesting that a better socioeconomic situation facilitates height catch-up and prevents height catch-down growth

How to prevent ROP in preterm infants in Indonesia?

Background and Aims: Retinopathy of prematurity (ROP) is a severe disease in preterm infants. It is seen more frequently in Low-Middle Income Countries (LMIC) like Indonesia compared to High-Income Countries (HIC). Risk factors for ROP development are -extreme- preterm birth, use of oxygen, neonatal infections, respiratory problems, inadequate nutrition, and blood and exchange transfusions. In this paper, we give an overview of steps that can be taken in LMIC to prevent ROP and provide guidelines for screening and treating ROP. Methods: Based on the literature search and data obtained by us in Indonesia's studies, we propose guidelines for the prevention, screening, and treatment of ROP in preterm infants in LMIC. Results: Prevention of ROP starts before birth with preventing preterm labor, transferring a mother who might deliver <32 weeks to a perinatal center and giving corticosteroids to mothers that might deliver <34 weeks. Newborn resuscitation must be done using room air or, in the case of very preterm infants (<29-32 weeks) by using 30% oxygen. Respiratory problems must be prevented by starting continuous positive airway pressure (CPAP) in all preterm infants <32 weeks and in case of respiratory problems in more mature infants. If needed, the surfactant should be given in a minimally invasive manner, as ROP's lower incidence was found using this technique. The use of oxygen must be strictly regulated with a saturation monitor of 91-95%. Infections must be prevented as much as possible. Both oral and parenteral nutrition should be started in all preterm infants on day one of life with preferably mothers' milk. Blood transfusions can be prevented by reducing the amount of blood needed for laboratory analysis. Discussion: Preterm babies should be born in facilities able to care for them optimally. The use of oxygen must be strictly regulated. ROP screening is mandatory in infants born <34 weeks, and infants who received supplemental oxygen for a prolonged period. In case of progression of ROP, immediate mandatory treatment is required. Conclusion: Concerted action is needed to reduce the incidence of ROP in LMIC. "STOP - R1O2P3" is an acronym that can help implement standard practices in all neonatal intensive care units in LMIC to prevent development and progression