Role of cytochrome c oxidase nuclear-encoded subunits in health and disease.

Cytochrome c oxidase (COX), the terminal enzyme of mitochondrial electron transport chain, couples electron transport to oxygen with generation of proton gradient indispensable for the production of vast majority of ATP molecules in mammalian cells. The review summarizes current knowledge of COX structure and function of nuclear-encoded COX subunits, which may modulate enzyme activity according to various conditions. Moreover, some nuclear-encoded subunits posess tissue-specific and development-specific isoforms, possibly enabling fine-tuning of COX function in individual tissues. The importance of nuclear-encoded subunits is emphasized by recently discovered pathogenic mutations in patients with severe mitopathies. In addition, proteins substoichiometrically associated with COX were found to contribute to COX activity regulation and stabilization of the respiratory supercomplexes. Based on the summarized data, a model of three levels of quaternary COX structure is postulated. Individual structural levels correspond to subunits of the i) catalytic center, ii) nuclear-encoded stoichiometric subunits and iii) associated proteins, which may constitute several forms of COX with varying composition and differentially regulated function.

Adult outpatients with depression: worse quality of life than in other chronic medical diseases in Argentina.

Current research into the impact of major depressive illness on society goes beyond estimating its prevalence, complications or comorbidity patterns, to include research that seeks to establish how this disorder affects individuals' daily functioning and well-being. However, it is unclear whether depression affects such broadly defined quality of life (QOL) outcomes to a similar or an even greater extent than chronic physical illness. The present study assessed QOL in a sample of 48 ambulatory depressed patients who sought psychiatric assistance at a centre in La Plata, Argentina, during a 15-month period. All of them met DSM-IV criteria for current major depression, as diagnosed by clinicians. For the purposes of comparison, we also evaluated the QOL of additional samples of persons who were healthy or who had chronic physical illness. QOL was assessed with the WHOQOL-100, a generic and transcultural instrument developed simultaneously in 15 centres, by the World Health Organization (WHO). Results indicated that QOL was significantly poorer in depressed persons than in either healthy persons or individuals with other frequent chronic pathologies in Argentina. The impact of depression was also found to be related to the seriousness of the episode. We suggest that it is important to include QOL assessments of patients with depressive disorders when evaluating the course and progress of their treatment. Such assessments can be used in health care decision making and resource allocation.

Genetic defects of cytochrome c oxidase assembly.

Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain, is one of the key functional and regulatory sites of the mammalian energy metabolism. Owing to the importance of the enzyme, pathogenetic mutations affecting COX frequently result in severe, often fatal metabolic disorders. No satisfactory therapy is currently available so that the treatment remains largely symptomatic and does not improve the course of the disease. While only few genetic defects of COX are caused by mutations in mitochondrial genome, during the last five years a large number of pathogenetic mutations in nuclear genes have been discovered. All these mutations are located in genes encoding COX-specific assembly proteins including SURF1, SCO1, SCO2, COX10, and COX15. Despite the identification of increasing number of mutations, their precise etiopathogenetic mechanisms, which are necessary for the development of future therapeutic protocols, still remain to be elucidated. This review summarizes recent developments, including our efforts in elucidation of the molecular basis of human mitochondrial diseases due to specific defects of COX with special focus on SURF1 assembly protein.

Airborne polycyclic aromatic hydrocarbons in the city of Zagreb, Yugoslavia.

The concentrations of six PAHs (benzo[a]pyrene, benzo[b]fluoranthene, ideno[1,2,3-c,d]-pyrene, benzo[a]anthracene, benzo[k]fluoranthene and fluoranthene), and lead have been measured systematically for six winter periods from 1977/78 to 1982/83 in the urban air of the city of Zagreb. The average mass concentrations of PAHs were approximately 10 ng m-3. The distribution of PAHs in urban air is discussed. The analytical method for PAH determination is based on filter extraction, two-dimensional thin-layer chromatography and fluorescence spectrometry; lead is measured by atomic absorption.

Nuclear genetic defects of mitochondrial ATP synthase.

Disorders of ATP synthase, the key enzyme of mitochondrial energy provision belong to the most severe metabolic diseases presenting as early-onset mitochondrial encephalo-cardiomyopathies. Up to now, mutations in four nuclear genes were associated with isolated deficiency of ATP synthase. Two of them, ATP5A1 and ATP5E encode enzyme's structural subunits alpha and epsilon, respectively, while the other two ATPAF2 and TMEM70 encode specific ancillary factors that facilitate the biogenesis of ATP synthase. All these defects share a similar biochemical phenotype with pronounced decrease in the content of fully assembled and functional ATP synthase complex. However, substantial differences can be found in their frequency, molecular mechanism of pathogenesis, clinical manifestation as well as the course of the disease progression. While for TMEM70 the number of reported patients as well as spectrum of the mutations is steadily increasing, mutations in ATP5A1, ATP5E and ATPAF2 genes are very rare. Apparently, TMEM70 gene is highly prone to mutagenesis and this type of a rare mitochondrial disease has a rather frequent incidence. Here we present overview of individual reported cases of nuclear mutations in ATP synthase and discuss, how their analysis can improve our understanding of the enzyme biogenesis.

Polyunsaturated fatty acids of marine origin upregulate mitochondrial biogenesis and induce beta-oxidation in white fat.

AIMS/HYPOTHESIS: Intake of n-3 polyunsaturated fatty acids reduces adipose tissue mass, preferentially in the abdomen. The more pronounced effect of marine-derived eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids on adiposity, compared with their precursor alpha-linolenic acid, may be mediated by changes in gene expression and metabolism in white fat. METHODS: The effects of EPA/DHA concentrate (6% EPA, 51% DHA) admixed to form two types of high-fat diet were studied in C57BL/6J mice. Oligonucleotide microarrays, cDNA PCR subtraction and quantitative real-time RT-PCR were used to characterise gene expression. Mitochondrial proteins were quantified using immunoblots. Fatty acid oxidation and synthesis were measured in adipose tissue fragments. RESULTS: Expression screens revealed upregulation of genes for mitochondrial proteins, predominantly in epididymal fat when EPA/DHA concentrate was admixed to a semisynthetic high-fat diet rich in alpha-linolenic acid. This was associated with a three-fold stimulation of the expression of genes encoding regulatory factors for mitochondrial biogenesis and oxidative metabolism (peroxisome proliferator-activated receptor gamma coactivator 1 alpha [Ppargc1a, also known as Pgc1alpha] and nuclear respiratory factor-1 [Nrf1] respectively). Expression of genes for carnitine palmitoyltransferase 1A and fatty acid oxidation was increased in epididymal but not subcutaneous fat. In the former depot, lipogenesis was depressed. Similar changes in adipose gene expression were detected after replacement of as little as 15% of lipids in the composite high-fat diet with EPA/DHA concentrate, while the development of obesity was reduced. The expression of Ppargc1a and Nrf1 was also stimulated by n-3 polyunsaturated fatty acids in 3T3-L1 cells. CONCLUSIONS/INTERPRETATION: The anti-adipogenic effect of EPA/DHA may involve a metabolic switch in adipocytes that includes enhancement of beta-oxidation and upregulation of mitochondrial biogenesis.

GUG is an efficient initiation codon to translate the human mitochondrial ATP6 gene.

A maternally inherited and practically homoplasmic mitochondrial (mtDNA) mutation, 8527A>G, changing the initiation codon AUG into GUG, normally coding for a valine, was observed in the ATP6 gene encoding the ATPase subunit a. No alternate Met codon could replace the normal translational initiator. The patient harboring this mutation exhibited clinical symptoms suggesting a mitochondrial disease but his mother who carried the same mtDNA mutation was healthy. The mutation was absent from 100 controls and occurred once amongst 44 patients suspected of Leber Hereditary Optic Neuropathy (LHON) but devoid of typical LHON mutations. In patient fibroblasts, no effect of 8527A>G mutation could be demonstrated on the biosynthesis of mtDNA-encoded proteins, on size and the content of ATPase subunit a, on ATP hydrolysis and on mitochondrial membrane potential. In addition, ATP synthesis was barely decreased. Therefore, GUG is a functional initiation codon for the human ATP6 gene.