Diseases caused by mutations in mitochondrial carrier genes SLC25: A review

In the 1980s, after the mitochondrial DNA (mtDNA) had been sequenced, several diseases resulting from mtDNA mutations emerged. Later, numerous disorders caused by mutations in the nuclear genes encoding mitochondrial proteins were found. A group of these diseases are due to defects of mitochondrial carriers, a family of proteins named solute carrier family 25 (SLC25), that transport a variety of solutes such as the reagents of ATP synthase (ATP, ADP, and phosphate), tricarboxylic acid cycle intermediates, cofactors, amino acids, and carnitine esters of fatty acids. The disease-causing mutations disclosed in mitochondrial carriers range from point mutations, which are often localized in the substrate translocation pore of the carrier, to large deletions and insertions. The biochemical consequences of deficient transport are the compartmentalized accumulation of the substrates and dysfunctional mitochondrial and cellular metabolism, which frequently develop into various forms of myopathy, encephalopathy, or neuropathy. Examples of diseases, due to mitochondrial carrier mutations are: combined D-2-and L-2-hydroxyglutaric aciduria, carnitine-acylcarnitine carrier deficiency, hyperornithinemia-hyperammonemia-homocitrillinuria (HHH) syndrome, early infantile epileptic encephalopathy type 3, Amish microcephaly, aspartate/glutamate isoform 1 deficiency, congenital sideroblastic anemia, Fontaine progeroid syndrome, and citrullinemia type II. Here, we review all the mitochondrial carrier-related diseases known until now, focusing on the connections between the molecular basis, altered metabolism, and phenotypes of these inherited disorders

Statins, fibrates and retinoic acid upregulate mitochondrial acylcarnitine carrier gene expression

In this study, we investigated the effects of statins, fibrates, 9-cis-retinoic acid and forskolin on the transcription of the mitochondrial carnitine/acylcarnitine carrier (CAC) gene. Statins, fibrates, retinoic acid and forskolin activate luciferase gene reporter activity driven by the -334/+3 bp region of the human CAC promoter containing wild-type (but not mutated) PPRE. These four agents also increase CAC transcript and protein levels. The combinations of statins and fibrates, retinoic acid and fibrates and fibrates and forskolin act synergistically. Mevalonate abolishes the activation of CAC gene expression by statins; the inhibitor of the PKA pathway H89 suppresses the stimulation of CAC gene expression by forskolin. Because CAC is essential for fatty acid beta-oxidation, the above results on the regulation of CAC gene expression provide a novel contribution to the understanding of the hypolipidemic action of statins, fibrates and retinoic acid

Statins, fibrates and retinoic acid upregulate mitochondrial acylcarnitine carrier gene expression

In this study, we investigated the effects of statins, fibrates, 9-cis-retinoic acid and forskolin on the transcription of the mitochondrial carnitine/acylcarnitine carrier (CAC) gene. Statins, fibrates, retinoic acid and forskolin activate luciferase gene reporter activity driven by the -334/+3 bp region of the human CAC promoter containing wild-type (but not mutated) PPRE. These four agents also increase CAC transcript and protein levels. The combinations of statins and fibrates, retinoic acid and fibrates and fibrates and forskolin act synergistically. Mevalonate abolishes the activation of CAC gene expression by statins; the inhibitor of the PKA pathway H89 suppresses the stimulation of CAC gene expression by forskolin. Because CAC is essential for fatty acid beta-oxidation, the above results on the regulation of CAC gene expression provide a novel contribution to the understanding of the hypolipidemic action of statins, fibrates and retinoic acid

Identification of a novel Sp1 splice variant as a strong transcriptional activator.

The transcription factor Sp1 regulates expression of numerous genes involved in many cellular processes. Different post-transcriptional modifications can influence the transcriptional control activity and stability of Sp1. In addition to these modifications, alternative splicing isoforms may also be the basis of its distinct functional activities. In this study, we identified a novel alternative splice isoform of Sp1 named Sp1c. This variant is generated by exclusion of a short domain, which we designate a, through alternative splice acceptor site usage in the exon 3. The existence of this new isoform was confirmed in vivo by Western blotting analysis. Although at very low levels, Sp1c is ubiquitously expressed, as seen in its fulllength Sp1. A preliminary characterization of Sp1c shows that: (a) Sp1c works as stronger activator of transcription than full-length Sp1; (b) percentage of HEK293 Sp1c-overexpressing cells is higher in G1 phase and lower in S phase than percentage of HEK293 Sp1-overexpressing cells

Efectos de un hidrocarburo aromático policíclico (ß naftoflavona) sobre biomarcadores de efecto en Corydoras paleatus en condiciones de campo y laboratorio

Polycyclic aromatic hydrocarbons (PAHs) are important anthropogenic sources of aquatic contamination. In this study, hepatic biomarker responses of Corydoras paleatus injected with one sublethal dose of a PAH (ß-naftoflavona, BNF) were assessed under laboratory and field conditions. Glutathion-S-transferase (GST) and catalase (CAT) hepatic activities, liver protein content (PC), condition factor (CF) and liver somatic index (LSI) were determined. Two bioassays were performed during winter time: laboratory (la) and field (ca). Fish were injected with 50 mg BNF/kg body weight dissolved in corn oil (ß-la y ßca); control fish received corn oil (C-la y C-ca). There were no differences between controls or in BNF injected fish in the assessed parameters. BNF provoked a tendency of increase in CAT and GST activities and lower values of CP; on the other hand, no differences were observed in the FC and IHS. In BNF field exposed fish (ß-ca) CAT activity was significantly stimulated vs. both field and laboratory controls; GST differences were detected both between ß-ca and ß-la and their respective controls. BNF exposure induced adverse effects principally in the enzymatic biomarkers of C. paleatus and those effects were modulated by the environmental conditions.Facultad de Ciencias Naturales y Muse

Efectos de un hidrocarburo aromático policíclico (ß naftoflavona) sobre biomarcadores de efecto en Corydoras paleatus en condiciones de campo y laboratorio

Polycyclic aromatic hydrocarbons (PAHs) are important anthropogenic sources of aquatic contamination. In this study, hepatic biomarker responses of Corydoras paleatus injected with one sublethal dose of a PAH (ß-naftoflavona, BNF) were assessed under laboratory and field conditions. Glutathion-S-transferase (GST) and catalase (CAT) hepatic activities, liver protein content (PC), condition factor (CF) and liver somatic index (LSI) were determined. Two bioassays were performed during winter time: laboratory (la) and field (ca). Fish were injected with 50 mg BNF/kg body weight dissolved in corn oil (ß-la y ßca); control fish received corn oil (C-la y C-ca). There were no differences between controls or in BNF injected fish in the assessed parameters. BNF provoked a tendency of increase in CAT and GST activities and lower values of CP; on the other hand, no differences were observed in the FC and IHS. In BNF field exposed fish (ß-ca) CAT activity was significantly stimulated vs. both field and laboratory controls; GST differences were detected both between ß-ca and ß-la and their respective controls. BNF exposure induced adverse effects principally in the enzymatic biomarkers of C. paleatus and those effects were modulated by the environmental conditions.Facultad de Ciencias Naturales y Muse

Efectos de un hidrocarburo aromático policíclico (ß naftoflavona) sobre biomarcadores de efecto en Corydoras paleatus en condiciones de campo y laboratorio

Polycyclic aromatic hydrocarbons (PAHs) are important anthropogenic sources of aquatic contamination. In this study, hepatic biomarker responses of Corydoras paleatus injected with one sublethal dose of a PAH (ß-naftoflavona, BNF) were assessed under laboratory and field conditions. Glutathion-S-transferase (GST) and catalase (CAT) hepatic activities, liver protein content (PC), condition factor (CF) and liver somatic index (LSI) were determined. Two bioassays were performed during winter time: laboratory (la) and field (ca). Fish were injected with 50 mg BNF/kg body weight dissolved in corn oil (ß-la y ßca); control fish received corn oil (C-la y C-ca). There were no differences between controls or in BNF injected fish in the assessed parameters. BNF provoked a tendency of increase in CAT and GST activities and lower values of CP; on the other hand, no differences were observed in the FC and IHS. In BNF field exposed fish (ß-ca) CAT activity was significantly stimulated vs. both field and laboratory controls; GST differences were detected both between ß-ca and ß-la and their respective controls. BNF exposure induced adverse effects principally in the enzymatic biomarkers of C. paleatus and those effects were modulated by the environmental conditions.Polycyclic aromatic hydrocarbons (PAHs) are important anthropogenic sources of aquatic contamination. In this study, hepatic biomarker responses of Corydoras paleatus injected with one sublethal dose of a PAH (ß-naftoflavona, BNF) were assessed under laboratory and field conditions. Glutathion-S-transferase (GST) and catalase (CAT) hepatic activities, liver protein content (PC), condition factor (CF) and liver somatic index (LSI) were determined. Two bioassays were performed during winter time: laboratory (la) and field (ca). Fish were injected with 50 mg BNF/kg body weight dissolved in corn oil (ß-la y ßca); control fish received corn oil (C-la y C-ca). There were no differences between controls or in BNF injected fish in the assessed parameters. BNF provoked a tendency of increase in CAT and GST activities and lower values of CP; on the other hand, no differences were observed in the FC and IHS. In BNF field exposed fish (ß-ca) CAT activity was significantly stimulated vs. both field and laboratory controls; GST differences were detected both between ß-ca and ß-la and their respective controls. BNF exposure induced adverse effects principally in the enzymatic biomarkers of C. paleatus and those effects were modulated by the environmental condition

An Overview of Mitochondrial Protein Defects in Neuromuscular Diseases

none8noNeuromuscular diseases (NMDs) are dysfunctions that involve skeletal muscle and cause incorrect communication between the nerves and muscles. The specific causes of NMDs are not well known, but most of them are caused by genetic mutations. NMDs are generally progressive and entail muscle weakness and fatigue. Muscular impairments can differ in onset, severity, prognosis, and phenotype. A multitude of possible injury sites can make diagnosis of NMDs difficult. Mitochondria are crucial for cellular homeostasis and are involved in various metabolic pathways; for this reason, their dysfunction can lead to the development of different pathologies, including NMDs. Most NMDs due to mitochondrial dysfunction have been associated with mutations of genes involved in mitochondrial biogenesis and metabolism. This review is focused on some mitochondrial routes such as the TCA cycle, OXPHOS, and β-oxidation, recently found to be altered in NMDs. Particular attention is given to the alterations found in some genes encoding mitochondrial carriers, proteins of the inner mitochondrial membrane able to exchange metabolites between mitochondria and the cytosol. Briefly, we discuss possible strategies used to diagnose NMDs and therapies able to promote patient outcomeopenMarra Federica, Lunetti Paola, Curcio Rosita, Lasorsa Francesco Massimo, Capobianco Loredana, Porcelli Vito, Dolce Vincenza, Fiermonte Giuseppe and Scarcia PasqualeMarra, Federica; Lunetti, Paola; Curcio, Rosita; Lasorsa Francesco, Massimo; Capobianco, Loredana; Porcelli, Vito; Dolce, Vincenza; Fiermonte Giuseppe and Scarcia, Pasqual

Efectos de un hidrocarburo aromático policíclico (ß naftoflavona) sobre biomarcadores de efecto en Corydoras paleatus en condiciones de campo y laboratorio

Polycyclic aromatic hydrocarbons (PAHs) are important anthropogenic sources of aquatic contamination. In this study, hepatic biomarker responses of Corydoras paleatus injected with one sublethal dose of a PAH (ß-naftoflavona, BNF) were assessed under laboratory and field conditions. Glutathion-S-transferase (GST) and catalase (CAT) hepatic activities, liver protein content (PC), condition factor (CF) and liver somatic index (LSI) were determined. Two bioassays were performed during winter time: laboratory (la) and field (ca). Fish were injected with 50 mg BNF/kg body weight dissolved in corn oil (ß-la y ßca); control fish received corn oil (C-la y C-ca). There were no differences between controls or in BNF injected fish in the assessed parameters. BNF provoked a tendency of increase in CAT and GST activities and lower values of CP; on the other hand, no differences were observed in the FC and IHS. In BNF field exposed fish (ß-ca) CAT activity was significantly stimulated vs. both field and laboratory controls; GST differences were detected both between ß-ca and ß-la and their respective controls. BNF exposure induced adverse effects principally in the enzymatic biomarkers of C. paleatus and those effects were modulated by the environmental conditions.Facultad de Ciencias Naturales y Muse

Rtg signaling sustains mitochondrial respiratory capacity in hog1-dependent osmoadaptation

Mitochondrial RTG-dependent retrograde signaling, whose regulators have been characterized in Saccharomyces cerevisiae, plays a recognized role under various environmental stresses. Of special significance, the activity of the transcriptional complex Rtg1/3 has been shown to be modu-lated by Hog1, the master regulator of the high osmolarity glycerol pathway, in response to osmotic stress. The present work focuses on the role of RTG signaling in salt-induced osmotic stress and its interaction with HOG1. Wild-type and mutant cells, lacking HOG1 and/or RTG genes, are compared with respect to cell growth features, retrograde signaling activation and mitochondrial function in the presence and in the absence of high osmostress. We show that RTG2, the main upstream regulator of the RTG pathway, contributes to osmoadaptation in an HOG1-dependent manner and that, with RTG3, it is notably involved in a late phase of growth. Our data demonstrate that impairment of RTG signaling causes a decrease in mitochondrial respiratory capacity exclusively under os-mostress. Overall, these results suggest that HOG1 and the RTG pathway may interact sequentially in the stress signaling cascade and that the RTG pathway may play a role in inter-organellar metabolic communication for osmoadaptation