Copper and bezafibrate cooperate to rescue cytochrome c oxidase deficiency in cells of patients with sco2 mutations

Background: Mutations in SCO2 cause cytochrome c oxidase deficiency (COX) and a fatal infantile cardioencephalomyopathy. SCO2 encodes a protein involved in COX copper metabolism; supplementation with copper salts rescues the defect in patients’ cells. Bezafibrate (BZF), an approved hypolipidemic agent, ameliorates the COX deficiency in mice with mutations in COX10, another COX-assembly gene. Methods: We have investigated the effect of BZF and copper in cells with SCO2 mutations using spectrophotometric methods to analyse respiratory chain activities and a luciferase assay to measure ATP production.. Results: Individual mitochondrial enzymes displayed different responses to BZF. COX activity increased by about 40% above basal levels (both in controls and patients), with SCO2 cells reaching 75-80% COX activity compared to untreated controls. The increase in COX was paralleled by an increase in ATP production. The effect was dose-dependent: it was negligible with 100 μM BZF, and peaked at 400 μM BZF. Higher BZF concentrations were associated with a relative decline of COX activity, indicating that the therapeutic range of this drug is very narrow. Combined treatment with 100 μM CuCl2 and 200 μM BZF (which are only marginally effective when administered individually) achieved complete rescue of COX activity in SCO2 cells. Conclusions: These data are crucial to design therapeutic trials for this otherwise fatal disorder. The additive effect of copper and BZF will allow to employ lower doses of each drug and to reduce their potential toxic effects. The exact mechanism of action of BZF remains to be determined

Continuit\ue0 e aderenza terapeutica nei giovani all\u2019esordio psicotico: il modello di intervento integrato del Servizio Psichiatrico di Bolzano. [Continuity of care and therapeutic adherence in young people at psychosis onset: the integrated intervention model of the Psychiatric Service of Bolzano]

Scopo. Presentare: 1) il percorso di trasformazione del Servizio Psichiatrico di Bolzano verso un assetto organizzativo orientato a un\u2019offerta tempestiva, intensiva, specifica e multimodale per gli utenti all\u2019esordio psicotico e i loro familiari; 2) l\u2019andamento clinico e sociale nel corso di 12 mesi della coorte dei pazienti avviati al progetto \u201cInterventi Precoci\u201d. Metodi. Studio naturalistico longitudinale che valuta l\u2019andamento nel corso di 12 mesi di una coorte di pazienti al primo episodio psicotico, reclutata nell\u2019area di competenza territoriale del Servizio Psichiatrico di Bolzano e avviata al progetto \u201cInterventi Precoci\u201d. Le caratteristiche socio-demografiche, abitative e lavorative, le erogazioni delle prestazioni (intervento medico, psicoterapia, psicoeducazione familiare, intervento sociale) e i ricoveri ospedalieri sono stati ricavati dalla cartella clinica informatizzata. Stato psicopatologico e funzionamento globale sono stati valutati, rispettivamente, con la Positive and Negative Syndrome Scale (PANSS) e la Global Assesment of Functioning (GAF). Risultati. Nei primi cinque anni di attivit\ue0 del progetto (2012-2017) sono stati trattati 116 pazienti. Al follow-up (FU) a 12 mesi, l\u201983,6% risulta in carico, il 7,7% si \ue8 trasferito in altra sede e l\u20198,5% ha abbandonato il percorso. Non risultano differenze di et\ue0 e genere tra pazienti in carico e quelli che hanno interrotto il progetto. Tutti i pazienti hanno usufruito di un trattamento integrato specifico; il 16% ha inoltre usufruito di un trattamento intensivo in regime residenziale. I punteggi PANSS totale, positiva e negativa, hanno registrato una riduzione significativa dal baseline (BL) al FU; parallelamente si \ue8 assistito a un aumento significativo dei punteggi GAF. Solamente il 13,5% \ue8 andato incontro a un ricovero ospedaliero (Servizio Psichiatrico Diagnosi e Cura, SPDC) nel corso di 12 mesi. Al FU il tasso di disoccupazione si riduce del 27,1% e il numero dei pazienti con un\u2019occupazione lavorativa raddoppia rispetto al BL. Discussione e conclusioni. Il progetto \u201cInterventi Precoci\u201d \ue8 risultato in grado di fornire trattamenti integrati, multiprofessionali e tempestivi fin dalle prime fasi del disturbo, secondo quanto raccomandato dalle linee guida internazionali, promuovendo un miglioramento significativo dei pazienti sia sul piano clinico che in termini di funzionamento sociale.Aim: To report on: 1) the modification process occurred within the Psychiatric Service of Bolzano toward an early, intensive, specific and multimodal system of care for patients experiencing their first psychotic episode and their family members; 2) the 12-month clinical and social course of a sample of patients referred to the "Early Intervention Project". Methods: Longitudinal naturalist study evaluating the 12-month clinical and outcome of a cohort of first-episode psychosis patients consecutively referred to the "Early Intervention Project" implemented within the Psychiatric Service of Bolzano. Socio-demographic characteristics, housing situation and occupational status, interventions offered (medical intervention, psychotherapy, psychoeducation to family members, social intervention) and hospital admissions were drawn from electronic medical records. Levels of psychopathology and global functioning were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Global assessment of Functioning (GAF), respectively. Results: During the first five years of activity (2012-2017) 116 patients had been referred to the Project. At 12 months 83.6%were still in charge, 7.76% moved to another area, 8.5% have abandoned the intervention. No significant difference in terms of age and gender was found between patients who remained in the project and those who lost contact. All patients had received specific integrated treatment; moreover, 16% had received intensive residential care. Notably, only 13.5% have had a hospital readmission over the 12 months of intervention. The PANSS total, positive and negative scores displayed significant reduction from baseline (BL) to follow-up (FU); in parallel, increase in GAF score from BL to FU was observed. All patients employed at BL were able to keep their job at FU; 17% of all patients unemployed at baseline were employed at FU. Discussion and conclusion: The "Early Intervention Project" implemented in Bolzano was found to ensure integrated, multidisciplinary and early treatment, as defined by the most recent international guidelines, which produced significant improvement in both clinical and social outcomes in a cohort of first-episode psychosis patients

COX16 is required for assembly of cytochrome c oxidase in human cells and is involved in copper delivery to COX2

Cytochrome c oxidase (COX), complex IV of the mitochondrial respiratory chain, is comprised of 14 structural subunits, several prosthetic groups and metal cofactors, among which copper. Its biosynthesis involves a number of ancillary proteins, encoded by the COX-assembly genes that are required for the stabilization and membrane insertion of the nascent polypeptides, the synthesis of the prosthetic groups, and the delivery of the metal cofactors, in particular of copper. Recently, a modular model for COX assembly has been proposed, based on the sequential incorporation of different assembly modules formed by specific subunits. We have cloned and characterized the human homologue of yeast COX16. We show that human COX16 encodes a small mitochondrial transmembrane protein that faces the intermembrane space and is highly expressed in skeletal and cardiac muscle. Its knockdown in C. elegans produces COX deficiency, and its ablation in HEK293 cells impairs COX assembly. Interestingly, COX16 knockout cells retain significant COX activity, suggesting that the function of COX16 is partially redundant. Analysis of steady-state levels of COX subunits and of assembly intermediates by Blue-Native gels shows a pattern similar to that reported in cells lacking COX18, suggesting that COX16 is required for the formation of the COX2 subassembly module. Moreover, COX16 co-immunoprecipitates with COX2. Finally, we found that copper supplementation increases COX activity and restores normal steady state levels of COX subunits in COX16 knockout cells, indicating that, even in the absence of a canonical copper binding motif, COX16 could be involved in copper delivery to COX2

The COQ2 genotype predicts the severity of Coenzyme Q10 deficiency

COQ2 (p-hydroxybenzoate polyprenyl transferase) encodes the enzyme required for the second step of the final reaction sequence of Coenzyme Q10 (CoQ) biosynthesis. Its mutations represent a frequent cause of primary CoQ deficiency and have been associated to the widest clinical spectrum, ranging from fatal neonatal multisystemic disease to late-onset encephalopathy. However, the reasons of this variability are still unknown.We have characterized the structure of human COQ2, defined its subcellular localization and developed a yeast model to validate all the mutant alleles reported so far.Our findings show that the main functional transcript of COQ2 is shorter than what was previously reported and that its protein product localizes to mitochondria with the C-terminus facing the intermembrane space. Complementation experiments in yeast showed that the residual activity of the mutant proteins correlates with the clinical phenotypes observed in patients.We defined the structure of COQ2 with relevant implications for mutation screening in patients and demonstrated that, contrary to other COQ gene defects such as ADCK3, there is a correlation between COQ2 genotype and patient's phenotype

Copper and bezafibrate cooperate to rescue cytochrome <it>c</it> oxidase deficiency in cells of patients with <it>sco2</it> mutations

Abstract Background Mutations in SCO2 cause cytochrome c oxidase deficiency (COX) and a fatal infantile cardioencephalomyopathy. SCO2 encodes a protein involved in COX copper metabolism; supplementation with copper salts rescues the defect in patients’ cells. Bezafibrate (BZF), an approved hypolipidemic agent, ameliorates the COX deficiency in mice with mutations in COX10, another COX-assembly gene. Methods We have investigated the effect of BZF and copper in cells with SCO2 mutations using spectrophotometric methods to analyse respiratory chain activities and a luciferase assay to measure ATP production.. Results Individual mitochondrial enzymes displayed different responses to BZF. COX activity increased by about 40% above basal levels (both in controls and patients), with SCO2 cells reaching 75-80% COX activity compared to untreated controls. The increase in COX was paralleled by an increase in ATP production. The effect was dose-dependent: it was negligible with 100 μM BZF, and peaked at 400 μM BZF. Higher BZF concentrations were associated with a relative decline of COX activity, indicating that the therapeutic range of this drug is very narrow. Combined treatment with 100 μM CuCl2 and 200 μM BZF (which are only marginally effective when administered individually) achieved complete rescue of COX activity in SCO2 cells. Conclusions These data are crucial to design therapeutic trials for this otherwise fatal disorder. The additive effect of copper and BZF will allow to employ lower doses of each drug and to reduce their potential toxic effects. The exact mechanism of action of BZF remains to be determined.</p

A multi-element psychosocial intervention for early psychosis (GET UP PIANO TRIAL) conducted in a catchment area of 10 million inhabitants: study protocol for a pragmatic cluster randomized controlled trial

Multi-element interventions for first-episode psychosis (FEP) are promising, but have mostly been conducted in non-epidemiologically representative samples, thereby raising the risk of underestimating the complexities involved in treating FEP in 'real-world' services