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14 páginas, 11 figuras, 1 tabla. ; Coenzyme Q10 (CoQ) is a small lipophilic molecule critical for the transport of electrons from complexes I and II to complex III in the mitochondrial respiratory chain. CoQ deficiency is a rare human genetic condition that has been associated with a variety of clinical phenotypes. With the aim of elucidating how CoQ deficiency affects an organism, we have investigated the pathophysiologic processes present within fibroblasts derived from 4 patients with CoQ deficiency. Assays of cultured fibroblasts revealed decreased activities of complex II+III, complex III, and complex IV, reduced expression of mitochondrial proteins involved in oxidative phosphorylation, decreased mitochondrial membrane potential, increased production of reactive oxygen species (ROS), activation of mitochondrial permeability transition (MPT), and reduced growth rates. These abnormalities were partially restored by CoQ supplementation. Moreover, we demonstrate that CoQ deficient fibroblasts exhibited increased levels of lysosomal markers (β-galactosidase, cathepsin, LC3, and Lyso Tracker), and enhanced expression of autophagic genes at both transcriptional and translational levels, indicating the presence of autophagy. Electron microscopy studies confirmed a massive degradation of the altered mitochondria by mitophagy. Autophagy in CoQ deficient fibroblasts was abolished by antioxidants or cyclosporin treatments suggesting that both ROS and MPT participate in this process. Furthermore, prevention of autophagy in CoQ deficient fibroblasts by 3-methyl adenine or wortmannin, as well as the induction of CoQ deficiency in cells lacking autophagy (by means of genetic knockout of the Atg5 gene in mouse embryonic fibroblasts) resulted in apoptotic cell death, suggesting a protective role of autophagy in CoQ deficiency. ; This work was supported by grants PI041617 from the FIS, Ministerio de Sanidad, Spain, and European Union contract LSHBCT-2004-005151 (UBIGENES). This group is founded by the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII. ; Peer reviewed

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License. ; [Objectives]: Coenzyme Q10 (CoQ10) deficiency syndrome is a rare condition that causes mitochondrial dysfunction and includes a variety of clinical presentations as encephalomyopathy, ataxia and renal failure. First, we sought to set up what all have in common, and then investigate why CoQ10 supplementation reverses the bioenergetics alterations in cultured cells but not all the cellular phenotypes. [Design Modelling study]: This work models the transcriptome of human CoQ10 deficiency syndrome in primary fibroblast from patients and study the genetic response to CoQ10 treatment in these cells. [Setting]: Four hospitals and medical centres from Spain, Italy and the USA, and two research laboratories from Spain and the USA. [Participants]: Primary cells were collected from patients in the above centres. [Measurements]: We characterised by microarray analysis the expression profile of fibroblasts from seven CoQ10-deficient patients (three had primary deficiency and four had a secondary form) and aged-matched controls, before and after CoQ10 supplementation. Results were validated by Q-RT-PCR. The profile of DNA (CpG) methylation was evaluated for a subset of gene with displayed altered expression. [Results]: CoQ10-deficient fibroblasts (independently from the aetiology) showed a common transcriptomic profile that promotes cell survival by activating cell cycle and growth, cell stress responses and inhibiting cell death and immune responses. Energy production was supported mainly by glycolysis while CoQ10 supplementation restored oxidative phosphorylation. Expression of genes involved in cell death pathways was partially restored by treatment, while genes involved in differentiation, cell cycle and growth were not affected. Stably demethylated genes were unaffected by treatment whereas we observed restored gene expression in either non-methylated genes or those with an unchanged methylation pattern. ; This work was supported by the following funders: Spanish Ministerio de Sanidad (FIS) grant numbers PI11/00078 and PI11/02350; National Institutes of Health (NIH, USA) grant number 1R01HD057543; Junta de Andalucía (Spanish Regional Government) grant number CTS-3988; Telethon (Italy) grant number GGP09207; and from a grant from Fondazione CARIPARO. ; Peer reviewed

8 páginas, 4 figuras, 1 tabla ; Supported by Grants from the Comitato Telethon Fondazione Onlus, the Amministrazione Autonoma dei Monopoli di Stato, the city of Gubbio, Italy (grant numbers GGP06209 and GGP10121), the Italian Ministry of Health ('Identification of tumor biomarkers through a biologydriven integrated approach'), and the Spanish and the Valencian Governments (grants BFU2011-30407 and Prometeo II/2014/029, respectively). NG holds a contract of CIBERER. ; Peer reviewed