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Título

Coenzyme Q deficiency triggers mitochondria degradation by mitophagy

AutorRodríguez-Hernández, Ángeles ; Cordero, Mario D. ; Salviati, Leonardo; Artuch, Rafael; Pineda, Mercé; Briones, Paz; Gómez Izquierdo, Lourdes; Cotán, David ; Navas, Plácido ; Sánchez-Alcázar, José Antonio
Palabras claveAutophagy
Coenzyme Q
Free radicals
Mitochondria
Mitochondrial disease
Mitochondrial permeability transition
Mitophagy
Fecha de publicación1-ene-2009
EditorLandes Bioscience
CitaciónAutophagy 5(1): 19-32 (2009)
ResumenCoenzyme 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.
Descripción14 páginas, 11 figuras, 1 tabla.
Versión del editorhttp://dx.doi.org/10.4161/auto.5.1.7174
URIhttp://hdl.handle.net/10261/40287
DOI10.4161/auto.5.1.7174
ISSN1154-8627
E-ISSN1554-8635
ReferenciasPMID: 19115482
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