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Secondary coenzyme Q10 deficiency triggers mitochondria degradation by mitophagy in MELAS fibroblasts

AuthorsCotán, David ; Cordero, Mario D. ; Garrido-Maraver, Juan; Oropesa-Ávila, Manuel; Rodríguez-Hernández, Ángeles ; Gómez Izquierdo, Lourdes; Mata, Mario de la ; Miguel, Manuel de; Bautista Lorite, Juan; Rivas Infante, Eloy; Jackson, Sandra; Navas, Plácido ; Sánchez-Alcázar, José Antonio
Free radicals
Mitochondrial diseases
Electron transport
MELAS syndrome
Microtubule-associated proteins
Issue Date6-May-2011
PublisherFederation of American Societies for Experimental Biology
CitationFASEB Journal 25(8): 2669-2687 (2011)
AbstractMitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a mitochondrial disease most usually caused by point mutations in tRNA genes encoded by mtDNA. Here, we report on how this mutation affects mitochondrial function in primary fibroblast cultures established from 2 patients with MELAS who harbored the A3243G mutation. Both mitochondrial respiratory chain enzyme activities and coenzyme Q(10) (CoQ) levels were significantly decreased in MELAS fibroblasts. A similar decrease in mitochondrial membrane potential was found in intact MELAS fibroblasts. Mitochondrial dysfunction was associated with increased oxidative stress and the activation of mitochondrial permeability transition (MPT), which triggered the degradation of impaired mitochondria. Furthermore, we found defective autophagosome elimination in MELAS fibroblasts. Electron and fluorescence microscopy studies confirmed a massive degradation of mitochondria and accumulation of autophagosomes, suggesting mitophagy activation and deficient autophagic flux. Transmitochondrial cybrids harboring the A3243G mutation also showed CoQ deficiency and increased autophagy activity. All these abnormalities were partially restored by CoQ supplementation. Autophagy in MELAS fibroblasts was also abolished by treatment with antioxidants or cyclosporine, suggesting that both reactive oxygen species and MPT participate in this process. Furthermore, prevention of autophagy in MELAS fibroblasts resulted in apoptotic cell death, suggesting a protective role of autophagy in MELAS fibroblasts.
Description9 páginas.
Publisher version (URL)http://dx.doi.org/10.1096/fj.10-165340
Appears in Collections:(CABD) Artículos
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