title: Secondary coenzyme Q10 deficiency triggers mitochondria degradation by mitophagy in MELAS fibroblasts.
abstract: Mitochondrial 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.
authors.affiliation: Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-Consejo Superior de Investigaciones Científicas, Sevilla 41013, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Cotán
authors.forename: Mario D
authors.initials: MD
authors.lastname: Cordero
authors.forename: Juan
authors.initials: J
authors.lastname: Garrido-Maraver
authors.forename: Manuel
authors.initials: M
authors.lastname: Oropesa-Ávila
authors.forename: Angeles
authors.initials: A
authors.lastname: Rodríguez-Hernández
authors.forename: Lourdes
authors.initials: L
authors.lastname: Gómez Izquierdo
authors.forename: Mario
authors.initials: M
authors.lastname: De la Mata
authors.forename: Manuel
authors.initials: M
authors.lastname: De Miguel
authors.forename: Juan Bautista
authors.initials: JB
authors.lastname: Lorite
authors.forename: Eloy Rivas
authors.initials: ER
authors.lastname: Infante
authors.forename: Sandra
authors.initials: S
authors.lastname: Jackson
authors.forename: Plácido
authors.initials: P
authors.lastname: Navas
authors.forename: José A
authors.initials: JA
authors.lastname: Sánchez-Alcázar
mesh_terms: D001343:Autophagy / Q000235:genetics / Q000502:physiology; D000071187:Autophagy-Related Protein 5; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics; D004579:Electron Transport; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D017241:MELAS Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D017354:Point Mutation; D034741:RNA, Small Interfering / Q000235:genetics; D012356:RNA, Transfer, Leu / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000172:deficiency
chemical_list: C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; D017931:DNA Primers; D004272:DNA, Mitochondrial; D008869:Microtubule-Associated Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D034741:RNA, Small Interfering; D012356:RNA, Transfer, Leu; D017382:Reactive Oxygen Species; D014451:Ubiquinone; C024989:coenzyme Q10