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Recovery of MERRF Fibroblasts and Cybrids Pathophysiology by Coenzyme Q 10

AuthorsMata, Mario de la ; Garrido-Maraver, Juan; Cotán, David ; Cordero, Mario D. ; Oropesa-Ávila, Manuel; Gómez Izquierdo, Lourdes; Miguel, Manuel de; Bautista Lorite, Juan; Rivas Infante, Eloy; Ybot, Patricia; Jackson, Sandra; Sánchez-Alcázar, José Antonio
Issue Date2012
CitationNeurotherapeutics 9(2): 446-463 (2012)
AbstractMitochondrial DNA mutations are an important cause of human disease for which there is no effective treatment. Myoclonic epilepsy with ragged-red fibers (MERRF) is a mitochondrial disease usually caused by point mutations in transfer RNA genes encoded by mitochondrial DNA. The most common mutation associated with MERRF syndrome, m.8344A > G in the gene MT-TK, which encodes transfer RNA Lysine, affects the translation of all mitochondrial DNA encoded proteins. This impairs the assembly of the electron transport chain complexes leading to decreased mitochondrial respiratory function. Here we report on how this mutation affects mitochondrial function in primary fibroblast cultures established from patients harboring the A8344G mutation. Coenzyme Q 10 (CoQ) levels, as well as mitochondrial respiratory chain activity, and mitochondrial protein expression levels were significantly decreased in MERRF fibroblasts. Mitotracker staining and imaging analysis of individual mitochondria indicated the presence of small, rounded, depolarized mitochondria in MERRF fibroblasts. Mitochondrial dysfunction was associated with increased oxidative stress and increased degradation of impaired mitochondria by mitophagy. Transmitochondrial cybrids harboring the A8344G mutation also showed CoQ deficiency, mitochondrial dysfunction, and increased mitophagy activity. All these abnormalities in patient-derived fibroblasts and cybrids were partially restored by CoQ supplementation, indicating that these cell culture models may be suitable for screening and validation of novel drug candidates for MERRF disease. © 2012 The American Society for Experimental NeuroTherapeutics, Inc.
DYT1 dystonia is a childhood-onset movement disorder with autosomal dominant inheritance. The disease is caused by a 3-bp deletion (ΔGAG) in the TOR1A gene that removes a glutamic acid residue (ΔE) of the encoded protein, torsin A. Interestingly, the ΔGAG mutation shows reduced penetrance of only 30%. Thus, additional genetic and enviromental modifiers affecting the manifestation of DYT1 dystonia symptoms are likely to exist. A recent hypothesis proposed a molecular link between DYT1 and DYT6 dystonia based on the possible regulation of torsin A transcription by THAP1.1, 2 Aiming to expand on prior analysis testing whether THAP1 is a genetic modifier for DYT1 dystonia,3, 4 we performed a genetic screen for sequence variations in the THAP1 gene and also in THAP1-binding sites of the TOR1A promoter in carriers of the ΔGAG DYT1 deletion.
Identifiersdoi: 10.1007/s13311-012-0103-3
issn: 1933-7213
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