G.P.186: Gene expression profile of cybrid cells harbouring a mitochondrial DNA mutation in the MT-ATP6 gene reveals new pathogenic pathway

• Published in: Neuromuscular disorders : NMD Vol. 24; no. 9-10; p. 866
• Main Authors: Fayet, G., Aure, K., Lesimple, P., L’Hermitte-Stead, C., Chevalier, C., Magot, A., Houlgatte, R., Pereon, Y., Lombes, A., Savagner, F.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.10.2014
• ISSN: 0960-8966; 1873-2364
• DOI: 10.1016/j.nmd.2014.06.242

Mutations in the human mitochondrial MT-ATP6 gene, encoding ATP synthase subunit a, are causing different neurological disorders such as Neurogenic Ataxia and Retinitis Pigmentosa (NARP), Leigh’s syndrome, Charcot-Marie-Tooth neuropathy, and more recently paralysis episodes. The deleterious consequences of these MT-ATP6 mutations are still the matter of debate with respect to their cellular impact and influence of the nuclear background. To investigate the primary molecular mechanisms independently from the impact of nuclear genome, we constructed cybrids with homoplasmic levels of the MT-ATP6 m.9185T>C mutation previously associated with each type of clinical presentation encountered with MT-ATP6 mutations. Using cDNA microarray analysis (31,142 probes) coupled with bioinformatics and functional gene annotations studies, we compared 7 samples from four independent homoplasmic mutant 143B cybrid cells to 9 samples from four independent control cybrids with different wild type mtDNA. Hierarchical clustering revealed 6 main gene clusters. The significant Gene Ontology up-regulated terms in the mutant cybrids as compared to controls notably involved reactive oxygen species, monocarboxylic acid transport, activity and/or regulation of adaptive and/or inflammatory responses, MAP-kinases pathway, striated development muscle, tissue remodelling, extracellular matrix, cell cycle pathway and organelle fission. The significant Gene Ontology down-regulated terms in the mutant cybrids as compared to controls notably involved DNA replication, RNA splicing and a decrease of actin cytoskeleton regulation. These results will be discussed with respect to functional respiratory chain and cellular analyses searching for primary molecular pathways associated to MT-ATP6 mutations.