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Mitochondrial dysfunction in fibroblasts of Multiple System Atrophy

2018; Elsevier BV; Volume: 1864; Issue: 12 Linguagem: Inglês

10.1016/j.bbadis.2018.09.018

1879-260X

Giacomo Monzio Compagnoni, Giulio Kleiner, Andreina Bordoni, Francesco Fortunato, Dario Ronchi, Sabrina Salani, Marianna Guida, Corrado Corti, Irene Pichler, Christian Bergamini, Romana Fato, Maria Teresa Pellecchia, Annamaria Vallelunga, Francesca Del Sorbo, Antonio Emanuele Elia, Chiara Reale, Barbara Garavaglia, Gabriele Mora, Alberto Albanese, F. Cogiamanian, Gianluca Ardolino, Nereo Bresolin, Stefania Corti, Giacomo P. Comi, Catarina M. Quinzii, Alessio Di Fonzo,

Mitochondrial Function and Pathology

Multiple System Atrophy is a severe neurodegenerative disorder which is characterized by a variable clinical presentation and a broad neuropathological spectrum. The pathogenic mechanisms are almost completely unknown. In the present study, we established a cellular model of MSA by using fibroblasts' primary cultures and performed several experiments to investigate the causative mechanisms of the disease, with a particular focus on mitochondrial functioning. Fibroblasts' analyses (7 MSA-P, 7 MSA-C and 6 healthy controls) displayed several anomalies in patients: an impairment of respiratory chain activity, in particular for succinate Coenzyme Q reductase (p < 0.05), and a reduction of complex II steady-state level (p < 0.01); a reduction of Coenzyme Q10 level (p < 0.001) and an up-regulation of some CoQ10 biosynthesis enzymes, namely COQ5 and COQ7; an impairment of mitophagy, demonstrated by a decreased reduction of mitochondrial markers after mitochondrial inner membrane depolarization (p < 0.05); a reduced basal autophagic activity, shown by a decreased level of LC3 II (p < 0.05); an increased mitochondrial mass in MSA-C, demonstrated by higher TOMM20 levels (p < 0.05) and suggested by a wide analysis of mitochondrial DNA content in blood of large cohorts of patients. The present study contributes to understand the causative mechanisms of Multiple System Atrophy. In particular, the observed impairment of respiratory chain activity, mitophagy and Coenzyme Q10 biosynthesis suggests that mitochondrial dysfunction plays a crucial role in the pathogenesis of the disease. Furthermore, these findings will hopefully contribute to identify novel therapeutic targets for this still incurable disorder.