Mitochondrial dysfunction in fibroblasts of Multiple System Atrophy

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 Elia, Chiara Reale, Barbara Garavaglia, Gabriele Mora, Alberto Albanese, Filippo CogiamanianGianluca Ardolino, Nereo Bresolin, Stefania Corti, Giacomo P. Comi, Catarina M. Quinzii, Alessio Di Fonzo

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)3588-3597
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Issue number12
Publication statusPublished - Dec 1 2018


  • Cellular models
  • Fibroblasts
  • Mitochondria
  • Multiple System Atrophy

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology


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