Impairment of mitochondrial oxidative phosphorylation in skin fibroblasts of SALS and FALS patients is rescued by in vitro treatment with ROS scavengers

• Published in: Experimental neurology Vol. 339; p. 113620
• Main Authors: Debska-Vielhaber, Grazyna, Miller, Irina, Peeva, Viktoriya, Zuschratter, Werner, Walczak, Jaroslaw, Schreiber, Stefanie, Petri, Susanne, Machts, Judith, Vogt, Susanne, Szczepanowska, Joanna, Gellerich, Frank N., Hermann, Andreas, Vielhaber, Stefan, Kunz, Wolfram S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2021
• Subjects: Amyotrophic lateral sclerosis; Mitochondrial dysfunction; Oxidative stress; Skin fibroblasts; Oxidative stress; Amyotrophic lateral sclerosis; Skin fibroblasts; Mitochondrial dysfunction
• ISSN: 0014-4886; 1090-2430; 1090-2430
• DOI: 10.1016/j.expneurol.2021.113620

Amyotrophic lateral sclerosis (ALS) is a devastating, rapidly progressive, neurodegenerative disorder affecting upper and lower motor neurons. Approximately 10% of patients suffer from familial ALS (FALS) with mutations in different ubiquitously expressed genes including SOD1, C9ORF72, TARDBP, and FUS. There is compelling evidence for mitochondrial involvement in the pathogenic mechanisms of FALS and sporadic ALS (SALS), which is believed to be relevant for disease. Owing to the ubiquitous expression of relevant disease-associated genes, mitochondrial dysfunction is also detectable in peripheral patient tissue. We here report results of a detailed investigation of the functional impairment of mitochondrial oxidative phosphorylation (OXPHOS) in cultured skin fibroblasts from 23 SALS and 17 FALS patients, harboring pathogenic mutations in SOD1, C9ORF72, TARDBP and FUS. A considerable functional and structural mitochondrial impairment was detectable in fibroblasts from patients with SALS. Similarly, fibroblasts from patients with FALS, harboring pathogenic mutations in TARDBP, FUS and SOD1, showed mitochondrial defects, while fibroblasts from C9ORF72 associated FALS showed a very mild impairment detectable in mitochondrial ATP production rates only. While we could not detect alterations in the mtDNA copy number in the SALS or FALS fibroblast cultures, the impairment of OXPHOS in SALS fibroblasts and SOD1 or TARDBP FALS could be rescued by in vitro treatments with CoQ10 (5 μM for 3 weeks) or Trolox (300 μM for 5 days). This underlines the role of elevated oxidative stress as a potential cause for the observed functional effects on mitochondria, which might be relevant disease modifying factors. •ALS skin fibroblasts show functional and structural impairment of mitochondria.•Mitochondrial dysfunction is not related to mtDNA content.•Mitochondrial impairment is rescued by treatment with antioxidants.•Mitochondrial vulnerability in ALS should be considered in future treatment trials.