Mitochondrial Dysfunction in Spinocerebellar Ataxia Type 3 Is Linked to VDAC1 Deubiquitination

• Published in: International journal of molecular sciences 2022-05, Vol.23 (11), p.5933
• Main Authors: Harmuth, Tina, Weber, Jonasz J, Zimmer, Anna J, Sowa, Anna S, Schmidt, Jana, Fitzgerald, Julia C, Schöls, Ludger, Riess, Olaf, Hübener-Schmid, Jeannette
• Format: Article
• Language: English
• Subjects: Ataxia; Ataxin; ataxin-3; Ataxin-3 - genetics; Ataxin-3 - metabolism; Autophagy; Cell viability; Fibroblasts; Humans; Kinases; Machado-Joseph disease; Machado-Joseph Disease - genetics; Machado-Joseph Disease - metabolism; Membrane permeability; Microscopy; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; mitochondria dysfunction; Mitochondrial DNA; Mitochondrial permeability transition pore; Morphology; Parkin protein; Parkinson's disease; Patients; Phenotypes; Phosphorylation; Protein expression; Proteins; Quality control; spinocerebellar ataxia type 3; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; VDAC1 ubiquitination; Voltage-Dependent Anion Channel 1 - genetics; Voltage-Dependent Anion Channel 1 - metabolism
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23115933

Dysfunctional mitochondria are linked to several neurodegenerative diseases. Metabolic defects, a symptom which can result from dysfunctional mitochondria, are also present in spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, the most frequent, dominantly inherited neurodegenerative ataxia worldwide. Mitochondrial dysfunction has been reported for several neurodegenerative disorders and ataxin-3 is known to deubiquitinylate parkin, a key protein required for canonical mitophagy. In this study, we analyzed mitochondrial function and mitophagy in a patient-derived SCA3 cell model. Human fibroblast lines isolated from SCA3 patients were immortalized and characterized. SCA3 patient fibroblasts revealed circular, ring-shaped mitochondria and featured reduced OXPHOS complexes, ATP production and cell viability. We show that wildtype ataxin-3 deubiquitinates VDAC1 (voltage-dependent anion channel 1), a member of the mitochondrial permeability transition pore and a parkin substrate. In SCA3 patients, VDAC1 deubiquitination and parkin recruitment to the depolarized mitochondria is inhibited. Increased p62-linked mitophagy, autophagosome formation and autophagy is observed under disease conditions, which is in line with mitochondrial fission. SCA3 fibroblast lines demonstrated a mitochondrial phenotype and dysregulation of parkin-VDAC1-mediated mitophagy, thereby promoting mitochondrial quality control via alternative pathways.