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

Abstract

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.

• Authors: Tina Harmuth, Jonasz J Weber, Anna J Zimmer, Anna S Sowa, Jana Schmidt, Julia C Fitzgerald, Ludger Schöls, Olaf Riess, Jeannette Hübener-Schmid
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 23 Issue 11 (May 25 2022) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 35682609 (Publication Type: Journal Article)

Chemical References

• VDAC1 protein, human
• Voltage-Dependent Anion Channel 1
• Ubiquitin-Protein Ligases
• Ataxin-3

Topics

• Ataxin-3 (genetics, metabolism)
• Humans
• Machado-Joseph Disease (genetics, metabolism)
• Mitochondria (genetics, metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)
• Voltage-Dependent Anion Channel 1 (genetics, metabolism)