Mitochondrial impairments contribute to Spinocerebellar ataxia type 1 progression and can be ameliorated by the mitochondria-targeted antioxidant MitoQ

• Published in: Free radical biology & medicine Vol. 97; pp. 427 - 440
• Main Authors: Stucki, David M., Ruegsegger, Céline, Steiner, Silvio, Radecke, Julika, Murphy, Michael P., Zuber, Benoît, Saxena, Smita
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2016
• Subjects: Animals; Antioxidant MitoQ; Antioxidants - pharmacology; Antioxidants - therapeutic use; Disease Progression; DNA Damage; DNA, Mitochondrial - genetics; Drug Evaluation, Preclinical; Electron transport chain (ETC) activities; Mice, Inbred C57BL; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - pathology; Neurodegeneration; Organophosphorus Compounds - pharmacology; Organophosphorus Compounds - therapeutic use; Oxidative Stress; Proteome - metabolism; Purkinje cells; Spinocerebellar ataxia type 1; Spinocerebellar Ataxias - drug therapy; Spinocerebellar Ataxias - metabolism; Spinocerebellar Ataxias - pathology; Ubiquinone - analogs & derivatives; Ubiquinone - pharmacology; Ubiquinone - therapeutic use; Oxidative stress; Electron transport chain (ETC) activities; Mitochondria; Purkinje cells; Neurodegeneration; Spinocerebellar ataxia type 1; Antioxidant MitoQ
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2016.07.005

Spinocerebellar ataxia type 1 (SCA1), due to an unstable polyglutamine expansion within the ubiquitously expressed Ataxin-1 protein, leads to the premature degeneration of Purkinje cells (PCs), decreasing motor coordination and causing death within 10–15 years of diagnosis. Currently, there are no therapies available to slow down disease progression. As secondary cellular impairments contributing to SCA1 progression are poorly understood, here, we focused on identifying those processes by performing a PC specific proteome profiling of Sca1154Q/2Q mice at a symptomatic stage. Mass spectrometry analysis revealed prominent alterations in mitochondrial proteins. Immunohistochemical and serial block-face scanning electron microscopy analyses confirmed that PCs underwent age-dependent alterations in mitochondrial morphology. Moreover, colorimetric assays demonstrated impairment of the electron transport chain complexes (ETC) and decrease in ATPase activity. Subsequently, we examined whether the mitochondria-targeted antioxidant MitoQ could restore mitochondrial dysfunction and prevent SCA1-associated pathology in Sca1154Q/2Q mice. MitoQ treatment both presymptomatically and when symptoms were evident ameliorated mitochondrial morphology and restored the activities of the ETC complexes. Notably, MitoQ slowed down the appearance of SCA1-linked neuropathology such as lack of motor coordination as well as prevented oxidative stress-induced DNA damage and PC loss. Our work identifies a central role for mitochondria in PC degeneration in SCA1 and provides evidence for the supportive use of mitochondria-targeted therapeutics in slowing down disease progression. [Display omitted] •Morphological and functional mitochondrial alterations in SCA1 Purkinje cells.•Mitochondrial impairments coincides with elevated levels of oxidative stress.•Administration of antioxidant MitoQ to SCA1 mice ameliorates mitochondrial deficits.•Restoring mitochondrial function improves motor coordination and neuropathology.