Mass spectrometry analyses of normal and polyglutamine expanded ataxin-3 reveal novel interaction partners involved in mitochondrial function

Mitochondrial Morphology, Function and Homeostasis Are Impaired by Expression of an N-terminal Calpain Cleavage Fragment of Ataxin-3

“…Understanding this link between neurodegenerative diseases and mitochondria may pave the way for future therapeutic interventions in neurodegenerative disorders. Both wildtype and polyglutamine-expanded ataxin-3, the disease-causing protein in SCA3, were shown to interact with mitochondria ( Pozzi et al, 2008 ; Kristensen et al, 2018 ). Up to date, it is unclear, if full-length wildtype and/ or polyglutamine-expanded ataxin-3 or N- and C-terminal fragments generated by proteolytic cleavage events during the pathogenesis are responsible for the observed impaired mitochondrial function and homeostasis.…”

“…While the exact correlation between disruption of the mitochondrial network and mitochondrial function and biogenesis is still a matter of debate in the case of HD (reviewed in Costa and Scorrano, 2012 ), complex-II impairment emerges as key event of mitochondrial dysfunction in SCA3 and has been observed in different SCA3 cell and animal models as well as in peripheral cells of SCA3 patients ( Laço et al, 2012 ). Additionally, mass spectroscopy analyses of polyglutamine-expanded ataxin-3 identified SDHA and SDHB, which are constitute part of the complex-II, as potential interactors ( Kristensen et al, 2018 ). Concordantly, the fragmented mitochondrial network observed in the SCA3 model analyzed in the present study came along with reduced complex-I and complex-II activities and reduced uncoupled respiration upon FCCP treatment.…”

“…Normally, ataxin-3 localizes in the cytoplasm but in SCA3 patients’ aberrant ataxin-3 also aggregates in the nucleus of a specific subset of neurons. Both, wildtype and polyglutamine-expanded ataxin-3, are also associated with mitochondria ( Pozzi et al, 2008 ; Kristensen et al, 2018 ). Whether ataxin-3 binds directly to mitochondria or indirectly through interaction partners remains elusive.…”

“…One possible interaction partner linking ataxin-3 to mitochondria is Parkin, a PD-associated E3 ubiquitin ligase, which is recruited to dysfunctional mitochondria, ubiquitinates outer membrane proteins and targets mitochondria for degradation under stress conditions ( Narendra et al, 2008 ; Durcan et al, 2011 ). Recent mass spectrometry analyses revealed several new mitochondrial proteins as confirmed or potential interaction partners of wildtype and/ or mutant ataxin-3, including cytochrome C oxidase subunit NDUFA4 (NDUFA4), succinate dehydrogenase (ubiquinone) iron-sulfur subunit (SDHB) and cytochrome C oxidase assembly factor 7 (COA7) ( Kristensen et al, 2018 ). Mitochondrial DNA (mtDNA) deletions were frequently found in SCA3 transgenic mice as well as in most SCA3 patients and were more pronounced in the preclinical stage but not present in healthy individuals or SCA3 mutation carriers ( Yu et al, 2009 ; Kazachkova et al, 2013 ; Ramos et al, 2015 ; Raposo et al, 2018 ).…”

“…Additionally, the protein mitochondrial genome maintenance exonuclease 1 (MGME1) which is linked to mitochondrial DNA repair was found enriched in ataxin-3 overexpressing HEK293 cells by mass spectrometry analysis. Based on the same methodology, succinate dehydrogenase complex, subunit A (SDHA) and SDHB which are constitute parts of the complex-II of the electron transport chain, were identified as interaction partners of ataxin-3 and therefore, may explain the reduced complex-II activity in SCA3 patient lymphoblast cell lines and cerebellar granule cells from transgenic SCA3 mice ( Laço et al, 2012 ; Kristensen et al, 2018 ).…”