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

Abstract

Alterations in mitochondrial morphology and function have been linked to neurodegenerative diseases, including Parkinson disease, Alzheimer disease and Huntington disease. Metabolic defects, resulting from dysfunctional mitochondria, have been reported in patients and respective animal models of all those diseases. Spinocerebellar Ataxia Type 3 (SCA3), another neurodegenerative disorder, also presents with metabolic defects and loss of body weight in early disease stages although the possible role of mitochondrial dysfunction in SCA3 pathology is still to be determined. Interestingly, the SCA3 disease protein ataxin-3, which is predominantly localized in cytoplasm and nucleus, has also been associated with mitochondria in both its mutant and wildtype form. This observation provides an interesting link to a potential mitochondrial involvement of mutant ataxin-3 in SCA3 pathogenesis. Furthermore, proteolytic cleavage of ataxin-3 has been shown to produce toxic fragments and even overexpression of artificially truncated forms of ataxin-3 resulted in mitochondria deficits. Therefore, we analyzed the repercussions of expressing a naturally occurring N-terminal cleavage fragment of ataxin-3 and the influence of an endogenous expression of the S256 cleavage fragment in vitro and in vivo. In our study, expression of a fragment derived from calpain cleavage induced mitochondrial fragmentation and cristae alterations leading to a significantly decreased capacity of mitochondrial respiration and contributing to an increased susceptibility to apoptosis. Furthermore, analyzing mitophagy revealed activation of autophagy in the early pathogenesis with reduced lysosomal activity. In conclusion, our findings indicate that cleavage of ataxin-3 by calpains results in fragments which interfere with mitochondrial function and mitochondrial degradation processes.

Physiological and pathophysiological characteristics of ataxin-3 isoforms

“…3, A and B). Even more interesting, a fragment of ataxin-3, which was recently described to cause mitochondrial dysfunction (47), was highly enriched in the nucleus as well ( Fig. 3C).…”

“…This is of special interest, as it was previously reported that cleavage of mutant ataxin-3 leads to a nuclear translocation of the polyQcontaining fragment (4,9). At the same time, these fragments are considered to be more toxic and show an increased propensity to form aggregates compared with the full-length protein (2,24,26,27,47,89,90). Ataxin-3 is known to be a deubiquitinating enzyme (7,8), and that cellular turnover of ataxin-3, as well as its steady-state level, is regulated by its catalytic activity (13).…”

MUL1 gene polymorphisms and Parkinson’s disease risk

“…bioenergy defects and mitochondrial dysfunction can lead to progressive decline of the central nervous system, and can even lead to endogenous apoptosis of neurons 16,18. Parkinson's disease may occur when the same pathological changes occur in dopaminergic cells in the substantia nigra.…”

“…bioenergy defects and mitochondrial dysfunction can lead to progressive decline of the central nervous system, and can even lead to endogenous apoptosis of neurons 16,18. The link between mitochondrial defects and the risk of neurodegenerative diseases may lay the foundation for individualized therapeutic interventions for future neurodegenerative disorders 18,19. The link between mitochondrial defects and the risk of neurodegenerative diseases may lay the foundation for individualized therapeutic interventions for future neurodegenerative disorders 18,19.…”

“…Parkinson's disease may occur when the same pathological changes occur in dopaminergic cells in the substantia nigra. The link between mitochondrial defects and the risk of neurodegenerative diseases may lay the foundation for individualized therapeutic interventions for future neurodegenerative disorders 18,19. Evidences suggested MUL1 had a biologically sound role in PD susceptibility.…”