Progressive mitochondrial dysfunction in cerebellar synaptosomes of cystatin B-deficient mice

Katarin Gorski; Christopher B Jackson; Tuula A Nyman; Veronika Rezov; Brendan J Battersby; Anna-Elina Lehesjoki

doi:10.3389/fnmol.2023.1175851

Progressive mitochondrial dysfunction in cerebellar synaptosomes of cystatin B-deficient mice

Front Mol Neurosci. 2023 May 12:16:1175851. doi: 10.3389/fnmol.2023.1175851. eCollection 2023.

Authors

Katarin Gorski^{1

2}, Christopher B Jackson³, Tuula A Nyman⁴, Veronika Rezov^{1

2}, Brendan J Battersby⁵, Anna-Elina Lehesjoki^{1

2}

Affiliations

¹ Folkhälsan Research Center, Helsinki, Finland.
² Medicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
³ Department of Biochemistry and Developmental Biology, Medicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁴ Department of Immunology, Oslo University Hospital, University of Oslo, Oslo, Norway.
⁵ Institute of Biotechnology, University of Helsinki, Helsinki, Finland.

Abstract

The involvement of mitochondrial dysfunction in cystatin B (CSTB) deficiency has been suggested, but its role in the onset of neurodegeneration, myoclonus, and ataxia in the CSTB-deficient mouse model (Cstb^-/-) is yet unknown. CSTB is an inhibitor of lysosomal and nuclear cysteine cathepsins. In humans, partial loss-of-function mutations cause the progressive myoclonus epilepsy neurodegenerative disorder, EPM1. Here we applied proteome analysis and respirometry on cerebellar synaptosomes from early symptomatic (Cstb^-/-) mice to identify the molecular mechanisms involved in the onset of CSTB-deficiency associated neural pathogenesis. Proteome analysis showed that CSTB deficiency is associated with differential expression of mitochondrial and synaptic proteins, and respirometry revealed a progressive impairment in mitochondrial function coinciding with the onset of myoclonus and neurodegeneration in (Cstb^-/-) mice. This mitochondrial dysfunction was not associated with alterations in mitochondrial DNA copy number or membrane ultrastructure. Collectively, our results show that CSTB deficiency generates a defect in synaptic mitochondrial bioenergetics that coincides with the onset and progression of the clinical phenotypes, and thus is likely a contributor to the pathogenesis of EPM1.

Keywords: OXPHOS; mitochondria; myoclonus; neurodegeneration; proteomics; respiration; synaptosome.