Mitochondrial dysfunction and steroidogenesis in Parkinson disease
Date
2023-09-06
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Patients with Parkinson disease (PD), one of the most common neurodegenerative disorders, have elevated levels of the glucocorticoid cortisol, a stress-related steroid hormone. Increased stress or glucocorticoids in experimental models of PD worsens neurodegeneration, implicating elevated glucocorticoids in disease pathogenesis. However, the mechanism behind dysregulated glucocorticoid levels is unclear. The rate-limiting step of steroidogenesis, cholesterol import into the mitochondria, is mediated by steroidogenic acute regulatory protein (STARD1). STARD1 transports cholesterol while transiently localized to the outer mitochondrial membrane. Impairments in mitochondrial protein import, a key aspect of cellular dysfunction linked to PD, increase STARD1-mediated mitochondrial cholesterol import, providing a potential mechanism connecting PD with increased steroidogenesis. To test how steroidogenesis is affected by mitochondrial function in PD, we used PD-related toxins and genetic variants to model the effects of PD. We looked at the import of STARD1 overexpressed in HEK293 cells and steroid production in steroidogenic adrenocortical cell lines. We found that the PD toxin rotenone slowed STARD1 import and increased cholesterol import. Cortisol production increased only under lower levels of rotenone-induced mitochondrial stress. This is intriguing as milder mitochondrial stress may be more relevant to the progressive nature of PD. Additionally, overexpression of PD pathogenic variant alpha synuclein A53T upregulated basal production of pregnenolone and cortisol in steroidogenic cells. To explore further connections between steroidogenesis and PD, we also looked for miRNA biomarkers related to steroidogenesis in PD patients. We found expression of hsa-mir-320a in PD patient serum exosomes was negatively correlated with disease duration. As this miRNA negatively regulates expression of certain enzymes involved in cortisol synthesis, dysregulation of this miRNA could contribute to elevated cortisol levels in PD. Overall, our findings are consistent with cellular dysfunction in PD upregulating cortisol production. We delineated a novel pathway where mitochondrial dysfunction in PD activates cholesterol import by STARD1 to promote steroidogenesis. STARD1 may be a novel therapeutic target in PD. Additionally, as steroid signalling can be acutely protective against cellular stress, we propose this could be a stress response mechanism that couples steroid production to mitochondrial status, but which can be detrimental upon prolonged activation.
Description
Keywords
Citation
Lee-Glover, L. P. (2023). Mitochondrial dysfunction and steroidogenesis in Parkinson disease (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.