Year: 2025
Type: dissertation
Abstract: Steroid hormones are indispensable signaling molecules for organismal homeostasis. Steroid synthesis is known to be regulated by control of the supply of cholesterol to mitochondria where the first steroid in the pathway, pregnenolone, is produced. All other steroids are produced from pregnenolone in reactions taking place in mitochondria and the endoplasmic reticulum. Endolysosomal uptake, de novo synthesis in the endoplasmic reticulum, and mobilization from lipid droplets or plasma membrane can contribute cholesterol for steroidogenesis. How these different organelles coordinate their contributions to steroidogenesis is largely unknown. Here, I aimed to identify novel mechanisms of steroidogenesis regulation in adrenocortical carcinoma cells. I characterized organellar functions required for steroidogenesis, finding that while mitochondrial energy production is essential, mitochondrial biogenesis and fusion are not required for steroidogenesis. Furthermore, lysosomes and endoplasmic reticulum may support steroidogenesis beyond their known contributions to cholesterol supply and intermediate steroid synthesis. I also screened changes in the proteomes of mitochondria and the whole cell upon initiation of steroidogenesis for novel regulators of steroidogenesis. The candidates which emerged from this screen have known functions in biogenesis of lysosome-related organelles and insertion of newly translated proteins into the endoplasmic reticulum membrane and lumen, but they had no previously known role in steroidogenesis. Knock-out of these candidates was found to impair steroidogenesis. Specifically, I found the protein BLOC1S6 which is known to regulate biogenesis of lysosome-related organelles is required for production of glucocorticoids in adrenocortical carcinoma cells. This suggests that, in addition to the regulation of steroidogenesis at its initial step of cholesterol supply to mitochondria, the synthesis of downstream glucocorticoids is regulated in a BLOC1S6-dependent manner.
Author: Melchinger, Philipp Ferdinand
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: Deutsche Forschungsgemeinschaft
Award: G1179449648
OpenAlex ID: W7111684530