An electronic copy of the thesis may be ordered from the faculty up to 2 days prior to the public defence. Inquiries regarding the thesis after the public defence must be addressed to the candidate.
Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Christian Behrends, Ludwig-Maximilans-Universität München, Germany
- Second opponent: Project Leader, Senior Scientist Alicia Llorente, Oslo University Hospital
- Third member and chair of the evaluation committee: Professor Kåre-Olav Stensløkken, University of Oslo
Chair of the Defence
Professor Lars Eide, University of Oslo
Principal Supervisor
Professor Anne Gjøen Simonsen, University of Oslo
Summary
Intracellular trafficking events such as endocytosis, secretion, exocytosis, and autophagy are important for normal cellular function, for inter-organelle and extracellular communication. In this thesis, Ana Lapão and co-workers have characterized novel players involved in regulation of membrane trafficking and cellular homeostasis.
Autophagy is responsible for maintaining cellular homeostasis by targeting surplus or damaged cellular components for degradation and recycling at the lysosome. The cholesterol transport protein GRAMD1C was identified as a negative regulator of autophagy and found to be a regulator of mitochondrial cholesterol levels and ATP production. Importantly, we show that the expression of GRAM family members is associated with overall survival of clear cell renal carcinoma patients.
Mitochondria are essential organelles for cellular homeostasis and energy production. We show that the lipid-binding protein SYTL5 interacts with RAB27A, a protein known to regulate exocytosis. We demonstrate that SYTL5 localizes to mitochondria in a RAB27A-dependent manner and that both proteins are involved in regulation of mitochondrial bioenergetics. When analyzing adrenocortical carcinoma patient survival outcomes, we observed that lower SYTL5 expression is related to a lower survival prognosis. We hypothesize that SYTL5 regulates the export of newly synthesized steroid hormones from mitochondria to the extracellular space.
Mutations in the lipid-binding domain of SNX10 are linked to the bone disease osteopetrosis. We showed that SNX10 regulates endocytosis, participates in enzyme secretion, a process often defective in osteoclasts and is important for mitochondrial function.
Together, the results of this thesis unveil important roles of novel lipid-binding proteins in several intracellular trafficking events and human disease. As the proteins studied in this thesis are associated to severe, poorly characterized pathologies, a better understanding for their cellular function will pave the way for development of novel therapeutics and possibly new disease biomarkers.
Additional information
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