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: Researcher Ian Ganley, University of Dundee
- Second opponent: Associate Professor II Åsa Birna Birgisdottir, UiT
- Third member and chair of the evaluation committee: Associate Professor Coen Campsteijn, University of Oslo
Chair of the Defence
Professor Bjørn Steen Skålhegg, Faculty of Medicine, University of Oslo
Principal Supervisor
Professor Anne Gjøen Simonsen, Faculty of Medicine, University of Oslo
Summary
The human cell is an impressively complex system that is built up of macro and micro-molecules such as proteins and lipids, which are subsequently organized into specialized compartments called organelles. Many pathogenetic conditions such as cancer and neurodegenerative diseases are caused by disruption of these cellular components, and it is therefore crucial that their quality and function is tightly regulated to maintain cell health and normal function.
The quality control of proteins and organelles is achieved in large part through a degradation process called autophagy. Autophagy describes a complex pathway signalling and vesicle trafficking events that lead to the transport of cellular cargo to acidic cellular compartments called lysosomes, where the cargo is broken down. While autophagy is increasingly being recognized to play important roles in health and disease, the fundamental mechanisms of autophagy remain to be completely understood.
In this thesis, Matthew and colleagues investigated lipid-binding proteins through a series of biochemical assays and high-throughput microscopy-based siRNA screens in to identify regulators of non-selective (bulk cytoplasm) and selective (mitochondria) autophagy. From a large panel of positive and negative regulators of autophagy, Matthew characterized the role of 4 different proteins in mitophagy and non-selective autophagy: 4-Nitrophenylphosphatase Domain And Non-Neuronal SNAP25-Like (NIPSNAP1/2) were shown to be stabilized onto the mitochondrial membrane upon mitochondrial damage in order to recruit the autophagic machinery. The protein kinases cyclin G associated kinase (GAK) and protein kinase C delta
(PRKCD) were shown to be crucial for mitochondrial degradation in the face of hypoxia and hypoxia-like responses in a manner which is dependent on their kinase activities. The cholesterol transport protein GRAM domain containing 1C (GRAMD1C) was shown to be involved in the regulation of non-selective autophagy and mitochondrial bioenergetics.
These results contribute to our understanding of the complex process that takes place during autophagy and importantly, how autophagy is regulated in response to different cellular insults. These regulators represent interesting candidates for further work in relation to their role in cellular quality control and pathogenesis.
Additional information
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