Universität zu Köln

Ravanelli, Sonia ORCID: 0000-0002-8511-9339 (2022). Metabolic Regulation of the Ubiquitin-Proteasome System. PhD thesis, Universität zu Köln.

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Abstract

Metabolic and protein networks are highly dynamic and flexible; therefore, efficient surveillance of both networks is required to maintain cellular and organismal integrity. The ubiquitin proteasome system (UPS) ensures selective turnover of damaged proteins, avoiding accumulation of potentially toxic proteins and restoring the amino acid pool. Previously, our lab demonstrated that metabolic defects reduce the UPS function without activating the mitochondrial unfolded protein response (UPRmt). Depletion of the leucine catabolic enzyme isovaleryl CoA dehydrogenase (IVD) impaired the turnover of a fluorescently tagged UPS substrate both in C. elegans and in mammalian cells, identifying a previously unknown link between proteostasis loss and the metabolic disorder isovaleric acidemia. However, the mechanistic regulation of the UPS by leucine catabolism remained to be determined. Combining genetic and multi omics approaches in C. elegans, I demonstrated that altered BCAT-1, the enzyme responsible for the first step of the branched chain amino acid (BCAA) metabolism, can restore UPS defects observed upon defective IVD-1. Particularly, the transcription of proteasome regulatory subunits is reduced in ivd-1 loss-of function mutants, which might reflect an adaptive response mechanism. Conversely, the bcat 1(hh58) mutant allele promoted the expression of proteasome subunits in ivd 1 loss of function mutants suggesting a recovery of the proteasomal capacity. Supplementation of isovaleric acid (IVA), an intermediate metabolite accumulating in the body fluids of isovaleric acidemia patients, impaired the UPS and enhanced aggregation of metastable proteins. Collectively, my work contributes to the current knowledge related to the etiology of the metabolic disorder isovaleric acidemia, identifying proteostasis loss as a contributing pathological event and the BCAA transamination as a novel potential therapeutic target. Since impaired BCAA metabolism has been linked to a multitude of pathological states, the identified connection between BCAA metabolism and the UPS might also be relevant for the development of clinical interventions for the treatment of cardiovascular diseases, diabetes, cancer, and neurodegenerative disorders.

Item Type:	Thesis (PhD thesis)
Translated abstract:	Abstract Language UNSPECIFIED English
Creators:	Creators Email ORCID ORCID Put Code Ravanelli, Sonia sravanel@uni-koeln.de orcid.org/0000-0002-8511-9339 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-635531
Date:	30 September 2022
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases
Subjects:	Natural sciences and mathematics
Uncontrolled Keywords:	Keywords Language Proteostasis English Metabolism English C. elegans English Proteasome English Ubiquitin English
Date of oral exam:	26 January 2022
Referee:	Name Academic Title Hoppe, Thorsten Prof.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/63553