Universität zu Köln

Rozsivalova, Dieu Hien (2023). The role of LONP1 in the mammalian mitochondrial gene expression. PhD thesis, Universität zu Köln.

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Abstract

Mitochondria are a melting pot of several metabolic pathways and other cellular processes. Therefore, tight regulatory mechanisms must be in place and the maintenance of mitochondrial homeostasis is essential for the organism. Lon proteases are serine peptidases that are conserved throughout the kingdoms of living organisms. LON is encoded by the nuclear genome and belongs to the AAA+ protein family (ATPases associated with diverse cellular activities). In the mammalian mitochondrial matrix, the key role of LONP1 is to preserve mitochondrial proteostasis. LONP1 recognizes and degrades unfolded or damaged proteins to prevent their aggregation. LONP1 is also involved in the regulation of several mitochondrial processes, as it was shown to target specific folded proteins. A few examples of these processes are the heme biosynthesis (ALAS1), the lipid metabolism (StAR), adaptation to hypoxic conditions (COX4-1), etc. LONP1 was also reported to regulate the mitochondrial gene expression, e.g., by targeting TFAM, the most abundant mtDNA-binding protein. Furthermore, LONP1 has been reported to be involved in the mitoribosomal assembly and processing of some newly imported proteins. In yeasts, a catalytically inactive Pim1/LON was proposed to promote assembly of complex IV which indicates a possible chaperone-like function of the protease. In mammals, the general loss of LONP1 in mice resulted in embryonic lethality around E7.5, demonstrating its essential function in the early embryonic development. The goal of this project was to further understand LONP1 and its role in the mitochondrial gene expression, in the regulation of OXPHOS, and in the mitochondrial proteostasis. We established a conditional heart-specific model in C57BL/6N mice. Our results show that LONP1 absence in heart resulted in the accumulation of insoluble in mitochondria and downregulation of protein levels of OXPHOS complexes I, III, IV and V, but not complex II. Furthermore, the depletion led to an increase in the mitoribosomal proteins and a general upregulation of protein levels in factors involved in the mitochondrial gene expression. Interestingly, the de novo mtRNA synthesis is also increased, but it does not lead to a general accumulation of the steady-state levels of mtRNAs. The mitochondrial de novo protein synthesis in mildly decreased despite the accumulation of mitoribosomal steady-state protein levels. Collectively, these results suggest an important multitasking role of LONP1 in the mitochondrial biology.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Rozsivalova, Dieu Hien hien.hothidieu@gmail.com UNSPECIFIED UNSPECIFIED
Contributors:	Contribution Name Email Thesis advisor Trifunovic, Aleksandra atrifuno@uni-koeln.de
URN:	urn:nbn:de:hbz:38-708017
Date:	2023
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 Mitochondria, LONP1, protease, protein homeostasis, proteostasis, OXPHOS, mtDNA, mitoribosome English
Date of oral exam:	30 May 2023
Referee:	Name Academic Title Trifunovic, Aleksandra Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/70801