Universität zu Köln

Thewes, Britta (2022). Characterization of the Mitochondrial Scaffold Protein SLP2. PhD thesis, Universität zu Köln.

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Abstract

Mitochondria are essential organelles that perform diverse functions in eukaryotic cells. They possess a complex ultrastructure with two membranes and multiple compartments in which mitochondrial- and nuclear-encoded proteins ensure mitochondrial function in an organized manner. This organization within mitochondria is maintained by various proteins, protein complexes, and lipids, e.g., the ATP synthase, respiratory chain (super)complexes, the MICOS complex, the GTPase OPA1, the lipid cardiolipin, and the structural proteins PHB, PHB2 and SLP2. In contrast to the essential prohibitin complex, little is known about the functions of SLP2. Together with the proteases PARL and YME1L, SLP2 forms the so-called SPY complex at the inner membrane of mitochondria and influences respiratory chain supercomplex formation, mitochondrial calcium homeostasis and stress-induced hyperfusion of mitochondria. To understand the function of SLP2 in mitochondria, immunoprecipitation experiments of SLP2 as well as various omics approaches and biochemical experiments were performed in human SLP2 deficient cells. We found that SLP2 interacts with a variety of mitochondrial proteins and is thus tightly linked to the mitochondrial network. Loss of SLP2 resulted in global impairment of mitochondrial gene expression and increased turnover of the mitochondrial small ribosomal subunit and the interactors TMBIM5, DNAJC15 and APOO. This gene expression defect led to respiratory chain deficits and secondarily to impairment of the TCA cycle and a stress response of the cell, the integrated stress response. In conclusion, we show in this work that SLP2 is required for optimal mitochondrial function via gene expression. Furthermore, we uncover previously unknown connections of SLP2 to the protein import machinery, the MICOS complex and the respiratory chain, and discover protein-specific effects of SLP2 on protein turnover. Thus, with the results presented in this thesis, we demonstrate that SLP2 is an important structural protein with diverse roles in maintaining mitochondrial function.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Thewes, Britta UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-815223
Date:	2022
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Biology of Ageing
Subjects:	Life sciences
Uncontrolled Keywords:	Keywords Language mitochondria; scaffold; SLP2; prohibitin; SPY complex English
Date of oral exam:	2 December 2022
Referee:	Name Academic Title Langer, Thomas Prof. Dr. Riemer, Jan Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/81522