Universität zu Köln

Bock, Theresa (2023). Functional characterization of PERM1-dependent control of metabolic activity and mitochondrial network remodeling in contractile tissues. PhD thesis, Universität zu Köln.

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Abstract

Cardiac and skeletal muscle have a great demand of energy for contraction and ion transport, which can be covered by high fluxes of ATP. Therefore, cardiac and skeletal muscle function, particularly during development, rely on a dense network of mitochondria and oxidative metabolism. Major regulators of mitochondrial biogenesis in striated muscle are members of the peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1) and estrogen-related receptor (ERR) families. Here, we reported that PGC-1-and ERR-induced regulator in muscle 1 (PERM1) is increasingly expressed in cardiac and skeletal muscle tissue during early postnatal development. Furthermore, we determined the interactome of PERM1 and identified PERM1 as a tissue-specific interactor of the fully-assembled mitochondrial contact site and cristae organization system (MICOS)/mitochondrial intermembrane bridging (MIB) complex. Association of PERM1 with the outer mitochondrial membrane is dependent on a conserved C-terminal α-helical transmembrane domain. Moreover, we observed an interaction of the N-terminus of PERM1 with the N-terminal ankyrin-repeat domain of the costamere organizing protein ankyrin B (ANKB). Ablation of Perm1 using a systemic knockout mouse revealed overall downregulation of mitochondrial proteins, reduction in mitochondrial DNA, diminished mitochondrial membrane potential, increased presence of reactive oxygen species and antioxidant proteins, and reduced oxygen flux in isolated skeletal muscle tissue. Moreover, Perm1-/- muscles revealed a reduction in peripheral, subsarcolemmal mitochondria, particularly around capillaries. We suggest that interaction with ANKB and the intermediate filament proteins vimentin and nestin contributes to the establishment of a functional mitochondrial reticulum and enables optimal transport and supply with metabolites and ATP, and that PERM1 acts as a scaffold protein. Therefore, PERM1 might represent a major regulator of cardiac and skeletal muscle modulating mitochondrial metabolism and capacity.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Bock, Theresa tbock2@uni-koeln.de UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-735855
Date:	2023
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases
Subjects:	Chemistry and allied sciences Life sciences
Uncontrolled Keywords:	Keywords Language mitochondria English contractile tissues English
Date of oral exam:	2 November 2023
Referee:	Name Academic Title Krüger, Marcus Prof. Riemer, Jan Prof. Meissner, Felix Prof. Baumann, Ulrich Prof.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/73585