Universität zu Köln

Grotehans, Nils ORCID: 0009-0009-9418-267X (2023). Nucleotide metabolism and the control of mitochondrial gene expression. PhD thesis, Universität zu Köln.

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Abstract

Nucleotides are the building blocks of life, that make up the DNA and RNA in all living beings. Cellular nucleotide metabolism, a fundamental biological process, regulates the uptake, synthesis, distribution and recycling of nucleotides. The sufficient supply of nucleotides ensures the functional expression of genes, which not only takes place in the cytosol but also occurs in mitochondria, which contain their own genome. Mitochondria rely on the expression of their few but essential genes to fulfil their pleiotropic cellular functions such as ATP production, ironsulfur cluster biogenesis and innate immune signaling. Here we studied the impact of perturbed nucleotide homeostasis on mitochondrial gene expression and cellular function. We identified the mitochondrial nucleoside diphosphate kinase 6 (NME6) as a novel regulator of mitochondrial gene expression. NME6 provides ribonucleotides for mitochondrial transcription and deoxyribonucleotides for mitochondrial DNA replication. NME6 becomes essential for the maintenance of the mitochondrial DNA if the mitochondrial nucleotide uptake from the cytosol is impaired. Moreover, reduced mitochondrial cytidine triphosphate levels become rate-limiting for mitochondrial transcription in the absence of NME6 and lead to a respiratory deficiency. Pyrimidine nucleoside supplementation suffices to fully restore mitochondrial transcript levels and respiratory capacity upon loss of NME6. Thus, we describe NME6 as the first mitochondrial enzyme that regulates mitochondrial gene expression by the supply of ribonucleotides. Our work advances the current understanding of mitochondrial nucleotide metabolism and its contribution to mitochondrial function in health and disease.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Grotehans, Nils ngrotehans@age.mpg.de orcid.org/0009-0009-9418-267X UNSPECIFIED
URN:	urn:nbn:de:hbz:38-718305
Date:	2023
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Biology of Ageing
Subjects:	Life sciences
Uncontrolled Keywords:	Keywords Language NME6, nucleotide metabolism, RNA, mitochondria, SLC25A33, SLC25A36 UNSPECIFIED
Date of oral exam:	19 October 2023
Referee:	Name Academic Title Langer, Thomas Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/71830