Universität zu Köln

Sobek, Stefan, Dalla Rosa, Ilaria ORCID: 0000-0003-4801-2396, Pommier, Yves, Bornholz, Beatrice, Kalfalah, Faiza ORCID: 0000-0002-5186-8059, Zhang, Hongliang, Wiesner, Rudolf J., von Kleist-Retzow, Juergen-Christoph, Hillebrand, Frank, Schaal, Heiner, Mielke, Christian, Christensen, Morten O. and Boege, Fritz (2013). Negative regulation of mitochondrial transcription by mitochondrial topoisomerase I. Nucleic Acids Res., 41 (21). S. 9848 - 9858. OXFORD: OXFORD UNIV PRESS. ISSN 1362-4962

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Abstract

Mitochondrial topoisomerase I is a genetically distinct mitochondria-dedicated enzyme with a crucial but so far unknown role in the homeostasis of mitochondrial DNA metabolism. Here, we present data suggesting a negative regulatory function in mitochondrial transcription or transcript stability. Deficiency or depletion of mitochondrial topoisomerase I increased mitochondrial transcripts, whereas overexpression lowered mitochondrial transcripts, depleted respiratory complexes I, III and IV, decreased cell respiration and raised superoxide levels. Acute depletion of mitochondrial topoisomerase I triggered neither a nuclear mito-biogenic stress response nor compensatory topoisomerase II beta upregulation, suggesting the concomitant increase in mitochondrial transcripts was due to release of a local inhibitory effect. Mitochondrial topoisomerase I was co-immunoprecipitated with mitochondrial RNA polymerase. It selectively accumulated and rapidly exchanged at a subset of nucleoids distinguished by the presence of newly synthesized RNA and/or mitochondrial RNA polymerase. The inactive Y559F-mutant behaved similarly without affecting mitochondrial transcripts. In conclusion, mitochondrial topoisomerase I dampens mitochondrial transcription and thereby alters respiratory capacity. The mechanism involves selective association of the active enzyme with transcriptionally active nucleoids and a direct interaction with mitochondrial RNA polymerase. The inhibitory role of topoisomerase I in mitochondrial transcription is strikingly different from the stimulatory role of topoisomerase I in nuclear transcription.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Sobek, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Dalla Rosa, Ilaria UNSPECIFIED orcid.org/0000-0003-4801-2396 UNSPECIFIED Pommier, Yves UNSPECIFIED UNSPECIFIED UNSPECIFIED Bornholz, Beatrice UNSPECIFIED UNSPECIFIED UNSPECIFIED Kalfalah, Faiza UNSPECIFIED orcid.org/0000-0002-5186-8059 UNSPECIFIED Zhang, Hongliang UNSPECIFIED UNSPECIFIED UNSPECIFIED Wiesner, Rudolf J. UNSPECIFIED UNSPECIFIED UNSPECIFIED von Kleist-Retzow, Juergen-Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Hillebrand, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Schaal, Heiner UNSPECIFIED UNSPECIFIED UNSPECIFIED Mielke, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Christensen, Morten O. UNSPECIFIED UNSPECIFIED UNSPECIFIED Boege, Fritz UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-473624
DOI:	10.1093/nar/gkt768
Journal or Publication Title:	Nucleic Acids Res.
Volume:	41
Number:	21
Page Range:	S. 9848 - 9858
Date:	2013
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1362-4962
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language N-TERMINAL DOMAIN; RNA-POLYMERASE-II; MAMMALIAN MITOCHONDRIA; DNA NUCLEOIDS; MTDNA; CELLS; ACTIVATION; NUCLEAR; TFAM; REPLICATION Multiple languages Biochemistry & Molecular Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/47362