Negative regulation of mitochondrial transcription by mitochondrial topoisomerase I

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. Def...

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Bibliographic Details
Published in:Nucleic acids research 2013-11, Vol.41 (21), p.9848-9857
Main Authors: Sobek, Stefan, Dalla Rosa, Ilaria, Pommier, Yves, Bornholz, Beatrice, Kalfalah, Faiza, Zhang, Hongliang, Wiesner, Rudolf J, von Kleist-Retzow, Jürgen-Christoph, Hillebrand, Frank, Schaal, Heiner, Mielke, Christian, Christensen, Morten O, Boege, Fritz
Format: Article
Language:English
Subjects:
Animals
Cell Line, Tumor
Cells, Cultured
DNA Topoisomerases, Type I - metabolism
Gene Expression Regulation
Humans
Mice
Mitochondria - enzymology
Mitochondria - genetics
Mitochondria - metabolism
Nucleic Acid Enzymes
RNA - metabolism
Transcription, Genetic
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Summary: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 IIβ 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.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkt768