Negative regulation of mitochondrial transcription by mitochondrial topoisomerase I
| Autor: | Christian Mielke, Heiner Schaal, Frank Hillebrand, Rudolf J. Wiesner, Ilaria Dalla Rosa, Fritz Boege, Morten O. Christensen, Stefan Sobek, Hongliang Zhang, Faiza Kalfalah, Beatrice Bornholz, Yves Pommier, Jürgen-Christoph von Kleist-Retzow |
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| Rok vydání: | 2013 |
| Předmět: |
Mitochondrial DNA
Transcription Genetic biology RNA Mitochondrial Nucleic Acid Enzymes Topoisomerase Mitochondrion MT-RNR1 Mitochondrial apoptosis-induced channel Molecular biology Mitochondria Mice DNA Topoisomerases Type I Gene Expression Regulation Transcription (biology) Cell Line Tumor Genetics biology.protein DNAJA3 Animals Humans RNA ATP–ADP translocase Cells Cultured |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| DOI: | 10.1093/nar/gkt768 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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