Regulation of mtDNA gene expression and the role of respiratory chain supercomplexes in mammalian mitochondria
Author: Misic, Jelena
Date: 2024-03-21
Location: Ragnar Granit lecture hall, Karolinska Institutet Biomedicum, Solnavägen 9, Stockholm
Time: 09.00
Department: Inst för medicinsk biokemi och biofysik / Dept of Medical Biochemistry and Biophysics
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Thesis (1.200Mb)
Abstract
Mitochondria are cellular organelles found in nearly all eukaryotic cells, where they fulfill a plethora of functions, including energy conversion. They harness energy from carbon sources to synthesize adenosine triphosphate (ATP) through the process of oxidative phosphorylation (OXPHOS). Mammalian mitochondria contain ~1200 proteins and only 13 of these are encoded by mitochondrial DNA (mtDNA). Despite the small contribution to the mitochondrial proteome, expression of mtDNA is nevertheless critically important for biogenesis and normal function of the OXPHOS system. The expression of mtDNA is dependent on ~200 nucleus-encoded proteins that are imported into mitochondria to control maintenance, replication, and transcription of mtDNA, as well as translation of the mtDNA-encoded messenger RNAs (mRNAs). Mitochondrial gene expression is thus controlled at many different levels. In the first part of this thesis, molecular mechanisms are reported for initiation and completion of mtDNA replication. Furthermore, mechanisms controlling the switch from transcription initiation to elongation, as well as a putative link between transcription elongation and RNA processing are reported. These results were based on extensive analysis of conditional knockout mouse models for RNase H1, TEFM, and mtSSB. In the second part of the thesis, the organization of the OXPHOS system is studied. It consists of the respiratory chain enzyme complexes, two electron shuttles and the ATP synthase. A wide range of studies have shown that the different respiratory chain enzyme complexes can interact with each other to form higher order assemblies, so called supercomplexes. The respirasome is a particularly interesting supercomplex as it consists of a complete respiratory chain. Results from multiple studies have suggested that the respirasome plays a crucial role in cellular bioenergetics by facilitating translocation and routing of electrons. To address this question, we extensively characterized a knockin mouse model engineered to have normal levels of respiratory chain complexes that cannot interact to form respirasomes. Surprisingly, mice with drastically reduced levels of respirasomes are healthy without any clear impact on bioenergetics or whole animal physiology. Our results thus challenge the multiple proposed roles for respirasomes in physiology and disease.
List of papers:
I. Jelena Misic, Dusanka Milenkovic, Ali Al-Behadili, Xie Xie, Min Jiang, Shan Jiang, Roberta Filograna, Camilla Koolmeister, Stefan J. Siira, Louise Jenninger, Aleksandra Filipovska, Anders R. Clausen, Leonardo Caporali, Maria Lucia Valentino, Chiara La Morgia, Valerio Carelli, Thomas J. Nicholls, Anna Wredenberg, Maria Falkenberg, Nils-Göran Larsson†. (2022). Mammalian RNase H1 directs RNA primer formation for mtDNA replication initiation and is also necessary for mtDNA replication completion. Nucleic Acids Res. 50, 8749–8766. †Corresponding author(s).
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II. Shan Jiang, Camilla Koolmeister, Jelena Misic, Stefan Siira, Inge Kühl, Eduardo Silva Ramos, Maria Miranda, Min Jiang, Viktor Posse, Oleksandr Lytovchenko, Ilian Atanassov, Florian A. Schober, Rolf Wibom, Kjell Hultenby, Dusanka Milenkovic, Claes M. Gustafsson, Aleksandra Filipovska, Nils-Göran Larsson†. (2019). TEFM regulates both transcription elongation and RNA processing in mitochondria. EMBO Rep. 20, 1–18. †Corresponding author(s).
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III. Min Jiang*, Xie Xie*, Xuefeng Zhu*, Shan Jiang, Dusanka Milenkovic, Jelena Misic, Yonghong Shi, Nirwan Tandukar, Xinping Li, Ilian Atanassov, Louise Jenninger, Emily Hoberg, Sara Albarran-Gutierrez, Zsolt Szilagyi, Bertil Macao, Stefan J. Siira, Valerio Carelli, Jack D. Griffith, Claes M. Gustafsson, Thomas J. Nicholls, Aleksandra Filipovska, Nils-Göran Larsson†, Maria Falkenberg†. (2021). The mitochondrial single-stranded DNA binding protein is essential for initiation of mtDNA replication. Sci Adv. 7, eabf8631. *These authors contributed equally. †Corresponding author(s).
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IV. Dusanka Milenkovic, Jelena Misic, Johannes F. Hevler, Thibaut Molinié, Injae Chung, Ilian Atanassov, Xinping Li, Roberta Filograna, Andrea Mesaros, Arnaud Mourier, Albert J.R. Heck, Judy Hirst†, Nils-Göran Larsson†. (2023). Preserved respiratory chain capacity and physiology in mice with profoundly reduced levels of mitochondrial respirasomes. Cell Metab. 35, 1799-1813.e7. †Corresponding author(s).
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I. Jelena Misic, Dusanka Milenkovic, Ali Al-Behadili, Xie Xie, Min Jiang, Shan Jiang, Roberta Filograna, Camilla Koolmeister, Stefan J. Siira, Louise Jenninger, Aleksandra Filipovska, Anders R. Clausen, Leonardo Caporali, Maria Lucia Valentino, Chiara La Morgia, Valerio Carelli, Thomas J. Nicholls, Anna Wredenberg, Maria Falkenberg, Nils-Göran Larsson†. (2022). Mammalian RNase H1 directs RNA primer formation for mtDNA replication initiation and is also necessary for mtDNA replication completion. Nucleic Acids Res. 50, 8749–8766. †Corresponding author(s).
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Shan Jiang, Camilla Koolmeister, Jelena Misic, Stefan Siira, Inge Kühl, Eduardo Silva Ramos, Maria Miranda, Min Jiang, Viktor Posse, Oleksandr Lytovchenko, Ilian Atanassov, Florian A. Schober, Rolf Wibom, Kjell Hultenby, Dusanka Milenkovic, Claes M. Gustafsson, Aleksandra Filipovska, Nils-Göran Larsson†. (2019). TEFM regulates both transcription elongation and RNA processing in mitochondria. EMBO Rep. 20, 1–18. †Corresponding author(s).
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III. Min Jiang*, Xie Xie*, Xuefeng Zhu*, Shan Jiang, Dusanka Milenkovic, Jelena Misic, Yonghong Shi, Nirwan Tandukar, Xinping Li, Ilian Atanassov, Louise Jenninger, Emily Hoberg, Sara Albarran-Gutierrez, Zsolt Szilagyi, Bertil Macao, Stefan J. Siira, Valerio Carelli, Jack D. Griffith, Claes M. Gustafsson, Thomas J. Nicholls, Aleksandra Filipovska, Nils-Göran Larsson†, Maria Falkenberg†. (2021). The mitochondrial single-stranded DNA binding protein is essential for initiation of mtDNA replication. Sci Adv. 7, eabf8631. *These authors contributed equally. †Corresponding author(s).
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IV. Dusanka Milenkovic, Jelena Misic, Johannes F. Hevler, Thibaut Molinié, Injae Chung, Ilian Atanassov, Xinping Li, Roberta Filograna, Andrea Mesaros, Arnaud Mourier, Albert J.R. Heck, Judy Hirst†, Nils-Göran Larsson†. (2023). Preserved respiratory chain capacity and physiology in mice with profoundly reduced levels of mitochondrial respirasomes. Cell Metab. 35, 1799-1813.e7. †Corresponding author(s).
Fulltext (DOI)
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View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Larsson, Nils-Göran
Co-supervisor: Wredenberg, Anna
Issue date: 2024-02-22
Rights:
Publication year: 2024
ISBN: 978-91-8017-238-7
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