Mitochondrial RNA processing in health and disease
Author: Laine, Isabelle
Date: 2022-01-21
Location: Lars E. Gustafsson, D1012, Biomedicum, Karolinska Institutet, Solna
Time: 09.00
Department: Inst för medicinsk biokemi och biofysik / Dept of Medical Biochemistry and Biophysics
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Thesis (2.135Mb)
Abstract
Mitochondria are often described as the powerhouses of the cell, providing the main cellular energy source in the form of adenosine triphosphate. Five enzyme complexes, collectively termed the oxidative phosphorylation system, use the reducing power from nutrients to synthesise adenosine triphosphate via cellular respiration. This energy conversion is dependent on factors encoded by the nuclear and mitochondrial genome, with the latter encoding 13 subunits within four of the five oxidative phosphorylation system complexes. Adenosine triphosphate synthesis is therefore under dual genetic control, and this thesis addresses mechanisms that control and regulate mitochondrial gene expression.
The mitochondrial genome is transcribed as long, polycistronic premature transcripts, which need to undergo cleavage and maturation before they can be used for correct translation on mitochondrial ribosomes. However, the mechanisms of this RNA processing, as well as the mechanisms underlying mitochondrial RNA homeostasis, are not fully understood. Here I used the fruit fly, Drosophila melanogaster, to study factors involved in mitochondrial gene expression. In two studies I addressed the functions of factors involved in the mitochondrial degradosome, responsible for RNA turnover.
Additionally, I addressed the role of polyadenylation in RNA degradation, and studied how the polyadenylation machinery affects mitochondrial translation. Finally, defects of mitochondrial gene expression can have severe clinical consequences and form an important part of human pathology. One study of this thesis validated the pathogenicity of mutations in a tRNA aminoacyl transferase gene, identified in two siblings suffering from mitochondrial disease.
The mitochondrial genome is transcribed as long, polycistronic premature transcripts, which need to undergo cleavage and maturation before they can be used for correct translation on mitochondrial ribosomes. However, the mechanisms of this RNA processing, as well as the mechanisms underlying mitochondrial RNA homeostasis, are not fully understood. Here I used the fruit fly, Drosophila melanogaster, to study factors involved in mitochondrial gene expression. In two studies I addressed the functions of factors involved in the mitochondrial degradosome, responsible for RNA turnover.
Additionally, I addressed the role of polyadenylation in RNA degradation, and studied how the polyadenylation machinery affects mitochondrial translation. Finally, defects of mitochondrial gene expression can have severe clinical consequences and form an important part of human pathology. One study of this thesis validated the pathogenicity of mutations in a tRNA aminoacyl transferase gene, identified in two siblings suffering from mitochondrial disease.
List of papers:
I. Clemente, P., Pajak, A., Laine, I., Wibom, R., Wedell, A., Freyer, C.*, Wredenberg, A.*. SUV3 helicase is required for correct processing of mitochondrial transcripts. Nucleic Acid Research. 43, 7398–413 (2015). *Corresponding authors.
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II. Maffezzini, C.#, Laine, I.#, Dallabona, C., Clemente, P., Calvo-Garrido, J., Wibom, R., Naess, K., Barbaro, M., Falk, A., Donnini, C., Freyer, C.*, Wredenberg, A.*, Wedell, A.*. Mutations in the mitochondrial tryptophanyltRNA synthetase cause growth retardation and progressive leukoencephalopathy. Molecular Genetics & Genomic Medicine. (2019). #These authors contributed equally. *Corresponding authors.
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III. Pajak, A.#, Laine, I.#, Clemente, P., El-Fissi, N., Schober, FA., Maffezzini, C., Calvo-Garrido, J., Wibom, R., Filograna, R., Dhir, A., Wedell, A., Freyer, C.*, Wredenberg, A.*. Defects of mitochondrial RNA turnover lead to accumulation of double-stranded RNA in vivo. PLoS Genetics. (2019). #These authors contributed equally. *Corresponding authors.
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IV. Laine, I., Schober, FA., Clemente, P., Pajak, A., Haas, M., Filipovska, A., Wedell, A., Freyer, C., Wredenberg, A. Mitochondrial translation efficacy is dependent on RNA polyadenylation. [Manuscript]
I. Clemente, P., Pajak, A., Laine, I., Wibom, R., Wedell, A., Freyer, C.*, Wredenberg, A.*. SUV3 helicase is required for correct processing of mitochondrial transcripts. Nucleic Acid Research. 43, 7398–413 (2015). *Corresponding authors.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Maffezzini, C.#, Laine, I.#, Dallabona, C., Clemente, P., Calvo-Garrido, J., Wibom, R., Naess, K., Barbaro, M., Falk, A., Donnini, C., Freyer, C.*, Wredenberg, A.*, Wedell, A.*. Mutations in the mitochondrial tryptophanyltRNA synthetase cause growth retardation and progressive leukoencephalopathy. Molecular Genetics & Genomic Medicine. (2019). #These authors contributed equally. *Corresponding authors.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Pajak, A.#, Laine, I.#, Clemente, P., El-Fissi, N., Schober, FA., Maffezzini, C., Calvo-Garrido, J., Wibom, R., Filograna, R., Dhir, A., Wedell, A., Freyer, C.*, Wredenberg, A.*. Defects of mitochondrial RNA turnover lead to accumulation of double-stranded RNA in vivo. PLoS Genetics. (2019). #These authors contributed equally. *Corresponding authors.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Laine, I., Schober, FA., Clemente, P., Pajak, A., Haas, M., Filipovska, A., Wedell, A., Freyer, C., Wredenberg, A. Mitochondrial translation efficacy is dependent on RNA polyadenylation. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Wredenberg, Anna
Co-supervisor: Freyer, Christoph
Issue date: 2021-12-28
Rights:
Publication year: 2021
ISBN: 978-91-8016-412-2
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