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The Role of MRPL45 and OXA1L in Human Mitochondrial Protein Synthesis

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The Role of MRPL45 and OXA1L in Human Mitochondrial Protein Synthesis The role of MRPL45 and OXA1L in human mitochondrial protein synthesis Nicole Mai Supervisors: Professor Zofia Chrzanowska-Lightowlers Professor Robert Lightowlers A thesis submitted for the degree of Doctor of Philosophy Institute of Neuroscience Wellcome Trust Centre for Mitochondrial Research October 2016 Abstract Mitochondria produce 90% of the adenosine triphosphate (ATP) used by eukaryotic cells as a source of energy. ATP synthesis is carried out by the oxidative phosphorylation (OXPHOS) system whose components are partially-encoded by mitochondrial DNA and translated by mitoribosomes found in the organelle itself. The interaction between mitoribosomes and the inner mitochondrial membrane (IMM) has been claimed to be important for efficient protein synthesis in these organelles, but how this association occurs is still unclear. The aim of this study was to investigate the association between mitoribosomes and IMM in human mitochondria. My attention focused on MRPL45, a component of the mitoribosome that might be a key player of this interaction due to its proximity to the polypeptide exit tunnel and its structural similarity to the IMM-interacting proteins TIM44 and Mba1. During the course of this study, in order to further investigate the interaction, interest in the IMM protein OXA1L arose. The yeast homologue of this protein has been reported to interact with the mitoribosome, offering an interacting point between the IMM and the translation machinery. I performed depletion studies that confirmed the importance of MRPL45 for the stability of the mitoribosomal large subunit (mt-LSU) and mitochondrial translation. With the development of a protocol to investigate membrane-interaction, I demonstrated that MRPL45 is able to interact directly with the IMM. The addition of a FLAG-tag at the C-terminal of MRPL45 did not affect the ability of the protein to interact with the membrane and did not have effects on the homeostasis of the cells. Therefore, immunoprecipitation of MRPL45FLAG was performed in the absence of assembled mitoribosomal subunits to identify potential IMM binding partners. No obvious candidates, however, were detected from mass spectrometry analysis of the immunoprecipitated sample. Modifications of MRPL45 based on structural similarities with TIM44 and Mba1 were performed to identify the membrane-associating domain of the protein. Mutation of charged amino acids on a protruding α-helix of MRPL45 were performed. The resultant protein was completely integrated into the mt-LSU in the absence of the endogenous counterpart, partially rescuing the phenotype observed upon depletion of MRPL45. Membrane - interaction studies showed that the modifications did not affect the ability of this mutant to interact directly with the membrane. Another attempt to disrupt the interaction between MRPL45 and the membrane was performed by expressing a mutant protein lacking 117 amino acids at the N-terminal, which is predicted to correspond to the putative membrane-interacting domain of TIM44. Only a minor proportion of this protein was integrated in the mt-LSU in absence of the endogenous MRPL45, although the mutant protein retained the ability to interact directly with the membrane. The role of another mitochondrial protein, OXA1L, in mitochondrial translation was also investigated in this work. This was motivated by the discovery of a paediatric patient with mutations in the gene encoding OXA1L. Since the published studies showing OXA1L to interact with the mitoribosome were attempted in vitro, I performed immunoprecipitation studies which i confirmed the ability of OXA1L to associate with the mitoribosome in intact human cells. In order to characterise the role of OXA1L in mitochondrial translation, depletion studies were performed. These suggested that OXA1L was important for the stability of both the large and, unexpectedly, the small mitoribosomal subunit. Due to this surprising result, extensive studies were performed to confirm its robustness, which confirmed the reduction of the steady-state level of the mitoribosomal subunits and of OXPHOS components upon depletion of OXA1L. To conclude, my studies showed the importance of the mitoribosomal protein MRPL45 for the stability and the assembly of the large subunit of the mitochondrial translation machinery, as well as its ability to interact directly with the IMM. Although it was not possible to identify the domain of MRPL45 involved in membrane interaction, insights on the importance of the N- terminal domain for its integration in the mt-LSU were identified. The ability of OXA1L to interact with the mitoribosome in vivo was determined and a role of this protein in the stability and assembly of the mitoribosome was demonstrated. ii Acknowledgments First of all I want to thank my supervisors, Bob and Zosia, for the constant support and the guidance during this project. Thank you for giving me the chance to do this PhD and grow professionally. A special thanks to the Barbour Foundation for supporting my PhD studies as well as helping many other students. Thank you for to Prof Jeremy Lakey and Prof Rita Horvath for their contribution and support during the year reviews. Another thank goes to Prof Taylor, for involving me in his work and for putting me in touch with Dr. Rosalba Carrozzo, who I also thank. Thanks to (almost Dr.) Charlotte for all the help with the sequencing. Thanks to Dr Aurelio Reyes for sharing is mitochondrial fractionation protocol which helped the optimisation of the membrane- soluble fraction protocol presented in this work. Thank you to Dr Achim Treumann for the help with the mass spectrometry analysis. Thank you to all the members of the Mitochondrial Research Group for their help an d for always be up for a chat. A special thanks goes to Amy, for being a special friend, and to Ewen and Hannah. Thank you for sharing this adventure with me. Thank you Pav for being always there for me. A massive thanks goes to Monika, Rawaa, Christie, Kyle, Agata, Fei, Marysia and Francesco and whoever else has been in the Lightowler’s lab for the past 3 years. You had to deal with my roller-coaster of emotion throughout this PhD. Thank you for the kindness, for all the support and suggestions and for making me feel so welcome. This experience wouldn’t be the same without you. I wish you all the best for your future! Thank you to all my friends here in Newcastle. Being so far away from home can be very hard, and you made this a lot easier! How not to thank also my friends back home, which are still there despite the distance. The support of all of you has been immeasurable. A gigantic thank you to Matt. Thank you for dealing with me on a daily basis. I know that is not easy! Your love and support have been an unlimited source of energy that made me power through all the difficulties I had. The past year, which we both spent writing up, made us stronger. I am so happy that I’ve found you (with a little help from Pav and Stacey!). I wouldn’t have made it without you. Il grazie piu’ grosso e’dedicato ai miei miei genitori che hanno dovuto sopportare la lontananza cosi’ tanto a lungo. Grazie per il vostro sostegno continuo e illimitato che mi avete dato durante tutta la mia vita, e che ancora mi darete in future. Senza il vostro aiuto, oggi non sarei dove sono. iii iv Table of Contents Abstract .................................................................................................................................... i Acknowledgments ...................................................................................................................iii List of figures ...........................................................................................................................xi List of tables ...........................................................................................................................xv Abbreviations ....................................................................................................................... xvii Chapter 1: Introduction ............................................................................................................ 1 1.1. Mitochondria .............................................................................................................. 1 1.2. The origin and evolution of mitochondria .................................................................... 1 1.3. Mitochondrial structure............................................................................................... 3 1.3.1. Nucleoids and RNA granules.............................................................................. 5 1.4. Functions of mitochondria .......................................................................................... 6 1.4.1. Oxidative phosphorylation .................................................................................. 7 1.5. Mitochondrial diseases............................................................................................... 9 1.6. Mitochondrial DNA ................................................................................................... 10 1.6.1. Replication ....................................................................................................... 12 1.6.2. Transcription .................................................................................................... 13 1.7. Protein import in mitochondria.................................................................................. 14 1.8. Mitochondrial protein synthesis
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