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UCLA UCLA Electronic Theses and Dissertations UCLA UCLA Electronic Theses and Dissertations Title Matrix Processing Peptidase and Putative Roles in Mitochondrial Biogenesis. Nuc1 and Porin influence L-A Killer Virus Loads Co-dependently in Saccharomyces Cerevisiae. Permalink https://escholarship.org/uc/item/3600s4k4 Author Torres, Eric Publication Date 2019 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA Los Angeles Matrix Processing Peptidase and Putative Roles in Mitochondrial Biogenesis and Nuc1 and Porin influence L-A Killer Virus Loads Co-dependently in Saccharomyces Cerevisiae A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Biochemistry and Molecular Biology by Eric Rommel Torres 2019 © Copyright by Eric Rommel Torres 2019 ABSTRACT OF THE DISSERTATION Matrix Processing Peptidase and Putative Roles in Mitochondrial Biogenesis and Nuc1 and Porin Influence Killer Virus Loads Co-dependently in Saccharomyces Cerevisiae by Eric Rommel Torres Doctor of Philosophy in Biochemistry and Molecular Biology University of California, Los Angeles, 2019 Professor Carla Marie Koehler, Chair Matrix Processing Peptidase and Putative Roles in Mitochondrial Biogenesis The mitochondrial protein import and proteolytic system are important for homeostasis of the mitochondrion. Typically, precursor proteins are targeted to the mitochondria by an N- terminal targeting sequence and are imported via TOM and TIM translocons of the outer and inner membrane. A series of proteases is required for the import and processing of precursors as well assembly and degradation of mitochondrial proteins. The matrix processing peptidase (MPP) coordinates the removal of presequences from precursors and is important in maintaining mitochondrial homeostasis. Furthermore, MPP is associated with neurodegenerative diseases. A mutation in PMPCA causes a form of non-progressive cerebellar ataxia, because the Friedreich’s ii ataxia protein is not processed correctly. The Parkinson’s associated protein PINK1 is processed by MPP and attenuation of β-MPP has been shown to induce mitophagy. To characterize the function of MPP in mammalian systems and develop probes to attenuate MPP function, we developed a small molecule screening strategy to develop MPP-specific chemical probes from a library of over 100,000 drug-like small molecules. The screen yielded two structurally distinct and specific MPP inhibitors deemed MitoBloCK-50 and MitoBloCK-51. Our results suggest in addition to playing a role in the processing of precursors, MPP also plays a role in the import of precursors. Here I present data that characterize the utility of MitoBloCK-50 and MitoBloCK-51 for MPP attenuation in various model systems. In addition, an in vivo tagging system known as BioID identified an interaction between MPP and core subunit Qcr2 of Complex III, suggesting an evolutionary conserved interaction with the respiratory chain. Nuc1 and Porin Influence L-A Viral loads Co-dependently in Saccharomyces Cerevisiae The yeast double-stranded RNA (dsRNA) killer viruses of the Totiviridae family are well-characterized and one of the most prolific in laboratory yeast strains. Infected yeast are able to tolerate high levels of the killer virus without displaying any growth defects. The complex symbiotic relationship between host yeast and dsRNA viruses are still being elucidated. Notably, deletion of mitochondrial genes NUC1, which encodes the major mitochondrial nuclease, and POR1, the voltage-dependent anion channel of the outer mitochondrial membrane, lead to overproduction of the capsid Gag protein encoded by the L-A dsRNA helper genome of Killer virus. In this work we explore mechanisms of Nuc1 and porin regulation of the L-A dsRNA genome of yeast Killer viruses. We observed strains with NUC1 deletion have higher L-A levels than POR1 deleted strains. Furthermore, deletion of both NUC1 and POR1 have comparable L-A iii levels to single NUC1 mutants. Plasmid expression of Nuc1 mutants that are nuclease deficient or cytosolic localized fail to rescue L-A viral loads in NUC1 deleted strains. In addition, plasmid expression of NUC1 appears to increase the L-A viral load in the NUC1 and POR1 double knockout. Nuclease protection experiments demonstrate L-A transcripts are protected in ΔNUC1 and ΔPOR1 mitochondria but not in wildtype. We propose a model where ss(+) L-A transcripts are imported into the mitochondrial IMS and are subsequently degraded by Nuc1. Meanwhile, POR1 deletion disrupts the L-A regulating function of Nuc1. Overall these results demonstrate a role for mitochondria in regulating dsRNA viruses in yeast. iv The dissertation of Eric Rommel Torres is approved. Alexander M Van der Bliek Jorge Torres Carla Marie Koehler, Committee Chair University of California, Los Angeles 2019 v DEDICATION Friends, Family and Mentors that loved and supported me along the way to make this possible. vi TABLE OF CONTENTS List of Chapters, Figures and Tables ........................................................................................... vii Acknowledgements ..........................................................................................................................x Vita ............................................................................................................................................... xiv Chapter 1. Introduction- Mitochondrial Biogenesis and Methods for Probing Protein Import Pathways ..................................................................................................................1 Chapter 2. Characterizing Utility and Mitochondrial Effects by MitoBloCK-50 and MitoBloCK-51 .......................................................................................................37 Chapter 3. Characterization of Additional Selected MPP Inhibitors .......................................94 Chapter 4. The MPP BioID Proteome, Implications in Protein Import and Respiration ...........................................................................................................132 Chapter 5. Nuc1 and Porin Influence Killer Virus Loads Co-dependently in Saccharomyces Cerevisiae .............................................................................................................171 LIST OF FIGURES Chapter 1. Figure 1-1. Outer Membrane Protein Import through the SAM Pathway ................................19 Figure 1-2. Intermembrane Space Import through the Mia40/Erv1 Disulfide Relay ...............20 Figure 1-3. Inner Membrane Import through the Carrier Pathway ...........................................21 Figure 1-4. Presequence Pathway through the Tim23 Complex ..............................................22 Figure 1-5. MPP Cleavage Mechanism ....................................................................................24 Figure 1-6. Inhibitors of Mitochondrial Import Pathways ........................................................26 Chapter 2. Figure 2-1. Model of JPT fluorogenic peptide assay and plate layout for high-throughput screen .....................................................................................................................57 Figure 2-2. Structures of MitoBloCK-50, MitoBloCK-51 and associated analogs ..................59 Figure 2-3. MB-50 and MB-51 reduce MPP cleavage activity in vitro....................................60 Figure 2-4. Import and Cleavage of [35S] Su9-DHFR with MB-50/51 SAR compounds ........61 Figure 2-5. MB-50 and MB-51 do not interfere with general mitochondrial function .............63 Figure 2-6. MB-50 and MB-51 cause pigment deficiency and other morphological defects in zebrafish .................................................................................................................65 Figure 2-7. Treatment with excess divalent cation Mn2+ does not rescue MPP activity after MB-50 or MB-51 treatment ...................................................................................66 Figure 2-8. MB-50 and MB-51 inhibit the import of TIM23 substrates ..................................67 Figure 2-9. MB-50 and MB-51 inhibit the import of non-TIM23 substrates ...........................68 Figure 2-10. Effects of MB-50 and MB-51 on import of dual-localized Fum1 and Pink1 in yeast mitochondria .................................................................................................69 Figure 2-11. Overexpression of MPP increases mitochondrial membrane potential .................70 Figure 2-12. Overexpression of MPP increases import in isolated mitochondria ......................72 Figure 2-13. Overexpression of MPP does not rescue import defects induced by MB-50 or MB- 51............................................................................................................................74 vii Figure 2-14. Temperature sensitive MPP mutants show processing defects and no import defects ....................................................................................................................76 Figure 2-15. Pre-treatment with MB-50 and MB-51 uncouples respiration in isolated mouse liver mitochondria ..................................................................................................78 Figure 2-16. Morpholino knockdown of MPP subunits in zebrafish causes pigment deficiency and other morphological defects ............................................................................80 Chapter 3. Figure 3-1. Structures of MPP inhibitors selected
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