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Bidirectional Interactions Between Mitochondrial Function and Cell Mechanics University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2016 Bidirectional Interactions Between Mitochondrial Function and Cell Mechanics Judith Kandel University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Biomedical Commons, and the Cell Biology Commons Recommended Citation Kandel, Judith, "Bidirectional Interactions Between Mitochondrial Function and Cell Mechanics" (2016). Publicly Accessible Penn Dissertations. 1799. https://repository.upenn.edu/edissertations/1799 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/1799 For more information, please contact [email protected]. Bidirectional Interactions Between Mitochondrial Function and Cell Mechanics Abstract Energetic and structural maintenance are both critical to cellular homeostasis, and clinical disease is often characterized by alterations in both of these realms. While the manifestation of pathology in each of these fields has been extensively studied, little research has been done to characterize basic, direct interactions between mitochondrial function and cell mechanics. The experiments described in this dissertation endeavored to address that gap, first yb investigating the cytoskeletal and mechanical effects of mitochondrial dysfunction and then by considering the mitochondrial consequences of cytoarchitectural breakdown. Mechanical integrity of the cell following mitochondrial dysfunction was investigated through multiple experimental platforms, including the quartz crystal microbalance with dissipation (QCM-D). Early work thus focused on improving the suitability of QCM-D for cell experimentation by developing a method of covalently conjugating fibronectin to QCM-D sensors. We then subjected cells to mitochondrial toxins in order to address whether and how mitochondrial dysfunction affects cell mechanics and the cytoskeleton. Cells showed characteristic rounding after long-term exposure to rotenone, an inhibitor of complex I of the mitochondrial respiratory chain. Since mitochondrial dysfunction can also be caused by genetic defects in the mitochondrial DNA (mtDNA), we also studied the cytoskeletal and mechanical variations in cells heteroplasmic for the m.3243A>G mutation. We found a conserved, nonmonotonic relationship between m.3243A>G heteroplasmy and cell mechanics, originating in expression of actin- related genes and persisting at the levels of protein production, cytoskeletal structure, and single cell stiffness. The second half of the dissertation considered how cytoarchitectural breakdown influences mitochondria. We first developed a novel tool for tracking individual mitochondria throughout entire cells, and then used this method to demonstrate that microtubule and microfilament depolymerization affect mitochondrial motility in opposing ways. Another set of experiments found that cytoskeletal breakdown significantly decreased mitochondrial respiration, which sometimes only occurred when mitochondria were pre-stressed by increased demands of calcium maintenance. Together, these studies highlight direct, bidirectional interactions between mitochondrial function and cell mechanics. These findings will inform future mechanistic studies focused on a comprehensive understanding of human disease at the cellular level, which will hopefully contributing to advancing development of therapeutics. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Bioengineering First Advisor David M. Eckmann Keywords actin, atomic force microscopy, cell mechanics, mitochondria, mitochondrial motility, mitochondrial respiration Subject Categories Biomedical | Cell Biology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/1799 BIDIRECTIONAL INTERACTIONS BETWEEN MITOCHONDRIAL FUNCTION AND CELL MECHANICS Judith Kandel A DISSERTATION in Bioengineering Presented to the Faculties of the University of Pennsylvania In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2016 __________________________ David M. Eckmann, Ph.D, M.D, Professor of Anesthesiology and Critical Care and Bioengineering Supervisor of Dissertation __________________________ Jason A. Burdick, Ph.D, Professor of Bioengineering Graduate Group Chairperson Dissertation Committee Marni J. Falk, M.D, Assistant Professor of Pediatrics, Children's Hospital of Philadelphia Paul A. Janmey, Ph.D, Professor, Physiology and Institute for Medicine and Engineering Robert L. Mauck, Ph.D, Associate Professor of Orthopaedic Surgery and Bioengineering ACKNOWLEDGMENTS This work would not have been possible without the support of many people. First and foremost, thank you to my advisor, Dr. David M. Eckmann, for your research mentorship over the last 6 years. You have invested a tremendous amount of time, money, and energy in my development as a scientist, and I will forever be indebted to you for that. I would also like to thank my dissertation committee members, Drs. Paul Janmey, Marni Falk and Rob Mauck for their support and mentorship. There have been many other lab members, both from the Eckmann lab and beyond, who were instrumental in the success of this research. Drs. Peter Sobolewski and Alexandra Klinger were so giving of their time and knowledge in training me when I first came to the lab. Peter in particular gave me my very first exposures to live imaging of mitochondria and trained me in cell culture techniques. Dr. Hyun-Su Lee has also been dedicated to my success and has been particularly helpful with QCM-D research and any other projects involving chemical synthesis. Dr. M. Carme Coll Ferrer was also a wonderful friend and research mentor during her time in the lab. I would like to thank our lab technicians, Nancy Tomcyzk, Jessica Campo, Abhay Ranganathan, and Bruce Braender for keeping the lab running smoothly. Nancy was heavily involved in the chemical conjugation of fibronectin onto QCM-D crystals (Chapter 3) and is co-authored on the paper relating that work. Bruce Braender was an integral part of the QCM-D experiments presented in Chapter 4. Dr. Meg Grady, a post-doc in our lab, has been a valuable source of scientific feedback, particularly with AFM experiments. I would also like to thank Eric Abhold, who joined us for a summer research project, for teaching me Western blot fundamentals. I was lucky enough to enjoy the core facilities belonging to the Anesthesia and Critical Care research department on the third floor of the John Morgan Building. Thank you to Dr. Roderic Eckenhoff for his service as the Vice Chair for research in the Anesthesia department. In addition to Eric, Brian Weiser, Kellie Woll and Tim DeYoung were amazingly helpful with Western blotting. Dr. Bo Han has been a wonderful source of general scientific advice and ii immunofluorescence in particular. Drs. Qing Cheng Meng and Weiming Bu were great guides to both general and specific procedural questions. Thank you also to Drs. Max Kelz and Maryellen Eckenhoff for providing a listening ear and professional guidance when I needed it. I have also relied on our support staff on JM3 throughout my training: Cindy Bliven, Ann Marie Tenuto, and Randall Hardie. Thank you for doing everything from organizing potlucks to placing orders for reagents. My work certainly would not have gone as smoothly as it did without you. Like many interdisciplinary projects, my work has benefited from the collaboration of many other scientists in other laboratories. Thanks to Dr. Russell Composto, a longtime collaborator of the Eckmann lab, for his general involvement and encouragement, and his insights particularly on the chemFN functionalization of QCM-D crystals. The AFM experiments, as well, could not have been done without many other people. Dr. Prathima Nalam conjugated colloids onto my AFM tips and was helpful with general AFM questions. Dr. Matt Caporizzo’s expertise in the TIRF-AFM instrumentation saved my experiments on many different days, and Dr. Matt Brukman of the Nano-Bio Interface Center was also always available for AFM troubleshooting. Emmabeth Parrish Vaughn from Russ’s lab has been a great friend and collaborator in our push to publish the kurtosis method of measuring actin stress fiber alignment (Appendix A). Collaboration was also critical to some of our mitochondrial work. Thank you to Dr. Douglas C. Wallace and his lab members, Drs. Martin Picard and Alessia Angelin, for their help in bringing these projects to fruition. Martin was the one who shared the initial data showing altered actin gene expression in the m.3243A>G cybrids with me, which developed into the great story of mitochondrial genetics affecting single-cell mechanics told in Chapter 5. In addition to helping with Seahorse XF Analyzer experiments (Chapter 7), Alessia initially showed me some images of actin-stained cells in the hopes of quantifying them somehow. This work developed into the single-cell kurtosis analysis related in Appendix A. I would also like to thank Drs. Xilma Ortiz- Gonzalez and Tal Yardeni from the Wallace lab for their friendship and scientific collaboration. Perhaps more important than the network of scientific collaborators contributing to this work were the people standing behind me over the course of this degree. I would like to thank my iii parents and grandparents (those with us and those who have passed on) for their love and support. Now that I am a parent myself, I appreciate even more how
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