2018 Theses Doctoral
Investigations into pathophysiologic mechanisms and treatment of primary mitochondrial diseases
The present work addresses outstanding questions within the field of primary mitochondrial disease biology and treatment, by incorporating methods from structural biology, molecular biology, and animal studies. First, we utilize a mouse model of mitochondrial deoxyribose nucleic acid (mtDNA) disease to demonstrate the potential therapeutic benefit of low-dose chronic rapamycin treatment. Interestingly, rapamycin therapy significantly extends survival, but does so in the absence of correcting the underlying mitochondrial defect. Next, we focus on human cellular models of mtDNA-based diseases, and show that rapamycin treatment does not induce mitochondrial quality control-mediated clearance of pathogenic mtDNA mutation-harboring organelles. Finally, we investigate a mitochondrial disease phenotype at the level of the organelle, by utilizing in situ cryo-electron tomography to demonstrate the ultrastructural consequences of a pathogenic mutation affecting mitochondrial energy production. We conclude by highlighting the insights into disease biology and treatment that can be gained through a multi-level approach integrating techniques from multiple biomedical fields.
- Siegmund_columbia_0054D_14428.pdf application/pdf 250 MB Download File
More About This Work
- Academic Units
- Cellular, Molecular and Biomedical Studies
- Thesis Advisors
- Schon, Eric A.
- Ph.D., Columbia University
- Published Here
- February 16, 2018