Novel Functions Of Mitochondrial Proteins In Health And Disease
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Mitochondria are organelles critical for many cellular functions including energy production, ion homeostasis, cellular protein trafficking, and apoptosis induction. While the mitochondrial protein machinery that performs these roles has been studied for many years, the functions of many of these proteins have not been fully elucidated. This dissertation is focused on understanding the functions of two proteins in mitochondria, and their involvement in disease. We describe a novel function for estrogen receptor beta (ER?) in brain mitochondria. We find that ER? modulates cyclophilin D-dependent mitochondrial permeability transition (MPT) in brain. MPT is critical in cell death following brain injuries, such as stroke. Based on sex differences in ER? modulation of MPT, we suggest that it may contribute to sex differences in cellular responses to ischemia. We also explore the protein CHCHD10, a mitochondrial protein with yet unknown function. This protein is of particular interest, as its mutations have been recently associated with familial myopathy and neurodegenerative diseases, such as ALS. We find that CHCHD10 binds to its homolog CHCHD2, and both of these proteins bind to the mitochondrial protein P32. Transient silencing of CHCHD10 expression in HEK293 cells triggers the induction of mitochondria-dependent apoptosis. We also generated and began to characterize the first CHCHD10 knockout mouse model. Data from the cellular and mouse models suggest different yet similar roles for CHCHD10 and CHCHD2 in mitochondria. Uncovering these functions and understanding the pathways that these proteins participate in is critical to understanding of basic biology, but also of the pathophysiology of disease, as the brain relies heavily on mitochondria, and mitochondrial dysfunction occurs in many neurodegenerative diseases.
apoptosis; calcium; estrogen receptor; mitochondria; neurodegeneration; permeability transition
Doctor of Philosophy
Attribution-NonCommercial-NoDerivatives 4.0 International
dissertation or thesis
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International