| Description |
Mitochondria are a central hub for metabolism in the cell, housing numerous metabolic pathways. Because of their broad role in metabolism, maintenance of mitochondrial homeostasis is of utmost importance to the cell, and the failure to maintain mitochondrial function is linked to many metabolic and age-related disorders. Because of this, cells have developed numerous quality control mechanisms designed to maintain mitochondrial function. Additionally, there are also systems in place designed to mitigate the negative effects dysfunctional mitochondria can have on other cellular locations as these secondary effects can be just as devastating to a cell. This dissertation focuses on quality control mechanisms located at the mitochondrial surface designed to alleviate these problems. One hallmark of aging at the cellular level is mitochondrial decline and fragmentation of the normally fused mitochondrial network. The first part of this dissertation focuses on understanding the mechanism behind this fragmentation. We identify a proteolytic pathway that regulates the mitochondrial fusion GTPase Fzo1 as a method to potentially control mitochondrial structure. We identify the E3 ligases SCFMdm30 and Rsp5 as key mediators of this process and show this process is dependent on an amino acid signal from the vacuole during aging. This is a novel mechanism for stress-induced regulation of the mitochondrial structure during cellular aging. Another important form of quality control surrounding mitochondria is the iv regulation of nonimported mitochondrial precursor proteins. During mitochondrial stress, mitochondrial import is often impaired, leaving a large amount of proteins destined for the mitochondria unable to reach their proper localization. As the number of these proteins is quite large, this puts massive proteotoxic stress on the cell if not managed and it is not well understood how the cell handles these proteins. In the second part of this dissertation, we characterize a pathway by which a subset of these nonimported mitochondrial precursor proteins are degraded by the proteasome with the help of the AAA-ATPase Cdc48 at the mitochondrial surface showcasing a novel pathway for the regulation of nonimported mitochondrial proteins. Together, these studies help to advance our knowledge of how cells maintain mitochondrial function during stress and the mechanisms by which cells alleviate the negative effects of dysfunctional mitochondria. |
