The goal of this administrative supplement request is to provide a state-of-the-art microscope for cell biological studies of mitochondrial fission for R01GM067180. The requested instrument will be equally shared with Drs. Amy Hudson (R01GM120735) and Matt Scaglione (R35GM119544) for their cell biological studies in lysosomal trafficking and proteostasis, respectively. Altered mitochondrial fission has severe consequences even death. Yet the reasons for this are unknown. It is postulated that the mitochondria have their own lifecycle that involves fission of unhealthy mitochondria to remove them. In this model, the proper balance of fission is critical: either excess or impaired fission both result in unhealthy mitochondria. This model is compelling because it explains how alterations in fission can cause or contribute to many fundamentally different diseases including recovery from heart attack and stroke, increased metabolic stress from diabetes, normal aging, and neurodegenerative diseases such as Parkinson's and Alzheimer's disease. The proposed instrument will allow visualization of the multi-protein machinery responsible for mitochondrial fission. To understand the protein- protein interactions that govern this, biochemical and structural studies have identified mutations that will be imaged using the acquired microscope. A better understanding of the protein machinery and how it works will identify key points of regulation that may be targeted with small molecules to inhibit, and activate, fission. The discovery of such molecules may ultimately lead to treatments for diseases in which enhanced, or impaired, fission is central.
Mitochondria are components of cells that perform many functions critical for life and are known for being the 'power plant' of the cells. The mitochondria have their own life cycle with a mechanism to destroy damaged mitochondria that involves a splitting event that separates a healthy daughter mitochondrion from an unhealthy one that is subsequently removed by the cell. This splitting event is called mitochondrial fission and is vital to human health. Mitochondrial fission is accomplished by distinct protein machineries and defects in this machinery cause infant death. Disordered mitochondrial fission is increasingly recognized as a contributor to both rare and common human diseases, including cardiac and neurodegenerative diseases, cancer, diabetes, aging, and neonatal lethality syndrome. The work proposed will illuminate mechanistic details of these processes and represents an important step towards the discovery of new therapeutic strategies for these diseases.
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