Cells must adapt to their environment to grow and survive. The process of the cell learning about its external environment, for example nutrient availability, health of surrounding, etc. is called cell signaling. Cell signaling is usually conducted inside the cell by a series of specific proteins that talk to each other in a set order, to relay information from outside the cell to the cell itself to allow the cell to make decision about how to adapt. One recipient of this information in the cell may be the mitochondria. Mitochondria are responsible for energy production and are intimately involved in cell signaling pathways. To make energy, proteins in the mitochondria called Mitochondrial Complex proteins use a type of cellular electricity known as electrons to pass electrical energy to their neighbors in a line back and forth. At the very end of the line, a protein called ATP Synthase (also called Mitochondrial Complex V – CV) produces energy. In mitochondrial disease when mitochondria do not work properly, cell signaling, and the ability of the Mitochondrial Complex proteins are disrupted. Signals that were designed to be temporary ‘mitochondrial overwhelm’ signals may stay on permanently. Since mitochondrial diseases can be caused by multiple different abnormalities in the mitochondria, developing universal treatments is difficult. This proposal aims to study a specific mitochondrial disease called ATP Synthase (Complex V deficiency) and how it interacts with the mTOR pathway, one of the main cell signaling pathways to communicate nutrient availability. This work builds on the discovery that the mTOR pathway is abnormal in animal models of Complex V deficiency and that mTOR directly inhibits complex V in healthy animals. This work could help future researchers to develop and direct precision treatments for mitochondrial disease that manipulate cell signaling pathways.

Mitochondria have their own genetic material, the mitochondrial DNA (mtDNA). Having too little mtDNA is one of the causes that drives the onset of Mitochondrial Depletion Syndromes (MDSs). Patients with MDS experience a spectrum of symptoms which generally lead to death in a few months. mtDNA depletion could be due to a defect in the production of a primary building block or gene of the mitochondrial DNA. Currently, there are no animal models present to better understand MDS or to test the effectiveness of therapeutic treatments. This project proposes to create a mouse model that will be used to better understand the progression of MDS. With a mouse model available I will then test the effectiveness of gene therapy, an innovative therapeutic approach to restoring the defective gene that causes MDS. 

Our objective is to determine how internal factors, such as development and cell specification cues, as well as external stimulus, oxygen levels, energy substrates, and drug compounds influence mitochondria heteroplasmy. Our preliminary assessments suggest that cell-type development and cell division influence heteroplasmy in developing tissues, additionally our work on cell conditions, and small molecules has yielded promising preliminary results for possible therapeutics. This body of work serves as a template for discovering compounds that reduce mitochondrial heteroplasmy and thus disease burden in patients.