Mitochondria are commonly known as the “Powerhouses” of our cells, generating a large amount of the energy needed by our cells and bodies. In functioning as these cellular powerhouses, mitochondria can become damaged over time, and this damage can spread to other parts of the cell if not corrected. Therefore, cells have evolved ways to remove these damaged mitochondria to limit their accumulation in a process called “mitophagy”. One challenge for cells is being able to distinguish damaged from healthy mitochondria to ensure that only bad mitochondria are targeted for removal. If healthy mitochondria are accidentally labeled for removal, this can decrease the number of mitochondria in cells and, in some cases, causes Mitochondrial Disease. We recently discovered that cells have at least two proteins which act as superheroes (their science names are FBXL4 and PPTC7) to stop these removal signals and save healthy mitochondria. When these superhero proteins no longer do their jobs, cells remove mitochondria unnecessarily, even though they are healthy and functional. This means that patients are not able to produce enough energy to function and grow because they don’t have enough mitochondria. The good news is that our recent work has identified key information about the superhero proteins: we recently discovered how they mute the removal signals and preserve healthy mitochondria. In this project, we will use this knowledge to design a molecule that mimics these superhero proteins to mute the removal signals to save mitochondria. This molecule could, in principle, correct the accumulation of these removal signals, and could be used to preserve healthy mitochondrial populations in select Mitochondrial Diseases. The concept behind this treatment that is already in clinical trials as a cancer therapeutic, so we are hopeful that, if this project is successful, we may be able to translate it to treat a subset of Mitochondrial Diseases that currently have no cure.

Mitochondria, also known as the powerhouse of the cells, are critical for energy production to keep an organism healthy. However, genetic mutations can affect these structures causing their impaired function and leading to serious diseases affecting the brain and muscles. Leigh syndrome (LS) is a severe childhood brain disorder causing movement problems, seizures, and breathing difficulties, often leading to early death and there is currently no cure. Inflammation, including immune cells called monocytes and macrophages, has been discovered to play a key role in worsening LS. Blocking these immune cells, can, therefore, reduce pathology symptoms but some treatments are toxic. This project will explore safer treatments by using antibodies to remove these immune cells and prevent pathology in a mouse model of LS. This research could lead to better therapies for children with LS and other mitochondrial diseases.

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.