Mitochondria are often pictured in biology texts as static, individual organelles, when in reality they form highly dynamic and mobile networks constantly undergoing fusion and fission. Research in the last decade has revealed that mitochondrial fusion and fission impact nearly every aspect of mitochondrial function, from cellular metabolism, to calcium homeostasis, to the control of cell survival through apoptosis and autophagy. In addition, failure to properly maintain this dynamic mitochondrial network has been shown to play a role in a number of diseases, including Parkinson’s disease, Alzheimer’s disease, diabetes and cancer. The goals of our research are: (1) to uncover the molecular mechanisms that directly control mitochondrial dynamics, (2) to identify and characterize signaling pathways that interact with the mitochondrial dynamics machinery and (3) to determine how these interactions impact the pathology of diseases such as cancer.
1. Mitochondrial dynamics in cancer
Mitochondrial dynamics have been shown to be important for the cellular control of apoptosis, autophagy and metabolic function, processes that are critical regulators of tumorigenesis. As such, we seek to understand the molecular basis of how oncogenic signaling pathways converge upon the mitochondrial fusion and fission machinery and how mitochondrial dynamics contribute to oncogenic transformation and tumorigenesis. To that end, we use a combination of patient-derived xenografts and genetically engineered mouse models to determine the role that mitochondria shaping proteins play in the initiation and maintenance of human tumors.
2. The molecular mechanisms of mitophagy
Mitochondria accumulate damage over time, and the maintenance of mitochondrial health depends on a robust mechanism to remove these damaged mitochondria from the cell. Pink1-Parkin mitophagy is a recently described pathway that allows the cell to identify mitochondria that have lost their membrane potential, isolate them from the network and mark them for destruction in the lysosome. We are using a combination of cell biology and biochemistry to explore the molecular regulation of this pathway and to identify and characterize novel regulators of mitochondrial clearance.
3. Pathways that regulate mitochondrial dynamics
A number of important cellular processes are accompanied by changes in the mitochondrial network, but the signaling pathways that link these processes to the mitochondrial fusion and fission machinery are not well understood. Using unbiased approaches such as large-scale proteomic and RNAi screens, as well as more targeted gain- and loss-of-function analyses, we are identifying and characterizing signaling pathways that regulate mitochondrial fusion and fission. To facilitate this approach we are developing novel computational tools that will enable high throughput analysis of mitochondrial morphology in both cell lines and tissue. Furthermore, using a combination of biochemistry, molecular genetics and cell biology, we investigate how these pathways interact with the core mitochondrial fusion and fission machinery.
4. Cell cycle regulation of mitochondrial fission
Equal distribution of mitochondria to daughter cells requires that the mitochondrial network undergo fission prior to cell division. The mitotic division of mitochondria is a highly regulated process that depends on both the mitochondrial recruitment and phosphorylation of the large GTPase Drp1. Several proteins are known to play a role in this process, including the kinases Cdk1 and Aurora A, the small GTPase RalA, and the large, multifunctional protein RalBP1. Using a combination of biochemistry, cell biology and molecular genetics we are elucidating the molecular details of how these proteins collaborate to carry out this process and exploring the consequences when the process is disrupted.
5. The cellular response to nutrient withdrawal
Cells in the body regularly encounter differences in the availability of nutrients and a number of pathways have evolved that allow cells to maintain homeostasis under a broad range of conditions. Under starvation conditions, cells adapt in part by recycling cellular lipids and storing them in lipid droplets in the form of triglycerides. Eventually, these lipid stores can be transferred to the reticular mitochondrial network to be used as fuel. We are currently identifying novel regulators of this starvation response and exploring the importance of this response in both normal tissues and diseases such as cancer.