David Kashatus, Ph.D
Research Interests – The regulation of mitochondrial fission and fusion and the role of mitochondrial dynamics in tumorigenesis.
Exploring the link between mitochondrial dynamics and cancer.
Although mitochondria are often pictured in biology texts as static, individual organelles distributed throughout the cytoplasm, 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 the regulation of autophagy, to the control of cell survival through apoptosis. Given the importance of these mitochondrial functions in tumorigenesis, the Kashatus lab is focused on understanding how oncogenic signaling pathways impact the mitochondrial fusion and fission machinery and whether mitochondrial dynamics are important for tumor initiation and tumor progression. The lab uses a wide variety of tools, ranging from biochemistry, cell biology and molecular genetics to genetically engineered mouse models of human cancers. This multifaceted approach allows us to better understand how these important processes influence the process of tumorigenesis and to quickly identify potential avenues of therapeutic intervention.
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.
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. 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, the large fission GTPase Drp1, and the fusion-mediating GTPases Mfn1, Mfn2 and Opa1.
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, it is essential that we understand the molecular basis of how various oncogenic signaling pathways converge upon the fusion and fission machinery and how mitochondrial dynamics contribute to oncogenic transformation and tumorigenesis. To that end, we use xenografts of human cancer cell lines and genetically engineered mouse models to determine the role that mitochondria shaping proteins play in the initiation and maintenance of human tumors.