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Kashatus Lab
University of Virginia, Microbiology, Immunology and Cancer Biology
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We are fascinated by organelle dynamics and their intersection with disease pathology
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Research Summary
The Kashatus Lab, within the Department of Microbiology, Immunology and Cancer Biology at the University of Virginia, is interested in the regulation of mitochondrial dynamics and how alterations in mitochondrial fission and fusion affect basic cellular physiology. We explore these questions using a wide variety of approaches, from cell biology to mouse genetics to bioinformatics with the ultimate goal of identifying how mitochondrial dynamics and metabolic function impact the progression of cancer and other diseases.
Research Topics
The regulation of organelle dynamics by cellular stress
Cells in the body regularly encounter stress, and a number of pathways have evolved that allow cells to maintain homeostasis under a broad range of conditions. For example, under low nutrient 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 exploring the mechanisms through which the cell coordinates this cellular response. In particular, we are investigating how multiple organelles, including the ER, lysosomes, lipid droplets and mitochondria communicate with each other to facilitate efficient recycling of cellular lipids. In addition, we are employing both GEMM and PDX tumor models to understand how this stress response contributes to tumor cell dormancy and metastasis.
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 develop novel computational tools that 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.
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.
Publications
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The regulation of tumor cell physiology by mitochondrial dynamics
10.1016/j.bbrc.2017.06.192
David F. Kashatus
Mitochondrial dynamics in cancer stem cells
10.1007/s00018-021-03773-2
Dane T. Sessions; David F. Kashatus
Cellular and Molecular Life Sciences
RalA and RalB relocalization to depolarized mitochondria depends on clathrin-mediated endocytosis and facilitates TBK1 activation
10.1371/journal.pone.0214764
Sarah R. Pollock, Austin R. Schinlever, Ali Rohani, Jennifer A. Kashatus, David F. Kashatus
RalA and PLD1 promote lipid droplet growth in response to nutrient withdrawal
10.1016/j.celrep.2021.109451
Syed S. Hussain; Tuyet-Minh Tran; Timothy B. Ware; Melissa A. Luse; Christopher T. Prevost; Ashley N. Ferguson; Jennifer A. Kashatus; Ku-Lung Hsu; David F. Kashatus
MDVs: Spare the SOD and Spoil the Bug
10.1016/j.chom.2018.10.013
Syed Saad Hussain; David F. Kashatus
Mito Hacker: a set of tools to enable high-throughput analysis of mitochondrial network morphology
10.1038/s41598-020-75899-5
Ali Rohani; Jennifer A. Kashatus; Dane T. Sessions; Salma Sharmin; David F. Kashatus
Scientific Reports
(2020)
Drp1 Promotes KRas-Driven Metabolic Changes to Drive Pancreatic Tumor Growth.
10.1016/j.celrep.2019.07.031
Sarbajeet Nagdas; Jennifer A. Kashatus; Aldo Nascimento; Syed S. Hussain; Riley E. Trainor; Sarah R. Pollock; Sara J. Adair; Alex D. Michaels; Hiromi Sesaki; Edward B. Stelow; Todd W. Bauer; David F. Kashatus
(2019-08-13)
The interplay between oncogenic signaling networks and mitochondrial dynamics
Nagdas, Sarbajeet; Kashatus, David F
Antioxidants
(2017)
Restraining the divider: a Drp1-phospholipid interaction inhibits Drp1 activity and shifts the balance from mitochondrial fission to fusion
Kashatus, David F
Molecular cell
(2016)
High‐throughput detection and quantification of mitochondrial fusion through imaging flow cytometry
Nascimento, Aldo; Lannigan, Joanne; Kashatus, David
Cytometry Part A
(2016)
Erk2 Phosphorylation of Drp1 Promotes Mitochondrial Fission and MAPK-Driven Tumor Growth.
10.1016/j.molcel.2015.01.002
Jennifer A. Kashatus; Aldo Nascimento; Lindsey J. Myers; Annie Sher; Frances L. Byrne; Kyle L. Hoehn; Christopher M. Counter; David F. Kashatus
Molecular Cell
(2015-02-05)
Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth
Kashatus, Jennifer A; Nascimento, Aldo; Myers, Lindsey J; Sher, Annie; Byrne, Frances L; Hoehn, Kyle L; Counter, Christopher M; Kashatus, David F
Molecular cell
(2015)
Ral GTPases in tumorigenesis: emerging from the shadows
Kashatus, David F
Experimental cell research
(2013)
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