2024/2025 Seminar Abstracts
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11/20/2024:
Speaker: Itay Budin, Ph.D., Assistant Professor, University of California San Diego
Title: Phospholipid Curvature: A Biophysical Deep Dive
Abstract: Our lab investigates how – and why – cells control the composition of their lipid membranes. Lipids are traditionally challenging to study, and I will briefly present new chemical biology tools that can be used to interrogate their subcellular distributions. I will then focus on biophysical studies that seek to understand why small chemical changes to lipid chemistry are biologically important. I will show how the shape of lipid molecules – described by their spontaneous curvature – is a biophysical parameter that has driven adaptations in phospholipid chemistry. Lipid curvature is regulated in specific membranes in cells, like the inner mitochondrial membrane, where it can support function. Across organisms, lipid curvature is a property that is maintained through evolution. I will describe a wide-ranging investigation into the membranes of marine invertebrates that led us to discover how deep-sea environments act on lipid curvature and, in turn, how lipid metabolism must maintain this property.
Biography: Itay Budin is an Assistant Professor in the Departments of Chemistry & Biochemistry and Bioengineering at UC San Diego. Trained as a biophysicist, his lab investigates the interplay between lipid chemistry and cell membrane biology in a wide range of systems. Itay received his BS from Cornell University’s College of Engineering before carrying out PhD studies at Harvard University with Jack Szostak on model membranes relevant to the early evolution of cells. He then carried out postdoctoral research as a Miller Fellow at UC Berkeley, applying synthetic biology tools to lipids. He is the recipient of the Walter Shaw Young Investigator Award in lipid biology from the American Society for Biochemistry and Molecular Biology and early career awards from the National Science Foundation and Department of Energy.
11/6/2024:
First Speaker: Yaroslav Balytskyi, Ph.D., Postdoctoral Fellow, WSU Dept. of Physics
Title: Unsupervised Clustering of Docking Scores Predicts ABHD5 Ligands Activity
Abstract: We developed a model that efficiently clusters ABHD5 ligands into active and inactive categories with 92.9% accuracy using only their SMILES-based chemical structures. Notably, the model distinguishes between ligands with subtle structural differences, correctly classifying them into active or inactive groups, and provides interpretable predictions in terms of key residue interactions driving activity classification. Given ABHD5's therapeutic potential, this proof-of-concept work establishes a foundation for designing more selective drugs to modulate its activity with promising applications in treating metabolic disorders, lipid storage diseases, cancer, and inflammatory conditions.
Second Speaker: Mohamed Chakkour, PhD Candidate, WSU Dept. of Biological Sciences
Title: Phospholipids Out of Context: From Structure to Signaling
Abstract: In addition to their well-known role as structural components of cell membranes, phospholipids have been recognized as critical players in various cellular processes. This presentation explores the non-canonical roles of some phospholipids, highlighting their involvement in signaling pathways, gene expression regulation, enzymatic activation, and neuronal messaging. By examining these functions, I aim to shed light on the expanding roles of phospholipids beyond ordinary membrane precursors and delve into their importance in cellular communication and homeostasis.
10/16/2024:
Speaker: Mike Lange, Ph.D., Postdoctoral Fellow, University of California, Berkeley - Department of Nutritional Sciences & Toxicology, Department of Molecular & Cell Biology
Title: Protecting Stored Lipids From Damage: Ferroptosis Suppressor Protein 1 Prevents Lipid Peroxidation In Lipid Droplets
Abstract: Lipids are crucial for cellular function but their susceptibility to damage such as peroxidation, can have adverse effects on cellular wellbeing. Cells deploy diverse lipid quality control mechanisms to prevent the buildup of toxic oxidized lipids. Loss of lipid quality control, particularly on phospholipids in the plasma membrane, results in the catastrophic loss of membrane integrity leading to ferroptosis – a lipid peroxidation-dependent cell death modality.
Beyond membranes, lipids can form lipid droplets, organelles that consist of hydrophobic lipids such as triglycerides and steryl esters. Lipid droplets facilitate regulated lipid storage and release, thereby ensuring safe lipid metabolism in tissues such as adipose and liver, particularly under conditions of lipid overload. Dysregulation of lipid droplet levels is associated with pathological conditions such as obesity or fatty liver disease. Despite their importance, the existence of lipid quality control mechanisms that safeguard lipid droplets from damage remains uncertain. Furthermore, it is unknown what the consequences of lipid droplet damage are on cellular health.
We have identified the first lipid droplet quality control system executed by ferroptosis suppressor protein 1 (FSP1), a protein previously recognized as one of the essential membrane lipid quality control systems. Using chemical biology tools in genome-edited cancer cell lines, we found FSP1 bound to lipid droplets protects cells from lipid peroxidation-induced death. In vitro reconstitution biochemistry, combined with lipidomics and epilipidomics analyses, shows that lipid droplet resident FSP1 acts as a coenzyme Q10 reductase, locally generating the antioxidant ubiquinol, thus preventing lipid droplet damage. This marks the first description of a lipid droplet quality control system, and we are currently investigating how this novel pathway is involved in the disease pathogenesis of dysregulated metabolically active tissues such as adipose tissue during obesity.
10/2/2024:
First speaker: Laimar Garmo, PhD Candidate, WSU Dept. of Pharmacology
Title: Dysregulation of bone homeostasis through exposure to PFAS: the impact on bone marrow adipogenesis and osteoclastogenesis
Abstract: Per- and polyfluoroalkyl substances (PFAS) are environmental contaminants that tend to accumulate in bone. Peroxisome proliferator-activated receptors (PPARs), notably PPARa and PPARg, play essential roles in lipid metabolism, adipogenesis, osteoclastogenesis and bone turnover. PFAS exposure has been linked with PPAR activation, modulation of lipid metabolism, and reduced bone mineral density. However, little is known about the potential impact of PFAS exposure on bone homeostasis. We hypothesized that PFAS accumulating in bone disrupt bone homeostasis through the activation of PPARs. Using in vitro and in vivo approaches, we have identified two specific PFAS compounds, PFHxS and GenX, as a key modulators of PPAR-mediated marrow adipogenesis and osteoclastogenesis. Collectively, our data suggest that PFAS accumulating in bone have a potential to dysregulate bone homeostasis through PPAR-mediated mechanisms.
Second speaker: Aaron Lotvola, PhD Candidate, WSU Dept. of Oncology
Title: Regulation of c-Myc protein expression by ABHD5 in Prostate Cancer Cells
Abstract: Purpose: The survival outlook of prostate cancer patients remains poor and incurable when castration-resistant cells (hormone-resistant) adapt, evade, and proliferate to last-line therapy which ultimately results into castration-resistant prostate cancer (CRPC). To improve patient outcomes, the identification of key factors for resistance are essential to provide the foundation for the next generation of advanced therapeutics in CRPC. Metabolic rewiring, a hallmark of cancer in PCa, is enhanced in CRPC and ensures that resistant cells meet their anabolic demand for macromolecules, such as the shunting of glucose carbon to sustain the synthesis of nucleotides used in DNA replication, and energy to support continuous cellular proliferation. The lipolytic gene and co-activator for lipid turnover, ABHD5 (αβ-hydrolase domain containing 5), is also a novel tumor suppressor in CRPC. However, the mechanism behind ABHD5-dependent tumor suppression is not well understood. Our earlier results demonstrated that ABHD5-mediated lipolysis acts as a functional barrier suppressing the anabolic signaling of cancer cells. Mechanistically, ABHD5 triggers futile cycling of triglyceride hydrolysis and re-synthesis, resulting in AMP accumulation, AMPK activation, and mTORC1 inactivation. Methods and Results: RNA-seq analysis of ABHD5 overexpression revealed that without affecting mRNA levels, the MYC oncogene is a gene target of ABHD5 and strongly downregulated. Gene-set enrichment analysis (GSEA) indicated that Myc-target genes such as PHGDH and SHMT2, which are vital enzymes in serine-biosynthesis that support oncogenic activities, are also downregulated in presence of ABHD5 overexpression. Conclusion: Defining an ABHD5/cMYC/PHGDH regulatory axis will establish a new paradigm within cancer metabolism and potentially innovate cancer intervention by directly targeting cMYC via ABHD5’s regulatory cascade.