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CELLULAR LIPID HOMEOSTASIS:
LIPID DROPLETS AND FERROPTOSIS

Our research group integrates systems-level discovery methods and mechanistic cell biology approaches to achieve a comprehensive understanding of cellular lipid homeostasis in health and disease. We aim to elucidate the molecular mechanisms governing neutral lipid storage in lipid droplets and  oxidative lipid damage in ferroptosis. As we begin to understand these processes, we work to develop small molecule tools and therapeutics to benefit human health and combat prevalent diseases.

Lipotoxicity refers to the deleterious effects that lipids can have on cellular homeostasis and function. Accumulation of different types of lipids can induce distinct forms of lipotoxicity. For example, free fatty acids can induce ER stress by incorporation into ER lipids or can cause mitochondrial damage through incorporation into acylcarnitine. Some lipids play direct roles in cell death pathways. High levels of ceramide are associated with apoptotic signaling and the accumulation of oxidatively damaged phospholipids triggers the non-apoptotic cell death pathway known as ferroptosis. Ferroptosis has been implicated in the pathogenesis of a variety of degenerative conditions and targeted induction of ferroptosis is actively being pursued as a novel chemotherapeutic strategy to treat cancer.

     Our research aims to leverage genetic, cell biology, and biochemistry approaches to understand the mechanisms of ferroptosis and to discover the cellular factors that protect against these forms of damage. As we identify protective factors, we leverage chemical biology methods to develop small molecule inhibitors and activators as potential therapeutics. For example, we employed synthetic lethal CRISPR screens that led to the discovery of the oxidoreductase FSP1 as a new ferroptosis suppressor that generates the antioxidant form of CoQ to inhibit lipid peroxidation (Nature, 2019) and the discovery of LRP8 as a factor that enables cancer cell selenium scavenging to prevent ribosome stalling and disruptions in GPX4 translation (Nature Chem Biol, 2022). More recently, we developed small molecule inhibitors of FSP1 that sensitize cancer cells to ferroptosis (Cell Chem Biol, In Press).

LIPOTOXICITY AND FERROPTOSIS

Recent lipotoxicity and ferroptosis papers (selected)

Identification of structurally diverse FSP1 inhibitors that sensitize cancer cells to ferroptosis

Hendricks, J.M., Doubravsky, C.E., Wehri, E., Li, Z., Roberts, M.A., Deol, K.K., Lange, M., Lasheras-Otero, I., Momper, J.D., Dixon, S.J., Bersuker, K., Schlatetzky, J.#, Olzmann, J.A.# Cell Chemical Biology. (2023) S2451-9456(23)00114-9.

bioRxiv link posted 12.14.2022

Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability

Li., Z., Ferguson, L., Deol, K.K., Roberts, M.A., Magtanong, L., Hendricks, J.M., Mousa, G.A., Kilinc, S., Schaefer, K., Wells, J.A., Bassik, M.C., Goga, A., Dixon, S.J., Ingolia, N., Olzmann, J.A.​ Nature Chemical Biology. (2022) 18(7):751-761.

bioRxiv link posted 04.11.2022

Context-dependent regulation of ferroptosis sensitivity

Magtanong, L., Mueller, G.D., Williams, K.J., TKO Lab, Andrews, B., Boone, C., Moffat, J., Olzmann, J.A., Bensinger, S.J., Dixon, S.J. Cell Chemical Biology. (2022) S2451-9456(22)00236-7.

A genome-wide CRISPR screen implicates plasma membrane asymmetry in exogenous C6-ceramide toxicity

Morris, S.N.S., Deol, K.K., Lange, M., Olzmann, J.A. Biology Open. (2022) 11(12):bio059695.

bioRxiv link posted 09.28.2022

The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis

Bersuker, K., Hendricks, J., Li, Z., Magtanong, L., Ford, B., Tang, P.H., Roberts, M.A., Tong, B., Maimone, T.J., Zoncu, R., Nomura, D.K., Bassik, M.C., Dixon, S.J., Olzmann, J.A. Nature. (2019) 575(7784):688-692.

Exogenous monounsaturated fatty acids suppress non-apoptotic cell death

Magtanong, L., Ko, P.J., To, M., Cao, J.Y., Tarangelo, A.N., Ward, C., Nomura, D.K., Olzmann, J.A., Dixon, S. Cell Chemical Biology. (2019) 26, 420–432.

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Lipid droplets are dynamic neutral lipid (i.e. fat and sterol esters) storage organelles that function as hubs of lipid metabolism, providing an “on demand” source of fatty acids that can be used for energy, membrane biogenesis, and lipid signaling pathways. Lipid droplets are formed at the endoplasmic reticulum (ER) in a process involving the deposition of neutral lipids between the leaflets of the ER, followed by the emergence of the lipid droplet into the cytoplasm from the outer leaflet. The mature lipid droplet can be degraded by lipolysis or through a selective autophagic pathway known as lipophagy. How these pathways are regulated under different conditions and in different cell types remain to be determined. Furthermore, alterations in lipid droplet abundance are associated with a wide variety of diseases. Indeed, the accumulation of large hepatic lipid droplets is the pathological hallmark of fatty liver disease. Interestingly, mutations in certain genes (e.g. TM6SF2 and PNPLA3) are associated with increased risk of fatty liver.

    Our research aims to understand the mechanisms that regulate the biogenesis of lipid droplets and their functions in health and disease. For example, we discovered roles for lipid droplets in the prevent of lipotoxic damage to mitochondria (Dev Cell, 2017), developed chemoproteomic methods to study lipid droplet proteome remodeling (Dev Cell, 2018), and applied CRISPR screens to reveal new regulators of lipid droplet dynamics (bioRxiv, 2022). Some major questions include: How do lipid droplets form? How is the lipid and protein composition controlled? How are stored triacylglycerol molecules protected from oxidative damage? What are the functions of lipid droplets and how are these altered in diseases such as non-alcoholic fatty liver disease?

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Recent lipid droplet-related papers (selected)

LIPID DROPLET BIOGENESIS AND REGULATION

Parallel CRISPR-Cas9 screens reveal mechanisms of PLIN2 and lipid droplet regulation

Roberts, M.A., Deol, K.K., Lange, M., Leto, D., Mathiowetz, A.J., Stevenson, J., Hashemi, S.H., Morgens, D.W., Easter, E., Heydari, K., Nalls, M.A., Bassik, M.C., Kampmann, M., Kopito, R.R., Faghri, F., Olzmann, J.A. Developmental Cell. (Accepted).

bioRxiv link posted 08.29.2022

Protocol for performing pooled CRISPR-Cas9 loss of function screens to identify genetic modifiers

Mathiowetz, A.J.*, Roberts, M.A.*, Morgens, D.W., Olzmann, J.A.#, Li, Z.# STAR Protocols. (2023) 4(2):102201.

Optimized protocol for the identification of lipid droplet proteomes using proximity labeling proteomics in cultured human cells

Peterson, C.W.H.*, Deol, K.K.*, To, M., Olzmann, J.A. STAR Protocols. (2021) 5;2(2):100579.

Dynamics and functions of lipid droplets

Olzmann, J.A., Carvalho, P. Nature Review of Molecular and Cell Biology. (2019) 20(3): 137-155.

A proximity labeling strategy provides insights into the composition and dynamics of lipid droplet proteomes

Bersuker, K., Peterson, C.W., To, M., Sahl, S.J., Savikhin, V., Grossman, E.A., Nomura, D.K., Olzmann, J.A. Developmental Cell. (2018) 44, 97-112.

DGAT1-dependent lipid droplet biogenesis protects mitochondrial function during starvation-induced autophagy

Nguyen, T.B., Louie, S.M., Daniele, J., Tran, Q., Dillin, A., Zoncu, R., Nomura, D.K., Olzmann, J.A. Developmental Cell. (2017) 42, 9–21.

As we discover new mechanisms that impact lipid storage and lipotoxicity, our research seeks to translate these findings into meaningful tools and potential therapeutics. Through our chemistry collaborations, we employ small molecule screens and chemoproteomic approaches to identify hit compounds for development. For example, a recent high throughput small molecule screen in collaboration with Julia Schaletzky enabled the identification of structurally diverse FSP1 inhibitors that sensitize cancer cells to ferroptosis (Cell Chem Biol, In Press). In addition, chemoproteomic approaches with Dan Nomura have identified several compounds that impact cancer cell viability, including inhibitors of the ER shaping protein reticulon 4, focal adhesion kinase, and the regulator of cell growth and metabolism mTORC1. We have also contributed to the development of new E3 recruiters for targeted protein degradation. Current efforts focus on regulators of ferroptosis and new modalities of induced protein degradation. 

SMALL MOLECULE TOOLS AND THERAPEUTICS

Identification of structurally diverse FSP1 inhibitors that sensitize cancer cells to ferroptosis

Hendricks, J.M., Doubravsky, C.E., Wehri, E., Li, Z., Roberts, M.A., Deol, K.K., Lange, M., Lasheras-Otero, I., Momper, J.D., Dixon, S.J., Bersuker, K., Schlatetzky, J.#, Olzmann, J.A.# Cell Chemical Biology. (2023) S2451-9456(23)00114-9.

bioRxiv link posted 12.14.2022

Covalent targeting of the vacuolar H+-ATPase enhances cellular clearance through inhibition of lysosomal mTORC1 signaling

Chung C.Y.S., Shin, H.R., Berdan, C.A., Ford, B., Ward, C.C., Olzmann J.A., Zoncu, R., Nomura, D.K. Nature Chemical Biology. (2019) 15(8):776-785.

Harnessing the anti-cancer natural product nimbolide for targeted protein degradation

Spradlin, J.N., Hu, X., Ward, C.C., Brittain, S.M., Jones, M.D., Ou, L., To, M., Proudfoot, A., Ornelas, E., Woldegiorgis, M., Olzmann, J.A., Bussiere, D.E., Thomas, J.R., Tallarico, J.A., McKenna, J.M., Schirle, M., Maimone, T.J., Nomura, D.K. Nature Chemical Biology. (2019) 15(7):747-755.

Parthenolide impairs breast cancer pathogenicity through targeting an allosteric cysteine on focal adhesion kinase

Berdan, C.A., Ho, R., Lehtola, H.S., To, M., Hu, X., Huffman, T.R., Petri, Y., Altobelli, C.R., Demeulenaere, S.G., Olzmann, J.A., Maimone, T.J., Nomura, D.K. Cell Chemical Biology. (2019) 26(7):1027-1035.

 

Chemoproteomics-enabled covalent ligand screen reveals a cysteine hotspot in Reticulon 4 that impairs ER morphology and cancer pathogenicity

Bateman, L.A.*, Nguyen, T.B.*, Roberts, A.M.*, Miyamoto, D.K., Ku, W.M., Huffman, T.R., Petri, Y., Heslin, M.J., Contreras, C.M., Skibola, C.F., Olzmann, J.A.#, Nomura, D.K.# Chemical Communications. (2017) Jun 29;53(53), 7234-7237.

Recent small molecule tool and therpaeutic papers (selected)

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