Biology subjects

Fazeli, G.

Publications and source records attributed to Fazeli, G..

4 recordsLinked to original sources

bioRxiv2025

HMOX1 controls a heme/ferritin switch that protects cells from ferroptosis

Modulating the intracellular labile iron pool (LIP) has emerged as a promising strategy to induce ferroptosis in cancer cells, offering a way to overcome resistance to apoptosis-based therapies. One of the main contributors to LIP is heme catabolism mediated by heme oxygenase-1 (HMOX1), which promotes ferroptosis sensitivity by releasing free iron. Beyond its role as an iron donor, heme can influence diverse proteins and signaling pathways that drive tumor progression, but how heme regulates ferroptosis remains poorly understood. Here, we uncover a paradoxical, protective function of heme in the absence of HMOX1 activity. When HMOX1 is inactive, heme becomes stabilized, leading to ferritin upregulation, suppression of ferroptosis, and rescue of cell death induced by both pharmacological and genetic inhibition of GPX4. Our findings reveal an unrecognized heme-HMOX1-ferritin axis that controls ferroptosis sensitivity. Targeting this pathway may offer a new therapeutic strategy to modulate ferroptosis in cancer.

cancer biology↗

bioRxiv2024

PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance

Selenocysteine (Sec) metabolism is crucial for cellular function and ferroptosis prevention and has traditionally been thought to begin with the uptake of the Sec carrier selenoprotein P (SELENOP). Following uptake, Sec released from SELENOP undergoes metabolisation via selenocysteine lyase (SCLY), producing selenide, a substrate used by selenophosphate synthetase 2 (SEPHS2), which provides the essential selenium donor - selenophosphate - for the biosynthesis of the selenocysteine tRNA. Here, we report the discovery of an alternative pathway mediating Sec metabolisation that is independent of SCLY and mediated by peroxiredoxin 6 (PRDX6). Mechanistically, we demonstrate that PRDX6 can readily react with selenide and interact with SEPHS2, potentially acting as a selenium delivery system. Moreover, we demonstrate the presence and functional significance of this alternative route in cancer cells where we reveal a notable association between elevated expression of PRDX6 with a highly aggressive neuroblastoma subtype. Altogether, our study sheds light on a previously unrecognized aspect of Sec metabolism and its implications in ferroptosis, offering new avenues for therapeutic exploitation.

cell biology↗

bioRxiv2022

TORC1, BORC, and ARL-8 cycling drive vesiculation of cell corpse phagolysosomes

The dynamics of phagolysosomes leading to cargo clearance are important to provide cells with metabolites and avoid auto-immune responses, but little is known about how phagolysosomes finally resolve cell corpses and cell debris. We previously discovered that polar body phagolysosomes tubulate into small vesicles to facilitate corpse clearance within 1.5 hours in C. elegans. Here, we show that vesiculation depends on activating TORC1 through amino acid release by the solute transporter SLC-36.1. Downstream of TORC1, BLOC-1-related complex (BORC) recruits the Arf-like GTPase ARL-8 to the phagolysosome for tubulation by kinesin-1. We find that disrupting the regulated GTP-GDP cycle of ARL-8 reduces tubulation, delays corpse clearance, and mislocalizes ARL-8 away from lysosomes. We also demonstrate that mammalian phagocytes use BORC to promote phagolysosomal degradation, confirming the conserved importance of this pathway. Finally, we show that HOPS is required for rapid degradation of the small phagolysosomal vesicles. Thus, by observing single phagolysosomes over time, we identified the molecular pathway regulating phagolysosome vesiculation that promotes efficient resolution.

cell biology↗

bioRxiv2018

Degron tagging to label membrane-wrapped objects and probe membrane topology

Visualization of specific organelles in tissues over background fluorescence can be challenging, especially when reporters localize to multiple structures. Instead of trying to identify proteins enriched in specific membrane-wrapped structures, we used a selective degradation approach to remove reporters from the cytoplasm or nucleus of C. elegans embryos and mammalian cells. We demonstrate specific labelling of organelles using degron-tagged reporters, including extracellular vesicles, as well as individual neighbouring membranes. These degron-tagged reporters facilitate long-term tracking of released cell debris and cell corpses, even during uptake and phagolysosomal degradation. We further show that degron protection assays can probe the topology of the nuclear envelope and plasma membrane during cell division, giving insight into protein and organelle dynamics. As endogenous and heterologous degrons are used in bacteria, yeast, plants, and animals, degron approaches can enable the specific labelling and tracking of proteins, vesicles, organelles, cell fragments, and cells in many model systems.

cell biology↗