Biology subjects

Perne, P.

Publications and source records attributed to Perne, P..

4 recordsLinked to original sources

bioRxiv2026

Sfh3 is a sterol-modulated PI/PI4P transfer protein that confers azole resistance in yeast by specifically mediating lanosterol/PI exchange

Lipid transfer proteins precisely distribute lipids within eukaryotic cells, supporting functions such as vesicular trafficking and cellular signaling. Here, we analyzed whether Sfh3 (Sec14 homolog 3) functions as a sterol/phosphatidylinositol (PI) exchanger to clarify its role in neutral lipid mobilization from lipid droplets and in azole resistance in yeast. Using real-time assays, we found that its ergosterol transfer capacity is not activated by PI and is inhibited by ergosterol biosynthesis intermediates, such as lanosterol. Next, we found that Sfh3 exhibits both PI and PI4P transfer activities, which sterols can modulate. Through kinetic, structure-function, and thermal stability analyses, we identified remarkable Sfh3 mutants and ranked Sfh3's relative affinity for its lipid ligands. This allowed us to show that Sfh3 performs selective lanosterol/PI exchange, provided it recognizes PI, in the presence of ergosterol, and that this activity is necessary for yeast resistance to miconazole. Collectively, our data show that Sfh3 is a sterol-regulated PI/PI4P transfer protein, potentially linking sterol metabolism and PI4P signaling during lipid droplet utilization. In azole-treated yeast, elevated lanosterol levels may shift Sfh3 into an exclusive PI/lanosterol exchange mode, promoting cellular detoxification and conferring drug resistance. By revealing unanticipated Sfh-mediated lipid transfer mechanisms, our study provides new insights into the Sec14 family.

biochemistry↗

bioRxiv2026

Deletion of Ferritin Heavy Chain Limits Tumor Growth and Promotes Iron-Dependent Stress in Medulloblastoma

Iron is essential for tumor proliferation and metabolic adaptation but becomes cytotoxic when unbuffered, creating a potential metabolic vulnerability. Ferritin, a conserved iron-storage complex, limits labile iron and establishes the upper threshold of iron tolerance in cancer cells. Here, we report the first ferritin heavy chain (FTH) knockout in a brain tumor model system. Although FTH loss was tolerated under basal conditions through adaptive remodeling of iron metabolism, it exposed profound vulnerabilities under iron stress. FTH deficiency lowered the threshold for iron toxicity, sensitizing medulloblastoma (MB) cells to both canonical ferroptosis and a mechanistically distinct iron-dependent cell death pathway. Oxidative iron stress impaired tumor growth and prolonged survival in orthotopic xenografts, whereas vitamin C-induced iron reduction triggered a selective, iron-dependent, but non-ferroptotic elimination of MB-like cells in tumor organoids. Notably, sensitivity to iron toxicity correlated strongly with cellular phenotype, with mesenchymal-like cells displaying greater susceptibility than epithelial-like counterparts. Collectively, these findings identify ferritin as a central regulator of iron tolerance in MB and establish iron toxicity, not via iron deprivation, as a therapeutically exploitable vulnerability. More broadly, this work provides a mechanistic framework for targeting iron metabolism through modulation of ferritin-dependent iron buffering and iron redox homeostasis in cancers. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=170 SRC="FIGDIR/small/739635v1_ufig1.gif" ALT="Figure 1000"> View larger version (53K): org.highwire.dtl.DTLVardef@1c499a4org.highwire.dtl.DTLVardef@431c70org.highwire.dtl.DTLVardef@2b5borg.highwire.dtl.DTLVardef@11e9ac1_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2026

Ether lipid remodeling during neuronal differentiation prevents ferroptosis

Ferroptosis is a form of cell death driven by iron-dependent lipid peroxidation, with specific lipid species playing key roles in modulating susceptibility. Among these, ether lipids have shown conflicting effects, being linked to both protection and sensitization. Here, we dissect the relationship between lipid structure and ferroptosis sensitivity and explain how ether lipids exert context-dependent effects. Ether lipids can promote ferroptosis through a metabolic bias towards the accumulation of polyunsaturated acyl chains and ethanolamine head groups, whereas this pro-ferroptotic tendency is counterbalanced by the anti-ferroptotic vinyl ether moiety introduced by plasmanylethanolamine desaturase 1. We show that this protective effect is critical for preventing ferroptosis in hiPSC-derived neurons, which accumulate otherwise pro-ferroptotic ether lipids during differentiation. This effect is not solely due to its antioxidant properties but also stems from the reprogramming of mitochondrial respiration. The lack of vinyl ether bonds leads to multiple mitochondrial defects, including increased mitochondrial reactive oxygen species (ROS), lower membrane potential, and abnormal cristae structures. These findings indicate that vinyl ether bonds in ether lipids offer dual ferroptosis resistance by scavenging ROS and minimizing its production at the mitochondrial level. The disruption of this system in Caenorhabditis elegans leads to iron-induced death and impaired motility. Thus, our study reveals ether lipid structural remodeling as a key regulator of ferroptosis sensitivity in neurons.

cell biology↗

bioRxiv2025

Chain length defines the spatial segregation and metabolic fate of fatty acids in adipocytes

Adipocytes primarily store fatty acids (FAs) as triacylglycerols (TGs) within lipid droplets, releasing them through lipolysis to meet systemic energy demands. While the metabolism of long-chain fatty acids (LCFAs) in adipocytes has been extensively characterized, it remains ill-defined how adipocytes utilize fatty acids depending on chain length and structure. Our work demonstrates that short- and medium-chain fatty acids (SMCFAs) are esterified into TGs within lipid droplets, rather than being incorporated into other FA-containing lipid species. During lipolytic activation, TGs enriched in SMCFAs are hydrolysed more rapidly than those containing LCFAs. This accelerated mobilization is facilitated by the preferential localization of SMCFA-containing TGs at the lipid droplet surface, which enhances accessibility to adipose triglyceride lipase. Unlike LCFAs, which are efficiently released for utilization by peripheral tissues, SMCFAs are predominantly oxidized within adipocytes. These findings reveal a unique metabolic routing of SMCFAs, indicating their preferential intracellular oxidation to support adipocyte energy requirements.

biochemistry↗