Biology subjects

Jollivet, F.

Publications and source records attributed to Jollivet, F..

4 recordsLinked to original sources

bioRxiv2026

Lipid droplets accumulate and delay regulated cell death execution

Normal and cancer cells accumulate lipid droplets (LDs) under stress to buffer lipotoxicity, but their role in regulated cell death (RCD) remains incompletely understood. Here, we explored LD accumulation across multiple apoptotic and non-apoptotic RCD modalities in human cancer cells and Drosophila germ cells. We found that LD accumulation arises from de novo LD biogenesis, whereas LD lipolysis remains active--or even enhanced--in dying germ cells and cancer cells, respectively. In Drosophila, LD accumulation in ATGL/Bmm lipase loss of function mutant inhibited germ cell death, supporting a protective role of LDs. Proteomic and imaging analyses revealed a broad redistribution of LD-associated proteins, encompassing lipid metabolism and stress response factors, as well as the pro-apoptotic effector Bax in human cancer cells during cell death. Enhanced LD-mitochondria contacts promoted the translocation of conformationally active Bax from mitochondria to LDs, thereby delaying apoptosis execution. Consistently, LD depletion sensitizes cells to Bax-dependent apoptosis, whereas LD accumulation confers resistance. Collectively, these findings define LD accumulation during cell death as a delaying mechanism in which LDs sequester mitochondrial cell death regulators, attenuating their pro-death activity and revealing potential therapeutic implications for apoptosis-resistant cancers.

cell biology↗

bioRxiv2025

A dWDR45 knock-out Drosophila model to decipher the role of autophagy in BPAN

Beta-propeller protein-associated neurodegeneration (BPAN) is a rare neurological disorder characterized by severe cognitive and motor impairments. BPAN is caused by de novo pathogenic variants in the WDR45 gene on the X chromosome. WDR45 gene encodes the protein WDR45/WIPI4, a known regulator of autophagy. A defective autophagy has been observed in cellular models of BPAN disease and is associated with neurological dysfunctions in wdr45 knockout (KO) mice. However, it remains unclear whether the autophagic defect directly contributes to all WDR45 loss-induced phenotypes or whether other WDR45-dependent cellular functions are involved. To investigate this, we generated a CRISPR/Cas9-mediated KO of CG11975 (dwdr45 KO), the Drosophila homolog of WDR45. Our analysis revealed that dwdr45 KO flies display BPAN-like phenotypes, including impaired locomotor function, seizure-like behavior, autophagy dysregulation and iron dyshomeostasis. Additionally, dwdr45 KO flies exhibit shortened lifespan compared to control flies. These findings demonstrate that dwdr45 KO fly is a relevant in-vivo model for investigating the key cellular and molecular mechanisms underlying BPAN-associated phenotypes. Here we showed that induction of autophagy in dwdr45 KO flies improved both the shortened lifespan and the seizure-like behavior, but did not restore locomotor function. This suggests that defective autophagy contributes to some, but not all, aspects of the phenotypes resulting from loss of dWdr45 function.

cell biology↗

bioRxiv2024

MYC shapes ER-mitochondria calcium transfer by directly targeting ITPR1: implications for MYC-induced safeguard mechanisms and cancer

The MYC and NMYC transcription factors (TFs) play a key role in cell proliferation and are overexpressed in most cancer cells. However, in normal cells their overexpression triggers safeguard mechanisms promoting cell death and cellular senescence, which are bypassed in cancer cells. The mechanisms of action of this TF family are only partially understood. Here, we reveal that in normal cells MYC binds to the Inositol 1,4,5-Trisphosphate Receptor type 1 (ITPR1) gene and upregulates its expression, triggering an ER-mitochondria calcium (Ca2+) transfer, which is involved in MYC-induced cell death and senescence. Supporting a tumor suppressive role of MYC/ITPR1 axis, ITPR1 expression is generally decreased in cancer and reactivation of this pathway induces cancer cell death. Nevertheless, some cancer cells, generally expressing high levels of MYCN and/or MYC, also express high level of ITPR1, which correlates with high expression of BCL2, encoding an inhibitor of ITPR1. Strikingly, in high-risk MYCN-amplified neuroblastoma, ITPR1 expression is controlled by NMYC and its level correlates with worse patient survival. In these cells, blocking the interaction between BCL2 and ITPR1 induces mitochondrial Ca2+ accumulation and cell death, and decreases tumor size. Collectively these data highlight a new function of MYC factors by controlling Ca2+ signaling, which could constitute an unsuspected vulnerability for some cancer cells, including high-risk MYCN-amplified neuroblastoma cells.

cancer biology↗

bioRxiv2020

Alpha-synuclein enhances lipid droplet accumulation in neurons in a Drosophila model of Parkinson's disease

Parkinsons disease (PD) is a neurodegenerative disorder characterized by alpha-synuclein (Syn) aggregation and associated with abnormalities in lipid metabolism. The accumulation of lipids in cytoplasmic organelles called lipid droplets (LDs) was observed in cellular models of PD. To investigate the pathophysiological consequences of interactions between Syn and proteins that regulate the homeostasis of LDs, we used a transgenic Drosophila model of PD, in which human Syn is specifically expressed in photoreceptor neurons. We first found that overexpression of the LD-coating proteins perilipin 1 or 2 (dPlin1/2), which limit the access of lipases to LDs, markedly increased triacylglyclerol (TG) loaded LDs in neurons. However, dPlin-induced-LDs in neurons are independent of lipid anabolic (diacylglycerol acyltransferase 1/Midway, fatty acid transport protein/dFatp) and catabolic (lipase Brummer) enzymes, indicating that non-canonical mechanisms regulate neuronal LD homeostasis. Interestingly, the accumulation of LDs induced by several distinct LD proteins (dPlin1, dPlin2, CG7900 or KlarsichtLD-BD) was synergistically amplified by the co-expression of Syn, which was found at the surface of LDs both in photoreceptors neurons of Drosophila and in human neuroblastoma cells. Finally, the accumulation of LDs increased the resistance of Syn to proteolytic digestion, a phenomenon associated with Syn aggregation in human neurons. We thus propose that Syn cooperates with LD proteins to inhibit lipolysis and that binding of Syn to LDs contributes to the pathogenic misfolding and aggregation of Syn in neurons.

cell biology↗