ORIA Bioscience | Isolated Organelles for Drug Discovery

2026 - Seipin: A central lipid rheostat

Abdou Rachid Thiam, Maxime Carpentier – J Cell Biol Seipin is a conformationally flexible, oligomeric scaffold that regulates cellular lipid homeostasis beyond lipid droplet (LD) biogenesis. Seipin senses local lipid composition and membrane features to direct metabolic flux toward specific pathways and organelles. Its ring adopts multiple conformations, influenced by cofactors such as the LD assembly factor 1 and adipogenin, as well as lipid ligands including phosphatidic acid, diacylglycerol, and triacylglycerol, conferring broad functional versatility. Although seipin is an ER-resident protein primarily enriched at ER-LD junctions, a fraction relocates to mitochondria-associated membranes under specific metabolic conditions, where it regulates lipid synthesis, turnover, and local Ca2+ levels, thereby facilitating interorganelle communication and maintaining metabolic stability. Seipin dysfunction disrupts this multinodal regulation, causing lipid imbalance, organelle abnormalities, and a range of metabolic and neuronal disorders. We propose a unified model in which seipin functions as a multistate proteolipid regulatory hub: a rheostat whose structure and interactome dynamically adjust to control lipid pathway decisions in response to metabolic signals across organelle contact networks.

2025 - ATG2A-mediated DAG transfer recruits DGAT2 for lipid droplet growth

Abdou Rachid Thiam & al. – Nature Structural & Molecular Biology Lipid droplet (LD) growth mechanisms and the roles of LD-associated lipid transfer proteins remain poorly understood. Here we show that the autophagy lipid transfer protein ATG2A has an anabolic role and promotes LD expansion by transferring diacylglycerol (DAG), triacylglycerol (TAG) and phosphatidic acid, from the endoplasmic reticulum to LDs. In ATG2A deficiency, synthesized lipids are incorporated inefficiently into LDs and assemble new LDs. In addition, DAG O-acyltransferase 2 (DGAT2), which synthesizes TAG and expands LD, fails to relocate to LDs. In vitro, DAG recruits DGAT2 to LDs. These findings support the idea that ATG2A-mediated DAG transfer recruits DGAT2 to LDs, promoting LD expansion. ATG2A alone promotes LD growth by transferring TAG and DAG, but its effectiveness in LD expansion is reduced when DGAT2 is inhibited. This synergistic action with DGAT2 prevents the buildup of nonmembrane lipids within the endoplasmic reticulum and favors TAG synthesis on the LD surface.

2025 - Lysosomal Ion Channels and Transporters: Recent Findings, Therapeutic Potential, and Technical Approaches

Artem Kondratskyi & al. – BIOELECTRICITY In recent years, there has been a growing interest in lysosomal ion channels and transporters due to their critical role in maintaining lysosomal function and their involvement in a variety of diseases, particularly lysosomal storage diseases, cancer, and neurodegenerative disorders. Recent advancements in research techniques, including manual and automated patch clamp (APC) electrophysiology, solid-supported membrane-based electrophysiology (SSME), and fluorescence-based ion imaging, have further enhanced our ability to investigate lysosomal ion channels and transporters in both physiological and pathological conditions, spurring drug discovery efforts. Several pharmaceutical companies are now developing thera pies aimed at modulating these channels and transporters to improve lysosomal function in disease. Small molecules targeting channels like transient receptor potential mucolipin (TRPML) 1 and TMEM175, as well as drugs modulating lysosomal pH, are currently in preclinical and clinical development. This review provides an overview of the role of lysosomal ion channels and transporters in health and disease, high lights the cutting-edge techniques used to study them, and discusses the therapeutic potential of targeting these channels and transporters in the treatment of various diseases. Furthermore, in addition to summariz ing recent discoveries, we contribute novel functional data on cystinosin, TRPML1, and two-pore channel 2 (TPC2), utilizing both SSME and APC approaches.

2025 - Advancing drug discovery with electrophysiological tools for lysosomal and organellar ion channels

Niels fertig, Alexandre Santinho – Expert Opinion on Drug Discovery Ion channels, traditionally studied for their critical roles in cellular signaling and excitability, have been extensively characterized at the plasma membrane level using electrophysiological methods such as the patch clamp technique. Over the past two decades, the automation of patch clamp technology has revolutionized ion channel research, enabling high-throughput screening and transforming drug discovery. While automated patch clamp has become the gold standard for studying plasma membrane ion channels, its application to intracellular ion conducting proteins has been a more recent development.

2024 - Giant organelle vesicles to uncover intracellular membrane mechanics and plasticity

Alexandre Santinho, Maxime Carpentier, Julio Lopes Sampaio, Mohyeddine Omrane, Abdou Rachid Thiam – Nature Communications Tools for accessing and studying organelles remain underdeveloped. Here, we present a method by which giant organelle vesicles (GOVs) are generated by submitting cells to a hypotonic medium followed by plasma membrane breakage. By this means, GOVs ranging from 3 to over 10 µm become available for micromanipulation. GOVs are made from organelles such as the endoplasmic reticulum, endosomes, lysosomes and mitochondria, or in contact with one another such as giant mitochondria-associated ER membrane vesicles. We measure the mechanical properties of each organelle-derived GOV and find that they have distinct properties. In GOVs procured from Cos7 cells, for example, bending rigidities tend to increase from the endoplasmic reticulum to the plasma membrane. We also found that the mechanical properties of giant endoplasmic reticulum vesicles (GERVs) vary depending on their interactions with other organelles or the metabolic state of the cell. Lastly, we demonstrate GERVs’ biochemical activity through their capacity to synthesize triglycerides and assemble lipid droplets. These findings underscore the potential of GOVs as valuable tools for studying the biophysics and biology of organelles.

2023 - LC3B is lipidated to large lipid droplets during prolonged starvation for noncanonical autophagy

Abdou Rachid Thiam and al. – Developmental Cell Lipid droplets (LDs) store lipids that can be utilized during times of scarcity via autophagic and lysosomal pathways, but how LDs and autophagosomes interact remained unclear. Here, we discovered that the E2 autophagic enzyme, ATG3, localizes to the surface of certain ultra-large LDs in differentiated murine 3T3-L1 adipocytes or Huh7 human liver cells undergoing prolonged starvation. Subsequently, ATG3 lipidates microtubule-associated protein 1 light-chain 3B (LC3B) to these LDs. In vitro, ATG3 could bind alone to purified and artificial LDs to mediate this lipidation reaction. We observed that LC3B-lipidated LDs were consistently in close proximity to collections of LC3B-membranes and were lacking Plin1. This phenotype is distinct from macrolipophagy, but it required autophagy because it disappeared following ATG5 or Beclin1 knockout. Our data suggest that extended starvation triggers a noncanonical autophagy mechanism, similar to LC3B-associated phagocytosis, in which the surface of large LDs serves as an LC3B lipidation platform for autophagic processes.

Resources library

2026 - Seipin: A central lipid rheostat

2025 - ATG2A-mediated DAG transfer recruits DGAT2 for lipid droplet growth

2025 - Lysosomal Ion Channels and Transporters: Recent Findings, Therapeutic Potential, and Technical Approaches

2025 - Advancing drug discovery with electrophysiological tools for lysosomal and organellar ion channels

2024 - Giant organelle vesicles to uncover intracellular membrane mechanics and plasticity

2023 - LC3B is lipidated to large lipid droplets during prolonged starvation for noncanonical autophagy

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