bims-mecosi 2025-04-27 papers

Issue of 2025–04–27
five papers selected by
Verena Kohler, Umeå University

Proc Natl Acad Sci U S A. 2025 Apr 29. 122(17): e2426338122

PPARα regulates ER-lipid droplet protein Calsyntenin-3β to promote ketogenesis in hepatocytes.

Lauren F Uchiyama, Alexander Nguyen, Kevin Qian, Liujuan Cui, Khoi T Pham, Xu Xiao, Yajing Gao, Yuta Shimanaka, Marcus J Tol, Laurent Vergnes, Karen Reue, Peter Tontonoz.

Ketogenesis requires fatty acid flux from intracellular (lipid droplets) and extrahepatic (adipose tissue) lipid stores to hepatocyte mitochondria. However, whether interorganelle contact sites regulate this process is unknown. Recent studies have revealed a role for Calsyntenin-3β (CLSTN3β), an endoplasmic reticulum-lipid droplet contact site protein, in the control of lipid utilization in adipose tissue. Here, we show that Clstn3b expression is induced in the liver by the nuclear receptor PPARα in settings of high lipid utilization, including fasting and ketogenic diet feeding. Hepatocyte-specific loss of CLSTN3β in mice impairs ketogenesis independent of changes in PPARα activation. Conversely, hepatic overexpression of CLSTN3β promotes ketogenesis in mice. Mechanistically, CLSTN3β affects LD-mitochondria crosstalk, as evidenced by changes in fatty acid oxidation, lipid-dependent mitochondrial respiration, and the mitochondrial integrated stress response. These findings define a function for CLSTN3β-dependent membrane contacts in hepatic lipid utilization and ketogenesis.

Keywords: hepatocyte; ketogenesis; ketogenic diet; lipid metabolism

DOI: https://doi.org/10.1073/pnas.2426338122

J Cell Sci. 2025 May 01. pii: jcs263780. [Epub ahead of print]138(9):

Origin and evolution of mitochondrial inner membrane composition.

Kailash Venkatraman, Nicolas-Frédéric Lipp, Itay Budin.

Unique membrane architectures and lipid building blocks underlie the metabolic and non-metabolic functions of mitochondria. During eukaryogenesis, mitochondria likely arose from an alphaproteobacterial symbiont of an Asgard archaea-related host cell. Subsequently, mitochondria evolved inner membrane folds known as cristae alongside a specialized lipid composition supported by metabolic and transport machinery. Advancements in phylogenetic methods and genomic and metagenomic data have suggested potential origins for cristae-shaping protein complexes, such as the mitochondrial contact site and cristae-organizing system (MICOS). MICOS protein homologs function in the formation of cristae-like intracytoplasmic membranes (ICMs) in diverse extant alphaproteobacteria. The machinery responsible for synthesizing key mitochondrial phospholipids - which cooperate with cristae-shaping proteins to establish inner membrane architecture - could have also evolved from a bacterial ancestor, but its origins have been less explored. In this Review, we examine the current understanding of mitochondrial membrane evolution, highlighting distinctions between prokaryotic and eukaryotic mitochondrial-specific proteins and lipids and their differing roles in shaping cristae and ICM architecture, and propose a model explaining the concurrent specialization of the mitochondrial lipidome and inner membrane structure in eukaryogenesis. We discuss how advancements across a range of disciplines are shedding light on how multiple membrane components co-evolved to support the central functions of eukaryotic mitochondria.

Keywords: Cardiolipin; Cristae; Curvature; Evolution; Mitochondria; Phospholipids

DOI: https://doi.org/10.1242/jcs.263780

Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Apr 20. pii: S1388-1981(25)00023-X. [Epub ahead of print] 159615

Phosphatidylinositol 4-phosphate; A minor lipid with multiple personalities.

Tamas Balla.

Phosphorylated products of phosphatidylinositol (PI), named Diphosphoinositide (DPI) and triphosphoinositide (TPI) were identified long time ago and found to exhibit high turnover rates based on their rapid 32P-phosphate labeling. The PI kinase activities that were responsible for their production were subsequently identified and found to be associated with different organelle membranes, including the plasma membrane. These activities were then linked with a certain group of cell surface receptors that activated phospholipase C enzymes to hydrolyze PI and used calcium or cGMP as a second messenger. This visionary concept was introduced in the seminal BBA review written by Robert Michell, exactly 50 years ago. The enzymology and functional diversity of PI 4-phosphate (PI4P) (the term that has replaced DPI) has since underwent an expansion that could not have been foreseen. In this review I will attempt to revisit this expansion with some historical reflections celebrating the 50th anniversary of the Michell review.

Keywords: Endoplasmic reticulum; Golgi compartment; Membrane contact sites; Non-vesicular lipid transport; Phosphatidylinositol; Phosphatidylinositol 4-phosphate; Phosphoinositide kinase; Phospholipase C; Picornavirus

DOI: https://doi.org/10.1016/j.bbalip.2025.159615

mBio. 2025 Apr 24. e0011425

Endoplasmic reticulum facilitates the coordinated division of Salmonella-containing vacuoles.

Umesh Chopra, Priyanka Bhansali, Subba Rao Gangi Setty, Dipshikha Chakravortty.

Salmonella Typhimurium (STM) resides in a membrane-bound compartment called the Salmonella-containing vacuole (SCV) in several infected cell types where bacterial and SCV division occur synchronously to maintain a single bacterium per vacuole. However, the mechanism behind this synchronous fission is not well understood. Fission of intracellular organelles is known to be regulated by the dynamic tubular endoplasmic reticulum (ER). In this study, we evaluated the role of ER in controlling SCV division. Interestingly, Salmonella-infected cells show activation of the unfolded protein response (UPR) and expansion of ER tubules. Altering the expression of ER morphology regulators, such as reticulon-4a (Rtn4a) and CLIMP63, significantly impacted bacterial proliferation, suggesting a potential role of tubular ER in facilitating SCV division. Live-cell imaging revealed the marking of tubular ER at the center of 78% of SCV division sites. This study also explored the role of SteA (a known Salmonella effector in modulating membrane dynamics) in coordinating the SCV division. SteA resides on the SCV membranes and helps form membrane contact between SCV and ER. The colocalization of ER with SCV enclosing STMΔsteA was significantly reduced, compared with SCV of STM WT or STMΔsteA:steA. STMΔsteA shows profound defects in SCV division, resulting in multiple bacteria in a single vacuole with proliferation defects. In vivo, the STMΔsteA shows a defect in colonization in the spleen and liver and affects the initial survival rate of mice. Overall, this study suggests a coordinated role of bacterial effector SteA in promoting ER contact/association with SCVs and regulating SCV division.IMPORTANCEThis study highlights the essential role of the host endoplasmic reticulum in facilitating SCV division and maintaining a single bacterium per vacuole. The Salmonella effector SteA helps maintain the single bacterium per vacuole state. In the absence of SteA, Salmonella resides as multiple bacteria within a single large vacuole. The STMΔsteA shows reduced proliferation under in vitro conditions and exhibits colonization defects in vivo, highlighting the importance of this effector in Salmonella pathogenesis. These findings suggest that targeting SteA could provide a novel therapeutic approach to inhibit Salmonella pathogenicity.

Keywords: ER contact sites; ER tubules; Salmonella effectors; Salmonella-containing vacuole

DOI: https://doi.org/10.1128/mbio.00114-25

Nature. 2025 Apr 23.

Structural basis of lipid transfer by a bridge-like lipid-transfer protein.

Yunsik Kang, Katherine S Lehmann, Hannah Long, Amanda Jefferson, Maria Purice, Marc Freeman, Sarah Clark.

Bridge-like lipid-transport proteins (BLTPs) are an evolutionarily conserved family of proteins that localize to membrane-contact sites and are thought to mediate the bulk transfer of lipids from a donor membrane, typically the endoplasmic reticulum, to an acceptor membrane, such as that of the cell or an organelle1. Although BLTPs are fundamentally important for a wide array of cellular functions, their architecture, composition and lipid-transfer mechanisms remain poorly characterized. Here we present the subunit composition and the cryogenic electron microscopy structure of the native LPD-3 BLTP complex isolated from transgenic Caenorhabditis elegans. LPD-3 folds into an elongated, rod-shaped tunnel of which the interior is filled with ordered lipid molecules that are coordinated by a track of ionizable residues that line one side of the tunnel. LPD-3 forms a complex with two previously uncharacterized proteins, one of which we have named Spigot and the other of which remains unnamed. Spigot interacts with the N-terminal end of LPD-3 where lipids are expected to enter the tunnel, and experiments in multiple model systems indicate that Spigot has a conserved role in BLTP function. Our LPD-3 complex structural data reveal protein-lipid interactions that suggest a model for how the native LPD-3 complex mediates bulk lipid transport and provides a foundation for mechanistic studies of BLTPs.

DOI: https://doi.org/10.1038/s41586-025-08918-y