bims-mecosi 2025-05-18 papers

Issue of 2025–05–18
six papers selected by
Verena Kohler, Umeå University

J Cell Sci. 2025 May 01. pii: jcs263895. [Epub ahead of print]138(9):

Mitochondria-membranous organelle contacts at a glance.

Mitochondrial contact sites are specialized interfaces where mitochondria physically interact with other organelles. Stabilized by molecular tethers and defined by unique proteomic and lipidomic profiles, these sites enable direct interorganellar communication and functional coordination, playing crucial roles in cellular physiology and homeostasis. Recent advances have expanded our knowledge of contact site-resident proteins, illuminated the dynamic and adaptive nature of these interfaces, and clarified their contribution to pathophysiology. In this Cell Science at a Glance article and the accompanying poster, we summarize the mitochondrial contacts that have been characterized in mammals, the molecular mechanisms underlying their formation, and their principal functions.

Keywords: Contact sites; Mitochondria; Organelles

DOI: https://doi.org/10.1242/jcs.263895

Biochim Biophys Acta Mol Cell Biol Lipids. 2025 May 09. pii: S1388-1981(25)00034-4. [Epub ahead of print]1870(5): 159626

Regulation and function of PI4P at the Golgi complex.

Maria Antonietta De Matteis, Marianna Fico, Rossella Venditti.

Fifty years after Bob Michell's visionary prediction, phosphatidylinositol 4-phosphate (PI4P) has emerged as a central regulator of Golgi function, influencing membrane trafficking, lipid metabolism, and signaling. PI4P homeostasis is tightly controlled by phosphatidylinositol 4-kinases (PI4Ks), phosphatidylinositol transfer proteins (PITPs), and the phosphatase SAC1, ensuring precise regulation across Golgi subdomains. Beyond its classical role in vesicular transport, PI4P orchestrates lipid exchange at membrane contact sites, enabling dynamic Golgi maturation and functional specialization. The interplay between PI4P, lipid transfer proteins, and Golgi adaptors underlies cargo sorting, glycosylation, and organelle architecture. Emerging evidence also highlights PI4P's role in oncogenesis and cellular signaling, positioning the Golgi as a critical hub beyond secretion. Yet, key questions remain regarding PI4P compartmentalization and its broader physiological impact. This review revisits PI4P's essential functions, integrating historical insights with recent discoveries to illuminate its pivotal role in Golgi biology and beyond.

DOI: https://doi.org/10.1016/j.bbalip.2025.159626

Cell Rep. 2025 May 09. pii: S2211-1247(25)00465-6. [Epub ahead of print]44(5): 115694

IRE1α promotes phagosomal calcium flux to enhance macrophage fungicidal activity.

Michael J McFadden, Mack B Reynolds, Britton C Michmerhuizen, Einar B Ólafsson, Sofia M Marshall, Faith Anderson Davis, Tracey L Schultz, Takao Iwawaki, Jonathan Z Sexton, Mary X D O'Riordan, Teresa R O'Meara.

The mammalian endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1α (IRE1α) is essential for cellular homeostasis and plays key roles in infection responses, including innate immunity and microbicidal activity. While IRE1α functions through the IRE1α-XBP1S axis are known, its XBP1S-independent roles are less well understood, and its functions during fungal infection are still emerging. We demonstrate that Candida albicans activates macrophage IRE1α via C-type lectin receptor signaling independent of protein misfolding, suggesting non-canonical activation. IRE1α enhances macrophage fungicidal activity by promoting phagosome maturation, which is crucial for containing C. albicans hyphae. IRE1α facilitates early phagosomal calcium flux post-phagocytosis, which is required for phagolysosomal fusion. In macrophages lacking the IRE1α endoribonuclease domain, defective calcium flux correlates with fewer ER-early endosome contact sites, suggesting a homeostatic role for IRE1α-promoting membrane contact sites. Overall, our findings illustrate non-canonical IRE1α activation during infection and a function for IRE1α in supporting organelle contact sites to safeguard against rapidly growing microbes.

Keywords: CP: Immunology; CP: Microbiology; Candida albicans; IRE1α; calcium; fungal infection; innate immunity; phagosome

DOI: https://doi.org/10.1016/j.celrep.2025.115694

J Cell Sci. 2025 May 01. pii: jcs263639. [Epub ahead of print]138(9):

Snapshots of mitochondrial fission imaged by cryo-scanning transmission electron tomography.

Peter Kirchweger, Sharon Grayer Wolf, Neta Varsano, Tali Dadosh, Guenter P Resch, Michael Elbaum.

Mitochondria undergo constant remodeling via fission, fusion, extension and degradation. Fission, in particular, depends on the accumulation of mitochondrial fission factor (MFF) and subsequent recruitment of the dynamin-related protein DRP1 (also known as DNM1L). We used cryo-scanning transmission electron tomography (cryo-STET) to investigate mitochondrial morphologies in MFF mutant (MFF-/-) mouse embryonic fibroblast (MEF) cells in ATP-depleting conditions that normally induce fission. The capability of cryo-STET to image through the cytoplasmic volume to a depth of 1 µm facilitated visualization of intact mitochondria and their surroundings. We imaged changes in mitochondrial morphology and cristae structure, as well as contacts with the endoplasmic reticulum (ER), degradative organelles and the cytoskeleton at stalled fission sites. We found disruption of the outer mitochondrial membrane at contact sites with the ER and degradative organelles at sites of mitophagy. We identified fission sites where the inner mitochondrial membrane is already separated while the outer membrane is still continuous. Although MFF is a general fission factor, these observations demonstrate that mitochondrial fission can proceed to the final stage in its absence. The use of cryo-STET allays concerns about the loss of structures due to sample thinning required for tomography using cryo-transmission electron microscopy.

Keywords: Cryo-ET; Cryo-FM; Cryo-STET; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fission factor

DOI: https://doi.org/10.1242/jcs.263639

Nat Rev Mol Cell Biol. 2025 May 14.

Molecular machineries shaping the mitochondrial inner membrane.

Oliver Daumke, Martin van der Laan.

Mitochondria display intricately shaped deep invaginations of the mitochondrial inner membrane (MIM) termed cristae. This peculiar membrane architecture is essential for diverse mitochondrial functions, such as oxidative phosphorylation or the biosynthesis of cellular building blocks. Conserved protein nano-machineries such as F1Fo-ATP synthase oligomers and the mitochondrial contact site and cristae organizing system (MICOS) act as adaptable protein-lipid scaffolds controlling MIM biogenesis and its dynamic remodelling. Signal-dependent rearrangements of cristae architecture and MIM fusion events are governed by the dynamin-like GTPase optic atrophy 1 (OPA1). Recent groundbreaking structural insights into these nano-machineries have considerably advanced our understanding of the functional architecture of mitochondria. In this Review, we discuss how the MIM-shaping machineries cooperate to control cristae and crista junction dynamics, including MIM fusion, in response to cellular signalling pathways. We also explore how mutations affecting MIM-shaping machineries compromise mitochondrial functions.

DOI: https://doi.org/10.1038/s41580-025-00854-z

Front Neurosci. 2025 ;19 1534061

VPS13 and bridge-like lipid transporters, mechanisms, and mysteries.

Laura Elizabeth Swan.

Bridge-like lipid transporters (BLTPs) have recently been revealed as key regulators of intraorganellar lipid trafficking, with their loss being associated with defective synaptic signalling and congenital neurological diseases. This group consists of five protein subfamilies [BLTP1-3, autophagy-related 2 (ATG2), and vacuolar protein sorting 13 (VPS13)], which mediate minimally selective lipid transfer between cellular membranes. Deceptively simple in both structure and presumed function, this review addresses open questions as to how bridge-like transporters work, the functional consequences of bulk lipid transfer on cellular signalling, and summarises some recent studies that have shed light on the surprising level of regulation and specificity found in this family of transporters.

Keywords: ATG2; BLTP; VPS13; lipid transfer activity; membrane contacts; scramblase activity

DOI: https://doi.org/10.3389/fnins.2025.1534061