bims-mecosi 2025-03-09 papers

Issue of 2025–03–09
six papers selected by
Verena Kohler, Umeå University

J Cell Biol. 2025 May 05. pii: e202407190. [Epub ahead of print]224(5):

Ca2+ binding to Esyt modulates membrane contact site density in Drosophila photoreceptors.

Vaisaly R Nath, Harini Krishnan, Shirish Mishra, Padinjat Raghu.

Membrane contact sites (MCS) between the plasma membrane (PM) and endoplasmic reticulum (ER) regulate Ca2+ influx. However, the mechanisms by which cells modulate ER-PM MCS density are not understood, and the role of Ca2+, if any, in regulating these is unknown. We report that in Drosophila photoreceptors, MCS density is regulated by the Ca2+ channels, TRP and TRPL. Regulation of MCS density by Ca2+ is mediated by Drosophila extended synaptotagmin (dEsyt), a protein localized to ER-PM MCS and previously shown to regulate MCS density. We find that the Ca2+-binding activity of dEsyt is required for its function in vivo. dEsytCaBM, a Ca2+ non-binding mutant of dEsyt is unable to modulate MCS structure. Further, reconstitution of dEsyt null photoreceptors with dEsytCaBM is unable to rescue ER-PM MCS density and other key phenotypes. Thus, our data supports a role for Ca2+ binding to dEsyt in regulating ER-PM MCS density in photoreceptors thus tuning signal transduction during light-activated Ca2+ influx.

DOI: https://doi.org/10.1083/jcb.202407190

J Transl Med. 2025 Mar 06. 23(1): 277

Mitochondria-associated endoplasmic reticulum membranes and myocardial ischemia: from molecular mechanisms to therapeutic strategies.

Chen Chen, Guohua Dai, Maoxia Fan, Xingmeng Wang, Kaibin Niu, Wulin Gao.

Myocardial ischemia has the highest disease burden among all cardiovascular diseases making it a significant challenge to the global public health. It can result in myocardial cell damage and death due to impaired mitochondrial and endoplasmic reticulum (ER) functions. These two organelles are important regulators of cell death. In recent years, research has shifted from isolated studies of individual organelles to a more integrative approach, with a particular focus on their membrane contact sites-Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs). These dynamic microdomains play a crucial role in regulating material exchange and signal transduction between the endoplasmic reticulum and mitochondria. This review comprehensively describes the intricate structure of MAMs and their multifaceted roles in cellular pathophysiological processes. Particular focus was directed at the far-reaching effects of MAMs in regulating key pathological events including calcium homeostasis, mitochondrial dysfunction, ER stress, oxidative stress, and autophagy in ischemic heart disease (IHD). The potential treatment targets and regulatory mechanisms of MAMs were discussed and summarized, providing novel research directions and treatment approaches for improving myocardial ischemia-related diseases.

Keywords: Calcium homeostasis; Cellular stress; Mitochondria-associated endoplasmic reticulum membranes; Myocardial ischemia

DOI: https://doi.org/10.1186/s12967-025-06262-3

Nat Commun. 2025 Mar 03. 16(1): 2135

Proximity proteomics reveals a mechanism of fatty acid transfer at lipid droplet-mitochondria- endoplasmic reticulum contact sites.

Membrane contact sites between organelles are critical for the transfer of biomolecules. Lipid droplets store fatty acids and form contacts with mitochondria, which regulate fatty acid oxidation and adenosine triphosphate production. Protein compartmentalization at lipid droplet-mitochondria contact sites and their effects on biological processes are poorly described. Using proximity-dependent biotinylation methods, we identify 71 proteins at lipid droplet-mitochondria contact sites, including a multimeric complex containing extended synaptotagmin (ESYT) 1, ESYT2, and VAMP Associated Protein B and C (VAPB). High resolution imaging confirms localization of this complex at the interface of lipid droplet-mitochondria-endoplasmic reticulum where it likely transfers fatty acids to enable β-oxidation. Deletion of ESYT1, ESYT2 or VAPB limits lipid droplet-derived fatty acid oxidation, resulting in depletion of tricarboxylic acid cycle metabolites, remodeling of the cellular lipidome, and induction of lipotoxic stress. These findings were recapitulated in Esyt1 and Esyt2 deficient mice. Our study uncovers a fundamental mechanism that is required for lipid droplet-derived fatty acid oxidation and cellular lipid homeostasis, with implications for metabolic diseases and survival.

DOI: https://doi.org/10.1038/s41467-025-57405-5

J Inherit Metab Dis. 2025 Mar;48(2): e70008

Phosphoinositide Metabolism: Biochemistry, Physiology and Genetic Disorders.

Francis Rossignol, Foudil Lamari, Grant A Mitchell.

Phosphatidylinositol, a glycerophospholipid with a myo-inositol head group, can form seven different phosphoinositides (PItds) by phosphorylation at inositol carbons 3, 4 and/or 5. Over 50 kinases and phosphatases participate in PItd metabolism, creating an interconnected PItd network that allows for precise temporal and spatial regulation of PItd levels. We review paradigms of PItd action, including (1) the establishment of subcellular organelle identity by the acquisition of specific PItd signatures, permitting regulation of key processes of cell biology including trafficking (exocytosis, clathrin-dependent and -independent endocytosis, formation and function of membrane contact sites, cytoskeletal remodeling), (2) signaling through phospholipase C cleavage of phosphatidylinositol 4,5-bisphosphate to inositol 1,4,5-trisphosphate and DAG, and (3) roles of PItds in molecular transport at membrane contact sites. To date, variants in 34 genes of PItd metabolism account for at least 41 distinguishable monogenic conditions. Clinical presentations of these disorders produce a broad and often multisystemic spectrum of effects. The nervous system is often involved, and muscular, immunological, skeletal, renal, ophthalmologic and dermatologic features occur in several conditions. Some syndromes involving PItd metabolism can be distinguished clinically, but most diagnoses currently result from broad molecular diagnostic testing performed for the patient's presenting clinical complaint. Genetic disorders of PItd metabolism are a broad, expanding and challenging category of inborn errors. Challenges include improved documentation of the clinical spectra, development of broad biochemical diagnostic methods for these conditions and better understanding of the PItd networks in different cells and subcellular compartments necessary for the development of disease-specific therapies.

Keywords: cellular trafficking; inborn error of metabolism; inherited metabolic disease; phosphatidylinositol; phosphoinositide; polyphosphoinositide

DOI: https://doi.org/10.1002/jimd.70008

Neurosci Biobehav Rev. 2025 Mar 01. pii: S0149-7634(25)00087-9. [Epub ahead of print]172 106087

The effect of mitochondrial-associated endoplasmic reticulum membranes (MAMs) modulation: New insights into therapeutic targets for depression.

Maohui Yang, Xuemei Qin, Xiaojie Liu.

Depression is a prevalent mental disorder with high morbidity and mortality and its pathogenesis remains exactly unclarified. However, mitochondria and endoplasmic reticulum (ER) are two highly dynamic organelles that perform an indispensable role in the development of depression. Mitochondrial dysfunction and ER stress are recognized as vital pathological hallmarks in depression. The changes of intracellular activities such as mitochondrial dynamics, mitophagy, energy metabolism and ER stress are closely correlated with the progression of depression. Moreover, organelles interactions are conducive to homeostasis and cellular functions, and mitochondrial-associated endoplasmic reticulum membranes (MAMs) serve as signaling hubs of the two organelles and the coupling of the pathological progression. The main roles of MAMs are involved in metabolism, signal transduction, lipid transport, and maintenance of its structure and function. At present, accumulating studies elucidated that MAMs have gradually become a novel therapeutic target in treatment of depression. In the review, we focus on influence of mitochondria dysfunction and ER stress on depression. Furthermore, we discuss the underlying role of MAMs in depression and highlight natural products targeting MAMs as potential antidepressants to treat depression.

Keywords: Depression; Endoplasmic reticulum; MAMs; Membranes couplings; Mitochondria; Natural products

DOI: https://doi.org/10.1016/j.neubiorev.2025.106087

J Cell Biol. 2025 Apr 07. pii: e202410013. [Epub ahead of print]224(4):

Any1 is a phospholipid scramblase involved in endosome biogenesis.

Jieqiong Gao, Rico Franzkoch, Cristian Rocha-Roa, Olympia Ekaterini Psathaki, Michael Hensel, Stefano Vanni, Christian Ungermann.

Endosomes are central organelles in the recycling and degradation of receptors and membrane proteins. Once endocytosed, such proteins are sorted at endosomes into intraluminal vesicles (ILVs). The resulting multivesicular bodies (MVBs) then fuse with the lysosomes, leading to the degradation of ILVs and recycling of the resulting monomers. However, the biogenesis of MVBs requires a constant lipid supply for efficient ILV formation. An ER-endosome membrane contact site has been suggested to play a critical role in MVB biogenesis. Here, we identify Any1 as a novel phospholipid scramblase, which functions with the lipid transfer protein Vps13 in MVB biogenesis. We uncover that Any1 cycles between the early endosomes and the Golgi and colocalizes with Vps13, possibly at a here-discovered potential contact site between lipid droplets (LDs) and endosomes. Strikingly, both Any1 and Vps13 are required for MVB formation, presumably to couple lipid flux with membrane homeostasis during ILV formation and endosome maturation.

DOI: https://doi.org/10.1083/jcb.202410013