bims-mecosi 2025-06-15 papers

Issue of 2025–06–15
five papers selected by
Verena Kohler, Umeå University

Trends Neurosci. 2025 Jun 05. pii: S0166-2236(25)00098-0. [Epub ahead of print]

PDZD8 orchestrates synaptic remodeling through autophagy.

In a recent study, Thakur and O'Connor-Giles identified PDZD8 as a novel regulator of activity-dependent synaptic growth in Drosophila. Localized at endoplasmic reticulum (ER)-late endosome/lysosome (LEL) membrane contact sites (MCSs), PDZD8 promotes autophagy by coupling lipid transfer to autolysosome maturation to drive synaptic bouton formation, providing in vivo evidence that autophagy contributes directly to synaptic remodeling.

Keywords: development; endosome; lipid; lysosome; neuron; plasticity

DOI: https://doi.org/10.1016/j.tins.2025.05.003

Cell Rep. 2025 Jun 11. pii: S2211-1247(25)00584-4. [Epub ahead of print]44(6): 115813

An adaptive organelle triad houses lipid droplets for dynamic regulation.

Hong Qiu, Can Miao, Cunqi Ye.

Cell organelles compartmentalize metabolic reactions and require inter-organelle communications to coordinate metabolic activities in fluctuating nutrient environments. While membrane contacts enable this communication by facilitating metabolite exchange, the functional organization of organelles through these contacts remains underexplored. Here, we show that excess lactate induces severe metabolic stress under nutrient deprivation in the budding yeast Saccharomyces cerevisiae, necessitating a rapid life cycle of lipid droplets (LDs) for cellular adaptation. This process uncovers a previously uncharacterized subcellular architecture-an organelle triad-comprising the vacuole, LDs, and the nuclear endoplasmic reticulum (ER). The vacuole undergoes expansion and deformation, enveloping the entire nucleus that is encircled by an orbit of LDs. Formation of this organelle triad depends on the timely and abundant expression of membrane-tethering proteins that mediate vacuole-LD contact sites and nuclear ER-vacuole junctions. This dynamic and reversible subcellular organization ensures efficient LD metabolism to support cell survival under nutrient stress.

Keywords: CP: Cell biology; LDO proteins; lipid droplet; membrane contact; nutrient stress; nvj1; subcellular architecture; the nucleus–vacuole junction; vac8; vacuole deformation

DOI: https://doi.org/10.1016/j.celrep.2025.115813

Circulation. 2025 Jun 10. 151(23): 1667-1685

FMO2 Prevents Pathological Cardiac Hypertrophy by Maintaining the ER-Mitochondria Association Through Interaction With IP3R2-Grp75-VDAC1.

BACKGROUND: Cardiac hypertrophy, as an important pathological change, contributes to heart failure. Recent studies indicate that the mitochondria-associated endoplasmic reticulum membranes (MAMs) play key roles in this pathological process. However, the molecular mechanism remains unclear. This study aims to elucidate the effects and mechanisms of MAM-resident FMO2 (flavin-containing monooxygenase 2) in cardiac hypertrophy and heart failure.
METHODS: We performed bulk RNA-sequencing analysis using heart tissue from patients with cardiac hypertrophy and carried out MAM-targeted mass spectrometry analysis using heart tissue from a mouse model of pathological cardiac hypertrophy. In vitro cell culture using neonatal rat cardiomyocytes was used to study how MAMs formation affected cardiomyocyte functions. By generating different genetic mouse models combined with using adeno-associated virus 9 under the cardiac troponin T promoter techniques, we further investigated and confirmed the effects of MAM structure changes on cardiac hypertrophy.
RESULTS: We detected an unexpected component of MAMs structure, which was the FMO2, an endoplasmic reticulum-resident protein. FMO2 levels decreased during pathological cardiac hypertrophy. The deletion and overexpression of FMO2 can either worsen or prevent the pathological heart failure progression in vivo, respectively. Our data further demonstrated that FMO2 localizes to MAM structure, where it binds to inositol 1,4,5-trisphosphate type 2 receptor (IP3R2) as a component of the IP3R2-Grp75 (glucose-regulated protein 75)-VDAC1 (voltage-dependent anion channel protein 1) complex, maintaining endoplasmic reticulum-mitochondria contact and regulating mitochondrial Ca2+ signaling for bioenergetics. Last, we showed that a synthetic peptide-enhancing endoplasmic reticulum-mitochondria contact promoted Ca2+ transfer and prevented pathological cardiac hypertrophy.
CONCLUSIONS: Our findings reveal a key role of FMO2 in myocardial hypertrophy and that FMO2 plays a pivotal role in maintaining MAM structure and function, which may represent a novel mechanism and therapeutic target for cardiac hypertrophy and heart failure.

Keywords: hypertrophy; mitochondria; mitochondria associated membranes

DOI: https://doi.org/10.1161/CIRCULATIONAHA.124.072661

Mol Ther Oncol. 2025 Jun 18. 33(2): 200995

ER-mitochondria tethering and its signaling: A novel therapeutic target in breast cancer.

Chamanthi Paidi, Yerusha Nuthalapati, Anuveda Sree Samudrala, Priyamvada Bhamidipati, Charanteja Mangam, Danny R Welch, Ganji Purnachandra Nagaraju, RamaRao Malla.

Communication between the endoplasmic reticulum (ER) and mitochondria through mitochondria-associated ER membranes (MAMs) is assisted by tethering proteins and signaling pathways, manifesting the dynamic exchange of lipids, calcium, and signaling molecules. However, dysregulation of tethering and signaling proteins contributes to the progression of breast cancer (BC). Abnormal MAM structures and altered ER-mitochondrial tethering impair mitochondrial functions and thereby drive BC progression. Altered mitochondrial dynamics, often characterized by dysregulated dynamin-related protein 1 (Drp1) and mitofusin-2 (Mfn2) activity, enhances BC cell survival. Similarly, ER stress and the unfolded protein response, both modulated by dysregulated ER-mitochondrial contacts, promote drug resistance. In BC, caveolae-dependent and -independent caveolin-1 signaling alongside Yes-associated protein (YAP) signaling pathway alters organelle dynamics by interacting with Drp1 and Mfn2, underscoring their therapeutic potential. This review explores potential therapeutic strategies targeting ER-mitochondrial communications and their potential for hindering BC progression. These strategies include modulating mitochondrial dynamics and promoting controlled ER stress by disrupting aberrant ER-mitochondrial tethering using chemotherapeutics, clinical inhibitors, and natural compounds, alone or in combination. Ultimately, targeting dysregulated ER-mitochondrial tethering has significant potential to improve patient outcomes in BC.

Keywords: ER-mitochondria tethering; MT: Regular Issue; ROS; YAP; breast cancer; caveolin-1

DOI: https://doi.org/10.1016/j.omton.2025.200995

J Mol Cell Cardiol Plus. 2025 Jun;12 100453

Structural and functional characterization of the cardiac mitochondria-associated reticular membranes in the ob/ob mouse model.

Hala Guedouari, Maya Dia, Juliette Geoffray, Camille Brun, Florentin Moulin, Lucas Givre, Lucid Belmudes, Christelle Leon, Stephanie Chanon, Jingwei Ji-Cao, Christophe Chouabe, Sylvie Ducreux, Claire Crola Da Silva, Ludovic Gomez, Yohann Couté, Helene Thibault, Jennifer Rieusset, Melanie Paillard.

Type 2 diabetes (T2D) and obesity strongly lead to diabetic cardiomyopathy (DCM). The involvement of mitochondria-associated reticular membranes (MAMs), a signaling hub in the cardiomyocyte, starts to be demonstrated in T2D-related metabolic disorders. We recently discovered a cardiac MAM Ca2+ uncoupling in a high-fat high-sucrose diet (HFHSD)-induced mouse model of DCM. To better determine the role of MAMs in the progression of DCM, we here aimed to characterize the proteomic composition and function of the cardiac MAMs of another obesogenic T2D mouse model, the leptin-deficient ob/ob mouse. 12-week old male C57Bl6-N ob/ob mice displayed strain rate dysfunction and concentric remodeling, while no change was observed in fractional shortening or diastolic function. Increased lipid deposition but no fibrosis was measured in the ob/ob heart compared to WT. Electron microscopy analysis revealed that cardiac MAM length and width were similar between both groups. A trend towards an increased MAM protein content was measured in the ob/ob heart. MAM proteome analyses showed mainly increased processes in ob/ob hearts: cellular response to stress, lipid metabolism, ion transport and membrane organization. Functionally, MAM-driven Ca2+ fluxes were unchanged but hypoxic stress induced a cell death increase in the ob/ob cardiomyocyte. Mitochondrial respiration, cardiomyocyte shortening, ATP and ROS content were similar between groups. To conclude, at that age, while being strongly hyperglycemic and insulin-resistant, the ob/ob mouse model rather displays a modest DCM without strong changes in MAMs: preserved structural and functional MAM Ca2+ coupling but increased response to stress.

Keywords: Database; Diabetic cardiopathy; ERMCs; MERCs; Mitochondrial calcium uniporter; SR-mitochondria coupling

DOI: https://doi.org/10.1016/j.jmccpl.2025.100453