bims-miptne 2026-07-05 papers

EMBO J. 2026 Jul 03.

Mitochondrial calcium regulates lipid metabolism by modulating tethering of mitochondria to lipid droplets.

Rebeca Acin-Perez, Essam A Assali, Michaela Veliova, Jennifer Ngo, Alexandra J Brownstein, Francisco Villalobos, Anton Petcherski, Pablo Hernansanz-Agustin, Doyeon Kim-Vasquez, Shili Xu, Mikayla Tamboline, Raquel Maria Silva, Alexander Upcher, Cynthia Shu, Daniel E Ferriss, Marc Liesa, Jose Antonio Enriquez, Israel Sekler, Orian S Shirihai.

Adrenergic stimulation of brown adipocytes induces a robust detachment of mitochondria from lipid droplets (LD), which is followed by lipolysis and lipid catabolism. However, the signals inducing mitochondria attachment or detachment, and their role in lipid metabolism, remain unknown. Here, we reconstituted mitochondria-LD interaction in brown adipocyte tissue (BAT) ex vivo. We find that removal of mitochondria from lipid droplets permits higher lipolytic activity of recombinant lipases. Testing the effect of thermogenic secondary messengers and metabolites on attachment and detachment identified elevated mitochondrial matrix calcium as a potent inducer of detachment. Further, deletion of the mitochondrial sodium/calcium exchanger, NCLX, resulted in reduced attachment and increased detachment, while activation of NCLX increased attachment. We find that elevated matrix calcium causes detachment by inducing architectural transformation of peridroplet mitochondria (PDM) from their typical LD-surface-bound crescent shape into a round shape. PDE2A inhibition activates NCLX and increases PDM content in BAT in vitro and in vivo. We conclude that a surge in mitochondrial matrix calcium ions serves as a potent signal to induce mitochondrial detachment from lipid droplets, thereby facilitating lipolysis.

DOI: https://doi.org/10.1038/s44318-026-00827-8

iScience. 2026 Jul 17. 29(7): 116487

Bioengineering advances in pancreatic cancer organoids for reproducible tumor microenvironment modeling.

Renyu Chen, Bohui Yin, Yaowei Zhang, Junya Peng, Xiaoliang Guo, Wenming Wu.

Pancreatic ductal adenocarcinoma (PDAC) remains lethal due to late-stage diagnosis and limited non-surgical treatment options. Its intratumoral heterogeneity and desmoplastic tumor microenvironment (TME) drive invasion, immune escape, and treatment failure. Patient-derived organoids (PDOs) have emerged as efficient model platforms for simulating the TME and preserving tumor heterogeneity and enabling functional testing in vitro; however, conventional PDO cultures lack defined and controllable microenvironmental components and often exhibited limited reproducibility, physiological fidelity, and observability. This review synthesizes recent bioengineering advances that upgrade pancreatic cancer PDO platforms across three interconnected dimensions: (1) engineered extracellular matrices and biofabrication for reproducible construction; (2) co-culture, microfluidic, and bioreactor systems for physiological fidelity; (3) imaging AI and biosensor pipelines for quantitative monitoring. We highlight practical design principles and remaining bottlenecks for standardization, scalability, and clinical translation.

Keywords: bioengineering; biological sciences; cancer

DOI: https://doi.org/10.1016/j.isci.2026.116487

Nat Commun. 2026 Jul 01.

Two-pore channel-2 controls calmodulin-dependent STIM1 inactivation.

Subo Lee, Raphael Néré, Kyoung Sun Park, Vincent Jaquet, Nicolas Demaurex, Kyu-Sang Park.

Lysosomal two-pore channels (TPC) trigger Ca2+ release from the endoplasmic reticulum (ER). The ensuing ER Ca2+ depletion activates STIM1-gated store-operated Ca2+ entry (SOCE) channels that sustain Ca2+ signals regulating fundamental cellular processes. How TPC channels and STIM1 integrate distinct intra and extracellular cues is unclear. Here, we show that TPC2 activation inhibits SOCE by enforcing rapid and persistent Ca2+-CaM-dependent inactivation of the STIM-Orai activating region (SOAR). The TPC2 activators NAADP and TPC2-A1-N abrogated SOCE in multiple cell lines and enhanced the slow Ca2+ dependent inactivation (SCDI) of STIM1-gated Orai1 channels. TPC2 engagement triggered lysosomal Ca2+ release and mobilized ER Ca2+ stores but prevented RFP-STIM1 recruitment to the TIRF plane by thapsigargin and disassembled RFP-STIM1 clusters forming after store depletion, preventing and acutely reversing SOCE. These effects persisted in STIM1 mutants truncated after the SOAR and were prevented by TPC2 genetic or pharmacological invalidation, Calmodulin (CaM) inhibition, and cytosolic Ca2+ chelation. We conclude that Ca2+ ions released by TPC2 channels on lysosomes regulate CaM-dependent STIM1 inactivation.

DOI: https://doi.org/10.1038/s41467-026-75158-7

Proc Natl Acad Sci U S A. 2026 Jul 07. 123(27): e2524943123

Junctophilin-2-orchestrated calcium signalosome regulates brown adipocyte thermogenesis and energy metabolism.

Dysfunctional adipocyte calcium handling is implicated in obesity and thermogenesis. Junctophilins (JPs) stabilize calcium microdomain junctions between the plasma membrane and endoplasmic reticulum, but whether JPs are required for adipocyte function is not known. We show that JP2 is enriched in thermogenic brown adipose tissue (BAT) relative to other fat depots and is downregulated under conditions of nutrient overload. Conditional knockdown of JP2 in adipocytes, and more selectively in BAT, exacerbates cold intolerance and susceptibility to diet induced obesity. Mechanistically, JP2-depleted brown adipocytes exhibit calcium handling dysfunction with elevated cytosolic calcium levels at baseline but diminished norepinephrine-induced calcium transients, reduced store-operated calcium entry. Basal cytosolic calcium overload accounts for an increase in calpain activation and ensuing downregulation of STIM1 and hormone-sensitive lipase in JP2-depleted cells. Furthermore, JP2 silencing in brown adipocytes reduced oxygen consumption rates and compromised mitochondrial structure and quality. Together, these findings demonstrate that JP2 is essential for normal calcium homeostasis in brown adipocytes and reveal a critical role for JP2 in thermogenesis and resistance to diet-induced metabolic dysregulation.

Keywords: Junctophilin-2; brown adipose tissue; calcium regulation; metabolism; thermogenesis

DOI: https://doi.org/10.1073/pnas.2524943123