bims-mecosi 2026-02-08 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2026–02–08
seven papers selected by
Verena Kohler, Umeå University

What Peroxisomes (Don't) do to Mitochondria.
The possible mechanism of L-arginine improved intestinal barrier health in grass carp (Ctenopharyngodon idella): via suppressing apoptosis and enhancing mitochondria-endoplasmic reticulum crosstalk.
Amyloid precursor protein interacts with the mitochondrial phosphatase PGAM5 and regulates mitochondrial respiration.
PRKN activation for mitophagy requires an NME3-regulated phosphatidic acid signal that separates mitochondria from endoplasmic reticulum tethering.
MIRO1-mediated mitochondrial fusion is required for stomatal immunity in Arabidopsis.
Inhibiting Endoplasmic Reticulum/Plasma Membrane Contact Ameliorates Endometrial Fibrosis by Preventing Senescence in Endometrial Epithelial Cells.
Phosphatidylserine Transporters ORP5 and ORP8 Control Cholesterol trafficking from the Plasma Membrane to the Endoplasmic Reticulum.

Contact (Thousand Oaks). 2026 Jan-Dec;9:9 25152564251413010

What Peroxisomes (Don't) do to Mitochondria.

Margret H Bülow, Sven Thoms.

  Mitochondria and peroxisomes have long been recognized as interconnected. More than half a century ago it was observed that both types of cell organelles exhibit defects in peroxisome biogenesis disorders. Remarkably, until today, the molecular basis of this connection remains elusive. This Short Review aims to highlight some of the functional links between peroxisomes and mitochondria, and how genetic defects in peroxisomes may impact mitochondria.

Keywords:  membrane contact sites; mitochondria; peroxisomes; plasmalogens; reactive oxygen species; zellweger syndrome

DOI:  https://doi.org/10.1177/25152564251413010
Free Radic Biol Med. 2026 Jan 28. pii: S0891-5849(26)00062-6. [Epub ahead of print]246 415-430

The possible mechanism of L-arginine improved intestinal barrier health in grass carp (Ctenopharyngodon idella): via suppressing apoptosis and enhancing mitochondria-endoplasmic reticulum crosstalk.

Qiu-Yan Chen, Yu-Long Ma, Wei-Dan Jiang, Pei Wu, Hong-Yun Zhang, Yang Liu, Yao-Bin Ma, Lu Zhang, Lin Feng, Xiao-Qiu Zhou.

  The intestinal mucosal barrier is fundamental to fish health and nutrient utilization. L-arginine (Arg) is a multifunctional amino acid and essential for maintaining intestinal integrity, yet its mechanisms, particularly concerning redox homeostasis and inter-organelle communication, remain unclear. Using a grass carp model, we investigated the effects of Arg deficiency and supplementation on intestinal barrier function, focusing on mitochondrial function and endoplasmic reticulum (ER) stress. This study reveals that Arg deficiency damaged the intestinal physical barrier, as evidenced by impaired morphology and reduced expression of tight junction proteins. Conversely, Arg supplementation significantly enhanced barrier integrity and digestive enzyme activity. This protective effect was achieved through two possible mechanisms: 1) Arg improving mitochondrial function by enhancing oxidative phosphorylation (OXPHOS) and promoting the mitochondrial quality control system, leading to elevated ATP production and a significant reduction in reactive oxygen species (ROS) levels. 2) Improving ER stress and facilitating organelle crosstalk: Arg supplementation mitigated ER stress and strengthened the physical and functional interaction at mitochondria-associated membranes (MAMs). This may be driven by the upregulation of calcium (Ca2+) transporters and MAM-associated proteins, which helped stabilize intracellular Ca2+ signaling and reduce apoptosis. Our findings suggest a potential role of Arg enhances intestinal barrier function by regulating the health of mitochondria and endoplasmic reticulum and coordinating the interactions mediated by mitochondrial-associated membranes (MAMs). This study underscores the critical role of redox balance and organelle interaction in maintaining intestinal homeostasis and positions Arg as a key nutrient for improving health in fish.

Keywords:  Apoptosis; Endoplasmic reticulum stress; Grass carp; Intestinal physical barrier; Mitochondria-associated membranes; Mitochondrial function

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.042
bioRxiv. 2026 Jan 21. pii: 2026.01.20.700642. [Epub ahead of print]

Amyloid precursor protein interacts with the mitochondrial phosphatase PGAM5 and regulates mitochondrial respiration.

Kriti Shukla, Zhi Zhang, Kendra S Plafker, Satoshi Matsuzaki, Casandra Salinas-Salinas, Yvonne Thomason, Samah Houmam, Dylan Barber, Anna Fakye, Kenneth M Humphries, Scott M Plafker, Jialing Lin, Heather C Rice.

Amyloid Precursor Protein (APP) has been reported to partially localize to mitochondria, and mitochondrial dysfunction is a key feature of Alzheimer's disease; however, the mechanisms linking APP to mitochondrial functions remain incompletely defined. In this study, we found that mitochondria isolated from the brains of APP knockout (KO) mice have impaired substrate-specific respiration and electron transport chain function. We identified a novel interaction between APP and phosphoglycerate mutase family member 5 (PGAM5), a mitochondrial phosphatase. We determined that APP and PGAM5 co-localize at mitochondria-ER contact sites (MERCS), and we confirm an endogenous interaction using proximity ligation assays in mouse brain slices. Using in vitro binding assays, we demonstrate a direct interaction between the linker region of APP and a region of PGAM5 that includes the Kelch-like ECH-associated protein 1 (Keap-1) binding domain. PGAM5 is known to anchor a portion of Nuclear respiratory factor 2 (Nrf2) through Keap1 at the outer mitochondrial membrane to regulate the expression of mitochondrial respiratory chain complexes and enzymes. Consistent with this, we found that the Nrf2-regulated genes Hmox1 (Heme oxygenase-1) and Nnqo1 (NADH:quinone oxidoreductase 1), which are involved in mitochondrial respiration, are downregulated in APP KO astrocytes. Together, these findings suggest that APP supports mitochondrial function by modulating PGAM5-Keap1-Nrf2 signaling, providing a mechanistic link between loss of APP function and impaired mitochondrial respiration.

DOI: https://doi.org/10.64898/2026.01.20.700642
Autophagy. 2026 Feb 04. 1-19

PRKN activation for mitophagy requires an NME3-regulated phosphatidic acid signal that separates mitochondria from endoplasmic reticulum tethering.

Chih-Wei Chen, Ying-Jung Chen, Xiaojing Cuili, Yi-Han Chen, Zee-Fen Chang.

  PINK1-dependent activation of PRKN/parkin on depolarized mitochondria causes mitophagy. The deficiency of NME3, a nucleoside diphosphate kinase/NDPK on the outer mitochondria membrane (OMM), is associated with a fatal neurodegenerative disorder. Here, we report that NME3 deficiency impairs p-S65-ubiquitin (Ub)-dependent PRKN binding on depolarized mitochondria without involving the loss of Ub phosphorylation by PINK1. Our mechanistic investigation revealed that NME3 interacts with PLD6/MitoPLD to generate phosphatidic acid (PA) from cardiolipin on the OMM of damaged mitochondria after depolarization. This lipid signal is essential for positioning MFN2 nearby PINK1 for phosphorylation of Ub conjugates on MFN2, thus enabling the subsequent amplification of PRKN binding to mitochondria. We provide further evidence that mitochondria-endoplasmic reticulum (Mito-ER) tethering prohibits the proximity of MFN2 with PINK1 and PRKN amplification on mitochondria. Importantly, the loss of NME3-regulated PA signal causes Mito-ER tethering. Overall, our findings suggest that NME3 cooperates with PLD6 to generate PA as a critical step in Mito-ER untethering, allowing MFN2 access to PINK1 for p-S65-poly-Ub-dependent feedforward activation of PRKN.Abbreviation ACTB: actin beta; BDNF brain derived neurotrophic factor; CL: cardiolipin; CRISPR: clustered regularly interspaced short palindromic repeats; DAG: diacylglycerol; ER: endoplasmic reticulum; FCCP: carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone; FRET: Förster resonance energy transfer; IF: immunofluorescence; KO: knockout; KD: knockdown; LPIN1: lipin 1; MERCS: mitochondria-endoplasmic reticulum contact sites; MFN2: mitofusin 2; Mito: mitochondria; OMM: outer mitochondrial membrane; p-Ub: phosphorylated ubiquitin; PA: phosphatidic acid; PD: Parkinson disease; PINK1: PTEN induced kinase 1; PLA: proximity ligation assay; PLD6/MitoPLD: phospholipase D family member 6; PRKN: parkin RBR E3 ubiquitin protein ligase; RA: retinoic acid; RT-qPCR: reverse transcription-quantitative polymerase chain reaction; TEM: transmission electron microscopy; TN-NME3: TOMM20-NΔ-NME3; TOMM20: translocase of outer mitochondrial membrane 20; TUBB: tubulin beta class I; Ub: ubiquitin; VDAC: voltage dependent anion channel; WB: western blot.

Keywords:  MFN2; NME3; PINK1; PRKN; mitophagy; phosphatidic acid

DOI:  https://doi.org/10.1080/15548627.2026.2623981
Nat Plants. 2026 Feb 05.

MIRO1-mediated mitochondrial fusion is required for stomatal immunity in Arabidopsis.

Pengfei Lu, Jintong Liu, Haijia Yu, Jiejie Li.

Stomatal immunity is a critical first barrier in plant defence, yet the organelle-level mechanisms underpinning this process remain poorly understood. Here we show that the outer mitochondrial membrane protein MIRO1 is essential for flg22-triggered stomatal closure in Arabidopsis. Upon immune activation, MIRO1 promotes mitochondrial fusion in guard cells. This mitochondrial remodelling is necessary to maintain mitochondrial function, including membrane potential, ATP synthesis, mitochondrial reactive oxygen species production and the activation of organic acid metabolism. In miro1 mutants, these mitochondrial functions are compromised, which is associated with defective stomatal closure and increased bacterial entry. We further show that flg22 triggers MPK3/6-dependent phosphorylation of MIRO1 at Ser14. Phosphorylated MIRO1 displays enhanced oligomerization at mitochondrial contact sites to facilitate fusion. Mutations disrupting MIRO1 phosphorylation or oligomerization abolish its immune function. Collectively, our findings establish MIRO1 as a key molecular link between immune signalling and mitochondrial dynamics during stomatal defence regulation.

DOI: https://doi.org/10.1038/s41477-026-02224-9
Free Radic Biol Med. 2026 Feb 04. pii: S0891-5849(26)00079-1. [Epub ahead of print]

Inhibiting Endoplasmic Reticulum/Plasma Membrane Contact Ameliorates Endometrial Fibrosis by Preventing Senescence in Endometrial Epithelial Cells.

Huan Yang, Yi Zhang, Mengxiong Li, Kaixuan Zeng, Yaoyao Xu, Ruohong Pan, Jiayu Huang, Lu Sun, Yuqing Yao, Jin Luo, Tian Li.

  Intrauterine adhesion (IUA) is characterized by the formation of endometrial fibrosis within the uterine cavity, which can lead to thin endometrium, hypomenorrhea, infertility, and recurrent abortion, exerting a detrimental impact on women's physical and psychological health. Currently, its pathogenesis is not fully elucidated, absence of effective therapies and coupled with a high recurrence rate. In this study, single-cell RNA sequencing was applied for the first time to a mouse IUA model, revealing significant changes in the expression of senescence markers in endometrial epithelial cells (EECs). Specifically, upregulation of Cdkn1a, and Il6, and downregulation of Lamin B1. Further bioinformatic analysis showed significant enrichment of gene sets related to calcium overload, ER stress, and Endoplasmic Reticulum/Plasma Membrane (ER/PM) contacts in the EECs of IUA mice. Mechanistically, ER/PM contacts in IUA activates the STIM1/Orai1 channel complex, leading to ER stress and intracellular calcium overload, which induces cellular senescence in EECs and ultimately drives IUA progression. Intrauterine administration of the STIM1/Orai1 channel inhibitor BTP2 significantly suppressed ER/PM contacts-induced senescence in EECs and effectively alleviated endometrial fibrosis in the mouse IUA model. In conclusion, targeting the STIM1/Orai1 calcium channel dependent on ER/PM contact sites significantly ameliorates endometrial fibrosis, offering a promising therapeutic strategy for IUA.

Keywords:  ER/PM contact; Endometrial Fibrosis; IUA; endometrial epithelial cells; senescence

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.059
J Lipid Res. 2026 Jan 28. pii: S0022-2275(26)00015-5. [Epub ahead of print] 100989

Phosphatidylserine Transporters ORP5 and ORP8 Control Cholesterol trafficking from the Plasma Membrane to the Endoplasmic Reticulum.

Fanqian N Xiao, Dougall M Norris, Guang Yang, Yang E Li, Andrew J Brown, Hongyuan Yang.

  Phosphatidylserine (PS), the most abundant negatively charged phospholipid in mammalian cells, is made in the endoplasmic reticulum (ER) but concentrated in the plasma membrane (PM). Similarly, cellular cholesterol is synthesised in the ER, yet enriched in the PM. Recently, PS has been shown to govern the transport of low-density lipoprotein (LDL)-derived cholesterol from the PM to the ER. Here, we investigated how cholesterol regulates delivery of PS from the ER to PM by the lipid-transfer proteins, ORP5 and ORP8. Adding exogenous cholesterol markedly increased the level of PI(4,5)P2 on the PM, which recruited ORP5/8 to promote the delivery of PS to the PM from the ER. Similar results were also obtained when the level of PM cholesterol was increased upon sphingomyelinase treatment. The increased delivery of PS to the PM helps recruit GRAMD1b, a cholesterol carrier transporting cholesterol from the PM to the ER. Importantly, we show ORP5 interacts with GRAMD1b, and this interaction further facilitates the recruitment of GRAMD1b to the PM. Our results thus unveil a new mechanism by which excess PM cholesterol promotes its own trafficking to the ER via PI(4,5)P2 and ORP5/8. Our results also provide fundamental new insights into how two major lipid species, PS and cholesterol, can impact each other's cellular homeostasis.

Keywords:  Cholesterol/Trafficking; Lipid transfer proteins; Membrane; Membrane contact sites; Non-vesicular lipid transport; Phospholipid/Metabolism; Phospholipids; Phospholipids/Trafficking; Transport

DOI:  https://doi.org/10.1016/j.jlr.2026.100989