bims-mecosi 2026-06-28 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2026–06–28
fourteen papers selected by
Verena Kohler, Umeå University

Lipid traffic: an enigmatic alliance between ORPs and a TMEM16-like protein at membrane contact sites.
Csf1 facilitates adaptive membrane lipid remodeling linked to ER-plasma membrane contact sites.
Mitochondria-endoplasmic reticulum contact sites as hubs where mitochondria acquire iron.
Mitochondria‑endoplasmic reticulum contact site nexus: Molecular integration, disease pathogenesis and therapeutic opportunities (Review).
Mitochondria-associated endoplasmic reticulum membrane (MAM): roles in innate immunity dysregulation.
Annexin A6 controls multi-organelle contact site formation and endolysosomal positioning, and remodels the STARD3 interactome.
Senp1 O-GlcNAcylation Promotes Mitochondrial Fragmentation by Regulating Fis1 SUMO1-ylation Underlying Diabetic Cataract.
A Subset of Caveolin-1 Interacts with a Fraction of Acyl-CoA:Cholesterol Acyltransferase 1 (ACAT1/SOAT1) at an Endoplasmic Reticulum Subdomain to Attenuate Cholesteryl Ester Biosynthesis.
PIKfyve influences inter-organelle contacts with lysosomes to modulate the endoplasmic reticulum.
Endoplasmic reticulum proteins MCTP-1 and ESYT-2 support presynaptic function during sustained activity in Caenorhabditis elegans.
Lipid transfer protein ORP3 mediates lysosomal repair via LC3B and ubiquitin-TAK1-p38 signaling.
Mitochondrial Communication with Cellular Organelles in the Pathogenesis of Fatty Liver Disease in Domestic and Model Animals.
PDZD8 overexpression alleviates early brain injury via regulating MERCs integrity after experimental subarachnoid hemorrhage.
Organelle Crosstalk in Renal Cells: Insights from Cell Biology and Implications for AKI-to-CKD Transition.

Biochem Soc Trans. 2026 Jun 24. 54(6): 793-802

Lipid traffic: an enigmatic alliance between ORPs and a TMEM16-like protein at membrane contact sites.

Alicia Fabbre, Guillaume Drin.

  Lipid transfer proteins (LTPs) play a critical role in distributing lipids within eukaryotic cells. In yeast, Osh6 and Osh7, which belong to the oxysterol-binding protein-related protein family, transfer phosphatidylserine (PS) from the endoplasmic reticulum (ER) to the plasma membrane (PM) in exchange for phosphatidylinositol 4-phosphate (PI(4)P). These proteins localize at ER-PM contact sites by associating with Ist2, an ER-resident TMEM16-like protein that bridges the ER and PM via a long intrinsically disordered region (IDR). Recent studies have shown that this association ensures accurate PS transfer by concentrating Osh6 and Osh7 at the ER-PM interface while preserving their ability to access both membranes. However, it remains unclear how these LTPs function when bound to the Ist2 IDR, whose length far exceeds the ER-PM distance at contact sites, and why they do not integrate both the tethering and the PS/PI(4)P exchange functions, like their human homologs. Additionally, it has been revealed that Ist2 can transfer lipids across the ER membrane via a scramblase activity. Yet, whether and why this activity is coupled to the PS/PI(4)P exchange activity of Osh6 and Osh7 remains unknown. The Ist2-Osh6/7 system emerges as a fascinating model that integrates tethering, scramblase, and lipid exchange functions. Future studies of this system are likely to provide important insights into how lipid transfer processes are coordinated at membrane contact sites.

Keywords:  intrinsically disordered proteins; lipid scramblase; lipid transfer; membrane contact sites; phosphatidylserine; phosphoinositides

DOI:  https://doi.org/10.1042/BST20250365
Mol Biol Cell. 2026 Jun 24. mbcE26010059

Csf1 facilitates adaptive membrane lipid remodeling linked to ER-plasma membrane contact sites.

Fumiyoshi Abe, Tetsuo Mioka, Yusuke Suzuki, Akane Ogasawara, Daisuke Mochizuki, Saki Imura, Yusuke Kato, Ayana Toda, Sana Nikaido, Takahiro Mochizuki.

Membrane lipid composition must be dynamically adjusted to preserve bilayer physical properties, yet the cellular mechanisms that support bulk lipid remodeling under physical stress remain incompletely understood. Here, we identify Csf1 as a regulator of membrane lipid remodeling functionally associated with endoplasmic reticulum-plasma membrane (ER-PM) contact sites in Saccharomyces cerevisiae, with features consistent with bridge-like lipid transfer proteins. Using high hydrostatic pressure as a defined physical perturbation that constrains membrane packing, we reveal a requirement for Csf1-dependent lipid remodeling linked to ER-PM contact sites that is masked under standard growth conditions. Quantitative lipidomic and membrane biophysical analyses show that, under hydrostatic compression, loss of Csf1 disrupts coordinated lipid remodeling, leading to reduced phospholipid unsaturation, increased membrane rigidity, and destabilization of PM permeases. We further show that Csf1 cooperates with Osh6/7 to sustain lipid flux and bilayer re-equilibration linked to ER-PM contact sites under conditions permissive for Osh6/7 activity. These findings identify Csf1 as a stress-dependent lipid-remodeling factor that enables adaptive membrane remodeling and preserves membrane protein stability under conditions of constrained membrane flexibility.

DOI: https://doi.org/10.1091/mbc.E26-01-0059
Nat Cell Biol. 2026 Jun 26.

Mitochondria-endoplasmic reticulum contact sites as hubs where mitochondria acquire iron.

DOI: https://doi.org/10.1038/s41556-026-02008-5
Int J Mol Med. 2026 Aug;pii: 227. [Epub ahead of print]58(2):

Mitochondria‑endoplasmic reticulum contact site nexus: Molecular integration, disease pathogenesis and therapeutic opportunities (Review).

Yi Liu, Xianda Che, Wei Wei, Chong Teng, Huimin Li.

  Mitochondria‑endoplasmic reticulum contact sites (MERCs) are dynamic, nanoscale membrane domains that serve as crucial signaling hubs for inter‑organellar communication. These specialized interfaces are maintained by a complex network composed of tethering, promoter, and disruptor proteins and coordinate a wide range of cellular processes, such as calcium and zinc ion homeostasis, lipid biosynthesis and transfer, redox signaling, mitochondrial dynamics (fission, fusion and mitophagy), autophagy, apoptosis, inflammation and cellular senescence. Accordingly, the structural and functional integrity of MERCs is vital for cellular adaptation and survival. Nevertheless, MERC plasticity is often impaired in various human pathologies. Alterations in MERC composition, abundance, or function are regarded as pathogenic mechanisms in neurodegenerative diseases, metabolic disorders, cardiovascular conditions, cancer and orthopedic diseases. Common manifestations of MERC dysfunction include disrupted ion signaling, bioenergetic failure, excessive oxidative stress, and impaired organelle quality control. Therefore, targeted modulation of MERCs represents a promising therapeutic avenue. However, translating this potential into clinical practice faces considerable challenges. This is because MERC function is dynamic, context‑dependent and dualistic; both excessive and deficient coupling can drive pathology. Future progress hinges on deciphering the precise regulatory codes that govern MERC assembly, developing tools for real‑time, high‑resolution in vivo analysis, and designing innovative, cell‑type‑specific interventions that normalize rather than simply inhibit or enhance MERC function. A multidisciplinary approach integrating spatial proteomics, super‑resolution imaging, and advanced disease modeling is warranted for unlocking the full diagnostic and therapeutic potential of these organelle contact sites.

Keywords:  endoplasmic reticulum; mitochondria; mitochondrial‑associated membranes; mitochondria‑endoplasmic reticulum contact sites

DOI:  https://doi.org/10.3892/ijmm.2026.5898
Cell Commun Signal. 2026 Jun 22.

Mitochondria-associated endoplasmic reticulum membrane (MAM): roles in innate immunity dysregulation.

Qingqi Zhang, Junyan Gao, Yiting Yang, Ping Guo, Huiqin Gao, Shuaiyong Zhao, Shuanglin Zhang, Yaping Shi, Guanxing Xie, Yutong Han, Hao Liu, Yunzeng Zou.

  Mitochondria-associated endoplasmic reticulum membrane (MAM), which serves as a signaling hub for interactions between the endoplasmic reticulum (ER) and mitochondria, dynamically coordinates innate immune processes by regulating calcium homeostasis, lipid metabolism, mitochondrial dynamics, mitochondrial protein modifications, and autophagy. MAM regulates calcium homeostasis to govern mitochondrial energy metabolism and inflammasome activation; maintains lipid metabolism for membrane integrity to support antiviral signaling pathways; controls mitochondrial fission and fusion dynamics, processes that are closely associated with mitochondrial DNA (mtDNA) release; regulates mitochondrial protein modifications to fine-tune the function of proteins localized at MAM; and facilitates the clearance of damaged mitochondria and leaked mtDNA through autophagy. Most critically, MAM dysfunction and innate immune dysregulation form a vicious cycle: immune activation disrupts MAM integrity, and MAM abnormalities exacerbate the release of mitochondrial damage-associated molecules, continuously driving overactivation of pathways such as inflammasomes and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, thereby promoting the development of autoimmune diseases. This review synthesizes current literature on the molecular mechanisms by which MAM regulates innate immunity. We summarize how disruptions in MAM-mediated mitochondrial homeostasis contribute to innate immune imbalance. By integrating these findings, we highlight potential intervention nodes. This underscores the clinical relevance of targeting MAM in immune-related pathological conditions.

Keywords:  Innate immunity; Mitochondria-associated endoplasmic reticulum membrane (MAM); Mitochondrial homeostasis; MtDNA

DOI:  https://doi.org/10.1186/s12964-026-03013-9
iScience. 2026 Jul 17. 29(7): 116387

Annexin A6 controls multi-organelle contact site formation and endolysosomal positioning, and remodels the STARD3 interactome.

Marc Bernaus-Esqué, Yangjing Liu, Eva Prats, Josep M Estanyol, Gemma Martin, Maria Calvo, Panagiota Areti Gigourtsi, Mai Khanh Linh Nguyen, Alejandra R Álvarez, Silvana Zanlungo, Neus Agell, Albert Lu, Francesc Tebar, Carlos Enrich, Thomas Grewal, Carles Rentero.

  Annexin A6 (ANXA6) regulates cholesterol transfer across membrane contact sites (MCSs) between late endosomes/lysosomes (LE/Lys) and the endoplasmic reticulum (ER) via the late endosomal StAR-related lipid transfer domain-3 (STARD3) transporter. Here, we describe a significant reduction of MCSs in ANXA6-depleted HeLa cells, which could be rescued by restoration of ANXA6 expression. Using AnxA6 as bait in BioID-based assays, we demonstrate that ANXA6 interacts with various tethers and bona fide MCS proteins that can modulate multi-organelle contacts. STARD3 interactors identified in BioID assays include the mitochondrial translocator protein (TSPO) and myosin heavy chain 9 (MYH9). Strikingly, reduced MCS formation in ANXA6-depleted cells was associated with changes in the STARD3 interactome that indicate altered MCS tethering functions of STARD3. Specifically, ANXA6 deficiency correlated with (1) altered positioning of STARD3-positive LE/Lys; (2) a new repertoire of cortical actin-binding proteins, including myosins interacting with STARD3; (3) and decreased microvillar structures and focal adhesions.

Keywords:  Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2026.116387
Invest Ophthalmol Vis Sci. 2026 Jun 01. 67(6): 44

Senp1 O-GlcNAcylation Promotes Mitochondrial Fragmentation by Regulating Fis1 SUMO1-ylation Underlying Diabetic Cataract.

Zaoxia Guo, Xinnan Li, Xi Chen, Xiaopan Ma, Hong Yan.

Purpose: Cataract is a major cause of blindness among patients with diabetes mellitus. The pathology underlying diabetic cataract (DC) is complex because of changes in biological processes caused by chronic hyperglycemia. O-GlcNAcylation is highly dependent on glucose availability and regulates mitochondrial functions. Dysregulation of O-GlcNAcylation has been reported in DC. Mitochondria in lens epithelial cells are key organelles for energy supply and redox homeostasis of the lens. Mitochondrial dysfunction is a hallmark of DC. However, whether O-GlcNAcylation regulates mitochondrial function underlying DC has not been fully studied.
Methods: An animal model of DC was established in Sprague-Dawley male rats by feeding a 60% high-fat diet and injecting streptozotocin. Mitochondria were visualized using confocal laser scanning microscope and transmission electron microscope. O-GlcNAcylated proteins were verified using liquid chromatography tandem mass spectrometry and immunoprecipitation assays. Lentivirus-encapsulated plasmids were constructed to generate stable transfected cell lines. The histomorphology of the lens was assessed by hematoxylin and eosin staining.
Results: High glucose levels promoted mitochondrial fission by upregulating Senp1 O-GlcNAcylation at the S137 site. Senp1 S137 O-GlcNAcylation inhibited Fis1 deSUMO1-ylation. Fis1 SUMO1-ylation decreased its interaction with Mfn2, which reduced the contact between mitochondria-associated ER membranes (MAMs), thereby promoting mitochondrial fragmentation. Site-specific mutation of Senp1 S137A released the inhibitory effect on Fis1 deSUMOylation and mitigated high-glucose induced mitochondrial fragmentation.
Conclusions: Senp1 S137 O-GlcNAcylation regulates mitochondrial fragmentation in lens epithelial cells underlying DC. Senp1 O-GlcNAcylation increase mediates mitochondrial fragmentation by upregulating Fis1 SUMO1-ylation, which in turn reduces the contact of mitochondria-associated endoplasmic reticulum membranes and promotes mitochondrial fragmentation.

DOI: https://doi.org/10.1167/iovs.67.6.44
Biomolecules. 2026 Jun 08. pii: 838. [Epub ahead of print]16(6):

A Subset of Caveolin-1 Interacts with a Fraction of Acyl-CoA:Cholesterol Acyltransferase 1 (ACAT1/SOAT1) at an Endoplasmic Reticulum Subdomain to Attenuate Cholesteryl Ester Biosynthesis.

Catherine C Y Chang, Toyoshi Fujimoto, Yoshio Yamauchi, Yasuomi Urano, Ta Yuan Chang.

  Caveolin-1 is a scaffolding protein of caveolae, flask-shaped membrane microdomains involved in diverse cellular processes. Caveolae are primarily localized to the plasma membrane, the trans-Golgi network, and mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs). Most enzymes involved in cholesterol biosynthesis reside in the ER, and although caveolin-1 avidly binds cholesterol, its role in cholesterol trafficking remains unclear. Acyl-coenzyme A:cholesterol acyltransferases (ACAT1 and ACAT2) convert free cholesterol into cholesteryl esters for storage, with ACAT1 serving as the predominant isoenzyme in most cell types. ACAT1 is an ER-resident protein, with a fraction associated with specialized ER subdomains, including the MAM. Here, we report that a subset of caveolin-1 molecules appears to be associated with a fraction of ACAT1 in ER subdomains. Using immunoprecipitation under detergent conditions, immunoadsorption of MAM-enriched membranes under detergent-free conditions, and electron microscopy, we provide evidence consistent with an association between a subset of caveolin-1 molecules and ACAT1. Functionally, in mouse embryonic fibroblasts, we show that genetic ablation of caveolin-1 significantly increases the esterification of low-density lipoprotein-derived cholesterol, suggesting that caveolin-1 may attenuate ACAT1 activity. Collectively, these findings indicate that caveolin-1 may modulate cholesterol esterification and contribute to the regulation of cholesterol distribution among cellular membranes.

Keywords:  acyl-CoA:cholesterol acyltransferase; caveolae; caveolin-1; cholesterol; cholesteryl oleate; endoplasmic reticulum; mitochondria-associated membranes; sterol O-acyltransferase; trans-Golgi network

DOI:  https://doi.org/10.3390/biom16060838
J Cell Biol. 2026 Sep 07. pii: e202507087. [Epub ahead of print]225(9):

PIKfyve influences inter-organelle contacts with lysosomes to modulate the endoplasmic reticulum.

Nicala Jenkins, Zainab Adamji, Maria R Narciso, Nourhan R Almasri, Sharifa Lomiyev, Roberto J Botelho.

Lysosomes clear unwanted cellular material delivered by constant membrane fusion. Membrane fission is thus required to balance lysosome size, number, and composition. PIKfyve is a lipid kinase that converts phosphatidylinositol-3-phosphate [PtdIns(3)P] to phosphatidylinositol-3,5-bisphosphate [PtdIns(3,5)P2] and promotes lysosome fission since lysosomes coalesce into larger, but fewer, organelles in its absence. Here, we reveal a role for PIKfyve in regulating ER dynamics. We show the ER is less reticulated and motile in cells inhibited for PIKfyve. Partly, this arises because lysosomes cluster perinuclearly and are less motile, which appears to arrest ER hitchhiking, a process in which lysosomes pull and form ER tubules. Secondly, the ER morphology is distorted because of hyper-tethering of protrudin, an ER transmembrane protein, to lysosomes via excess PtdIns(3)P and protrudin's FYVE domain. Our findings reveal that PIKfyve balances phosphoinositides at ER-lysosome contact sites to govern ER properties and have significant implications for our understanding of PIKfyve function and of diseases linked to its dysfunction.

DOI: https://doi.org/10.1083/jcb.202507087
Neuroscience. 2026 Jun 23. pii: S0306-4522(26)00420-3. [Epub ahead of print]

Endoplasmic reticulum proteins MCTP-1 and ESYT-2 support presynaptic function during sustained activity in Caenorhabditis elegans.

Fernando I Tovilla-Loza, José Luis Téllez-Arreola, Ignacio Martínez-García, Reinher Pimentel-Domínguez, Remy Avila, Marius Seidenthal, Alexander Gottschalk, Ataúlfo Martínez-Torres.

  The presynaptic terminal has a complex molecular organization where numerous proteins are involved in various processes, including vesicle trafficking and neurotransmitter release. Calcium ions play a central role in presynaptic function by triggering neurotransmitter release and synaptic vesicle recycling. Here, we investigated the role of two calcium binding proteins, MCTP-1 and ESYT-2, in the synaptic vesicle cycle of Caenorhabditis elegans. Both proteins are widely expressed in the nervous system and colocalize in endoplasmic reticulum subdomains, consistent with membrane contact sites. Loss-of-function mutants for both genes displayed slight defects in motility and similar resistance to acetylcholinesterase inhibition. Recordings of pharyngeal electrical activity revealed that aged (day 6 adult) esyt-2 and mctp-1 single mutants and mctp-1; esyt-2 double mutants exhibit significantly shorter muscle contraction events, but increased pumping rates compared to wild type, indicating altered age-dependent regulation of pharyngeal activity. We also found in an all-optical assay of synaptic transmission and synaptic vesicle recycling, that the endocytic rate was similarly reduced in mctp-1, esyt-2, and mctp-1; esyt-2 loss-of-function worms. Together, these findings show that MCTP-1 and ESYT-2 participate in similar and/or complementary roles, acting within a shared pathway to support efficient synaptic vesicle recycling and to maintain presynaptic function during sustained activity.

Keywords:  C2 domain; Calcium signaling; Optogenetics; Synapses

DOI:  https://doi.org/10.1016/j.neuroscience.2026.06.031
bioRxiv. 2026 Jun 10. pii: 2026.06.09.731146. [Epub ahead of print]

Lipid transfer protein ORP3 mediates lysosomal repair via LC3B and ubiquitin-TAK1-p38 signaling.

Christopher J Bott, Martyna O Iwaniek, James E Casanova.

Lysosomal membrane damage triggers a multi-stage repair response essential for cellular homeostasis. Here we identify the oxysterol-binding protein-related protein ORP3 as a critical mediator of late-stage lysosomal membrane repair. Following lysosomal damage induced by L-leucine-leucine methyl ester (LLOME) or cationic amphiphilic drugs (CADs), ORP3 is phosphorylated and recruited to ER-lysophagosome contact sites via a signaling cascade initiated by lysosomal membrane ubiquitination, TAK1, p38 MAPK, and, to a lesser extent, IKK. p38-dependent phosphorylation promotes direct interaction between ORP3 and LC3B, which together with PI(4,5)P₂ binding, is required for autophagic lysosome recruitment. ORP3 depletion impairs late-stage lysosomal recovery, elevates lysosomal lipid peroxidation, and reduces cell survival. A lipid transfer-deficient ORP3 mutant fails to restore lysosome function despite normal recruitment, indicating that ER-to-lysophagosome transfer of phosphatidylcholine by ORP3 is functionally required. ORP3 activity is subsequently terminated by VCP/p97-mediated deubiquitination of lysosomes. These findings define ORP3 as a MAPK regulated lipid transfer protein during the late autophagic phase of the endolysosomal damage response.
Summary: Lysosomal membrane damage triggers ubiquitination that activates a TAK1-p38 signaling cascade, phosphorylating the lipid transfer protein ORP3 and recruiting it to damaged lysosomes via LC3B interaction. ORP3-mediated phosphatidylcholine transfer from the ER is essential for late-stage lysosomal repair and cell survival.
Abstract Figure:

DOI: https://doi.org/10.64898/2026.06.09.731146
Animals (Basel). 2026 Jun 10. pii: 1800. [Epub ahead of print]16(12):

Mitochondrial Communication with Cellular Organelles in the Pathogenesis of Fatty Liver Disease in Domestic and Model Animals.

Tuoyu Geng, Amaal Omara, Ali Shoaib Moawad, Aneeqa Imtiaz, Wajeeha Tanveer, Minmeng Zhao, Jing Ge.

  Fatty liver disease represents a major metabolic disorder affecting domestic animals worldwide, with significant implications for animal health, welfare, and agricultural productivity. Disrupted communication between mitochondria and other organelles-particularly the endoplasmic reticulum, lipid droplets, and lysosomes-plays a critical role in disease pathogenesis. This review synthesizes knowledge on inter-organellar communication across domestic animals, with emphasis on species-specific adaptations. We address the "Dairy Cow Paradox"-periparturient dairy cows develop severe hepatic steatosis (>30% liver fat), yet under sterile conditions, they have a higher threshold for progressing to sterile steatohepatitis compared to rodents and humans. However, it is critical to note that severe fatty liver in dairy cows is indeed associated with impaired autophagy, inflammation, and liver damage, particularly when accompanied by ketosis or concurrent infections, and 39% of transition cows exhibit moderate to severe lymphocytic hepatitis. We propose that the tolerance to severe steatosis in dairy cows arises from three adaptations: (1) attenuated innate immune sensing via the cGAS-STING pathway; (2) enhanced lipid buffering from perilipin 5 (PLIN5) with a hypothesized ruminant-specific Val152 substitution that may stabilize lipid droplet-mitochondria contacts; and (3) dampened calcium signaling due to ER-mitochondria membrane lipid raft rigidity, elevated inositol 1,4,5-trisphosphate receptor 2 (IP3R2) expression, and reduced mitochondrial calcium uniporter (MCU) conductance. We contrast this with the inflammatory steatohepatitis common in rodent models driven by calcium overload and mitochondrial DNA (mtDNA) release, and glucocorticoid-mediated mitofusin 1 (MFN1) suppression, causing mitochondrial fragmentation in poultry. We identify critical knowledge gaps, including the need to define bovine and avian mitochondria-associated endoplasmic reticulum membrane (MAM) proteomes and spatially resolve hepatic zonal communication patterns. Targeting organellar communication hubs with nutraceuticals or pharmacological agents offers promising therapeutic strategies.

Keywords:  Dairy Cow Paradox; domestic animal; hepatic steatosis; mitochondria; mitochondria-associated endoplasmic reticulum membrane; organelle communication

DOI:  https://doi.org/10.3390/ani16121800
J Neuroinflammation. 2026 Jun 23.

PDZD8 overexpression alleviates early brain injury via regulating MERCs integrity after experimental subarachnoid hemorrhage.

Peng Deng, Xin Wu, Yangyang Liu, Bingyi Song, Xi Liu, Xiao Yang, Han Luo, Jiabei Peng, Haiying Li, Zhong Wang, Zongqi Wang, Wen Li.

  Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular disorder with high acute mortality and long-term neurological disability, and early brain injury (EBI) characterized by mitochondrial dysfunction, oxidative stress, and neuronal apoptosis is a pivotal determinant of poor prognosis. Mitochondria-endoplasmic reticulum contact sites (MERCs) are specialized membrane domains essential for maintaining cellular homeostasis via calcium trafficking and lipid exchange, but their regulatory mechanisms in SAH-induced EBI remain largely undefined. Here, we investigated the role and underlying mechanism of PDZD8, a core MERCs-stabilizing protein, in SAH pathogenesis using in vivo endovascular perforation models of male C57BL/6 mice and in vitro oxyhemoglobin (OxyHb)-challenged primary cortical neurons/HT22 cells, combined with PDZD8 overexpression, CRISPR/Cas9-mediated knockout, and C884A site-directed mutagenesis. Results demonstrated that PDZD8 was neuron-specifically downregulated at 48 h post-SAH, which closely correlated with MERCs structural disruption detected by transmission electron microscopy, impaired mitochondrial respiration analyzed via Seahorse assays, excessive reactive oxygen species production, and severe neuronal damage assessed by Nissl staining. PDZD8 overexpression preserved MERCs integrity, restored mitochondrial metabolic balance, mitigated oxidative stress, and ameliorated neurobehavioral deficits evaluated by modified neurological severity scores, rotarod, and open field tests. Mechanistically, SAH-induced PDZD8 downregulation was associated with enhanced global S-nitrosylation and post-translational regulation at cysteine 884 (C884), promoting its ubiquitination and proteasomal degradation, while C884A mutation abrogated this process. Our findings reveal a previously unrecognized mechanism involving S-nitrosylation-associated ubiquitination of PDZD8 in SAH-induced MERCs dysfunction and EBI, highlighting PDZD8 as a promising therapeutic target for SAH treatment.

Keywords:  Early Brain Injury (EBI); Mitochondria-Endoplasmic Reticulum Contact Sites (MERCs); PDZD8; S-nitrosylation; Subarachnoid Hemorrhage (SAH)

DOI:  https://doi.org/10.1186/s12974-026-03931-y
Int J Mol Sci. 2026 Jun 09. pii: 5207. [Epub ahead of print]27(12):

Organelle Crosstalk in Renal Cells: Insights from Cell Biology and Implications for AKI-to-CKD Transition.

Rossana Franzin, Monica Campioni, Anna Storelli, Gabriele Ruggieri, Sabrina Molino, Giorgio Ladisa, Anna Gallone, Marco Fiorentino, Loreto Gesualdo, Paola Pontrelli.

  The kidney is a highly specialized organ that maintains systemic homeostasis through tightly coordinated cellular and molecular mechanisms. Renal parenchymal cells regulate metabolic waste excretion, electrolyte and acid-base balance, and blood pressure control-functions that rely on the dynamic integration of intracellular organelles. Recent advances in molecular and biochemical research have highlighted how inter-organelle communication is essential for preserving renal cell function and adaptive responses to stress. This review focuses on the molecular crosstalk among key organelles-including the nucleus, endoplasmic reticulum (ER), Golgi apparatus, mitochondria, lysosomes, and peroxisomes-primarily in tubular epithelial cells. We discuss how these interactions coordinate metabolic signaling, protein homeostasis, redox balance, and energy production and how their disruption contributes to maladaptive pathways during acute kidney injury (AKI), ultimately promoting chronic kidney disease (CKD) transition. Particular focus is placed on emerging pathways linking organelle dysfunction to inflammation, fibrosis, and metabolic reprogramming. Furthermore, we highlight recent advances in genetics and molecular therapeutics targeting organelle communication, including modulation of ER stress responses, mitochondrial biogenesis, and lysosomal function. Clinically approved agents, such as mTOR inhibitors, and experimental approaches-such as chemical chaperones and mitochondrial transplantation-demonstrate the potential to restore organelle homeostasis and mitigate renal injury. Overall, elucidating the molecular networks governing organelle crosstalk provides critical insights into kidney disease pathogenesis and identifies novel targets for therapeutic intervention in AKI-to-CKD transition.

Keywords:  ER-mitochondria-associated membranes (MAMs); MFN2-PERK axis; PEX genes; autophagic flux; cGAS-STING axis; membrane contact sites (MCSs); mitochondrial dysfunction; organelle crosstalk; proteostasis; unfolded protein response (UPR)

DOI:  https://doi.org/10.3390/ijms27125207