bims-mecosi 2026-08-30 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2026–08–30
fourteen papers selected by
Verena Kohler, Umeå University

Potential Role of Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs) Abnormalities in Epileptogenesis: Multimodal Mechanisms and Therapeutic Targets.
BLTP2 bridges the ER and MVB for exosome biogenesis at SCAMP3-dependent ER contacts.
IBRV induces mitochondrial apoptosis via the ER-mitochondrial calcium axis mediated by unfolded protein response in MDBK cells.
PACS2 at Mitochondria-Associated Membranes: A Central Regulator of Cardiovascular and Metabolic Diseases.
Calcium dysregulation in breast cancer progression: mechanisms of calcicoptosis and therapeutic implications.
Caveolin-1 at the Crossroads of Diabetes and Alzheimer's Disease: New Mechanisms, Biomarkers, and Therapeutic Opportunities.
A novel Skp2 inhibitor triggers pyroptosis in leukemia via phospholipid metabolism disorder and mitochondria-associated endoplasmic reticulum membranes.
The role of Mfn2/PERK mediated ER-mitochondrial communication in autophagy induced by silica nanoparticles in HT22 cells.
The molecular basis of mitochondrial crista formation by the MIC10 complex.
CaMACPF1 and CaMACPF6 positively regulate hypoxia tolerance through modulating jasmonate and auxin metabolic pathways.
Excessive EFHD1-dependent ER-mitochondrial contacts drive a maladaptive antiviral response in metabolic liver disease.
Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Chronic Pain.
Organelle network dysfunction in primary cardiomyopathy: An integrated perspective on pathogenesis and therapeutics.
Apelin-13 drives VSMC proliferation and atherosclerosis through REEP5-dependent disruption of ER-mitochondria coupling and glycolytic shift.

Mol Neurobiol. 2026 Aug 29. pii: 867. [Epub ahead of print]63(1):

Potential Role of Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs) Abnormalities in Epileptogenesis: Multimodal Mechanisms and Therapeutic Targets.

Ruting Fu, Jiahao Liu, Liya Fang, Jin Guo.

  Epilepsy is a prevalent neurological disorder characterized by an incompletely understood etiology and a substantial unmet therapeutic need, particularly for drug-resistant forms. This review examines the potential role of mitochondria-associated endoplasmic reticulum membranes (MAMs) as emerging signaling hubs in epileptogenesis. We systematically analyze how MAMs regulate core cellular processes-including calcium signaling, lipid metabolism, mitochondrial dynamics, autophagy, and oxidative stress-and how dysregulation of these processes may contribute to seizure initiation and progression. Furthermore, we evaluate existing interventions, such as phytotherapeutics and the ketogenic diet, from the perspective of modulation of MAMs. The review also highlights novel strategies targeting MAMs, including small-molecule approaches, nanodelivery systems, and neuromodulation technologies, which offer promising avenues for precise therapeutic intervention. By consolidating current molecular and genetic evidence, we identify MAMs as a critical hub in epilepsy and propose that targeting their integrity and function may represent a strategy to overcome drug resistance and modify disease progression. By integrating current knowledge of MAMs biology with epilepsy pathophysiology, this work provides a mechanistic framework to guide future research. It offers insights for the development of targeted molecular therapies for epilepsy.

Keywords:  Calcium signaling regulation; Epilepsy; Epilepsy treatment strategies; Mitochondrial-associated endoplasmic reticulum membranes; Oxidative stress

DOI:  https://doi.org/10.1007/s12035-026-06141-y
Curr Biol. 2026 Aug 24. pii: S0960-9822(26)00997-8. [Epub ahead of print]

BLTP2 bridges the ER and MVB for exosome biogenesis at SCAMP3-dependent ER contacts.

Jingru Wang, Dongchen Li, Yazhou Liu, Tiantian Zhou, Lin Deng, Wei-Ke Ji.

  Multivesicular bodies (MVBs) contain intraluminal vesicles (ILVs) designated for degradation in lysosomes or release as exosomes for cell-to-cell communication. The mechanisms governing ILV/exosome formation are not fully understood. Here, we show that the integral endoplasmic reticulum (ER) membrane protein bridge-like lipid transfer protein 2 (BLTP2; KIAA0100) is indispensable for ILV/exosome formation and that secretory carrier membrane protein 3 (SCAMP3) recruits BLTP2 to ER-MVB membrane contact sites (MCSs) in a Rab5-dependent manner. Our results indicate that this recruitment is hindered by NEDD4-mediated ubiquitination of SCAMP3. Depletion of BLTP2 was found to impede ILV/exosome formation and selectively reduce the levels of cone-shaped phospholipids, including bis(monoacylglycero)phosphate (BMP), and of the BMP precursor phosphatidylglycerol (PG) within endosomes. BLTP2 knockout also hampered cell proliferation and tumorigenicity, which could be restored by supplementation with exosomes from wild-type cells. Our findings suggest that BLTP2 transfers the BMP/lysobisphosphatidic acid (LBPA) precursor PG to MVBs for BMP/LBPA synthesis and promotes ILV/exosome formation at SCAMP3-dependent ER-MVB MCSs.

Keywords:  ER; LBPA/BMP; MVB; bridge-like lipid transfer protein; exosome; membrane contact sites

DOI:  https://doi.org/10.1016/j.cub.2026.07.066
Int Immunopharmacol. 2026 Aug 25. pii: S1567-5769(26)01182-3. [Epub ahead of print]188 117335

IBRV induces mitochondrial apoptosis via the ER-mitochondrial calcium axis mediated by unfolded protein response in MDBK cells.

Yiming Wei, Xin Wang, Wanting Kou, Wenwen Yu, Shihui Zhao, An Liu, Yongli Zhu, Qinglong Gong, Jianming Li, Xiaoxuan Zhang, Guixue Hu, Kai Wang, Xue Leng, Qian Wang.

  Infectious bovine rhinotracheitis virus (IBRV), also known as bovine herpesvirus 1 (BoHV-1), is a globally important pathogen causing severe cattle diseases and substantial economic losses. However, the molecular mechanism by which IBRV induces host cell apoptosis through endoplasmic reticulum (ER)-mitochondria crosstalk remains largely unclear. In this study, Madin-Darby bovine kidney (MDBK) cells were used as an in vitro experimental model. Multiple experimental approaches including transmission electron microscopy, laser confocal microscopy, western blotting, flow cytometry, pharmacological inhibition, and siRNA interference, were applied to investigate the apoptotic mechanism triggered by IBRV infection. The results showed that IBRV infection destroyed ER ultrastructure and upregulated the expression of ER stress biomarker GRP78, accompanied by the full activation of three core branches of the unfolded protein response (UPR), including PERK, IRE1, and ATF6. Meanwhile, IBRV significantly promoted the formation of ER-mitochondrial membrane contact sites (MCSs) and triggered excessive Ca2+ release from the ER, leading to mitochondrial Ca2+ overload. Such Ca2+ dyshomeostasis further induced mitochondrial dysfunction, including reduced ATP production, collapsed mitochondrial membrane potential, and excessive reactive oxygen species accumulation, which ultimately activated caspase-dependent mitochondrial apoptosis. Inhibition of UPR signaling or ER-mitochondrial Ca2+ transport markedly alleviated mitochondrial damage, suppressed apoptosis, and reduced viral protein expression. Collectively, these findings demonstrate that the UPR-Ca2+-mitochondria axis serves as a key signaling pathway for IBRV-induced cell apoptosis, and that host UPR signaling is exploited by IBRV to support efficient viral replication, revealing a novel molecular pathogenic mechanism of IBRV and providing potential targets for the development of anti-IBRV therapeutic strategies.

Keywords:  Calcium homeostasis; ER stress; IBRV; Mitochondrial apoptosis; Unfolded protein response

DOI:  https://doi.org/10.1016/j.intimp.2026.117335
J Cell Mol Med. 2026 08;30(16): e71336

PACS2 at Mitochondria-Associated Membranes: A Central Regulator of Cardiovascular and Metabolic Diseases.

Baiyi Tang, Hui Wang, Jie Ouyang.

  Cardiovascular and metabolic diseases (CVMDs), which are characterized by metabolic dysregulation and cardiovascular impairment, constitute a major global cause of mortality, thus highlighting the urgent need for novel therapeutic strategies. Phosphofurin acidic cluster sorting protein 2 (PACS2), a multifunctional adapter protein localized to mitochondria-associated membranes (MAMs), regulates intracellular membrane trafficking and is pivotal for critical cellular processes, including apoptosis, autophagy and ferroptosis. Accumulating evidence implicates PACS2 dysregulation in the pathogenesis of diverse CVMDs, including metabolic disorders and cardiovascular conditions. This review examines the structural and functional basis of PACS2 and details its established and emerging roles in the pathogenesis of CVMDs. Collectively, these findings identify PACS2 as a crucial regulator of CVMD development and progression, underscoring its significant potential as both a diagnostic biomarker and a promising therapeutic target.

Keywords:  PACS2; cardiovascular and metabolic diseases (CVMDs); mitochondria‐associated membranes (MAMs)

DOI:  https://doi.org/10.1111/jcmm.71336
Cancer Gene Ther. 2026 Aug 25.

Calcium dysregulation in breast cancer progression: mechanisms of calcicoptosis and therapeutic implications.

Yu-Ting He, Jun-Hui Yin, Zhuo-Ling Li, Wen-Jing Zhang, Zi-Hao Gu, Na-Min Yang, Kang Li, Yi Zhou, Liang Ji.

Disruption of calcium ion (Ca2+) homeostasis represents a critical mechanism in breast cancer (BC) progression, with aberrant Ca2+ transport through store-operated Ca2+ entry pathways, plasma membrane channels, and membrane contact sites (MCSs) playing a significant role in malignant transformation, metastasis, and therapeutic resistance. This dysregulation involves complex interactions among endoplasmic reticulum Ca2+ storage systems, Ca2+-dependent signaling cascades, and specialized MCSs that facilitate abnormal Ca2+ transfer between cellular organelles. Of particular therapeutic relevance, calcicoptosis-a novel form of Ca2+ overload-induced cell death-exhibits remarkable selectivity for BC cells over normal tissues, offering promising avenues for therapy, particularly in aggressive subtypes with limited treatment options. The distinct Ca2+ handling properties of BC cells present opportunities for targeted interventions that exploit these vulnerabilities through pharmacological modulation of Ca2+ transport mechanisms. This review synthesizes current understanding of Ca2+-mediated pathways in BC and outlines a framework for developing precision medicine approaches that leverage Ca2+ dysregulation as both a biomarker and a therapeutic target, with the potential to transform treatment strategies for patients with treatment-resistant disease.

DOI: https://doi.org/10.1038/s41417-026-01076-x
Biomedicines. 2026 Jul 30. pii: 1709. [Epub ahead of print]14(8):

Caveolin-1 at the Crossroads of Diabetes and Alzheimer's Disease: New Mechanisms, Biomarkers, and Therapeutic Opportunities.

Andrei Surguchov.

  Type 2 diabetes mellitus (T2D) is increasingly recognized as a major risk factor for Alzheimer's disease (AD), supporting the concept that chronic metabolic dysfunction contributes to neurodegeneration. Recent advances have identified caveolin-1 (CAV-1), the principal structural protein of caveolae, as an important regulator of insulin signaling, lipid metabolism, mitochondrial homeostasis, neurovascular integrity, and amyloid precursor protein processing. Since our previous review published in 2020, substantial evidence has demonstrated that altered CAV-1 expression and function are associated with AD-related pathology under diabetic conditions through multiple mechanisms, including endothelial dysfunction, impaired brain insulin signaling, disruption of mitochondria-endoplasmic reticulum contact sites (MERCSs), neuroinflammation, mitochondrial dysfunction, and defective autophagy. Experimental studies further show that restoring neuronal or endothelial CAV-1 expression improves insulin signaling, preserves synaptic function, attenuates amyloid pathology, and ameliorates cognitive decline in preclinical models. This review summarizes recent advances in understanding of the CAV-1-dependent mechanisms linking T2D and AD and discusses the emerging potential of CAV-1 as a biomarker and therapeutic target for diabetes-associated neurodegeneration. Collectively, current evidence identifies CAV-1 as a central molecular hub integrating metabolic, vascular, and neurodegenerative pathways and supports its further investigation as a promising therapeutic target.

Keywords:  Alzheimer’s disease; amyloid beta; caveolin-1; diabetes mellitus; endoplasmic reticulum; insulin resistance; mitochondria; neurodegeneration; neurovascular unit; tau

DOI:  https://doi.org/10.3390/biomedicines14081709
Arch Pharm Res. 2026 Aug 24.

A novel Skp2 inhibitor triggers pyroptosis in leukemia via phospholipid metabolism disorder and mitochondria-associated endoplasmic reticulum membranes.

Xiaolong Tian, Jiarun Li, Guancui Yang, Peijie Jiang, Xueqing Yang, Shijie Yang, Xi Zhang, Jinyi Liu.

  Philadelphia chromosome-positive (Ph+) leukemia is among the most aggressive forms of leukemia and arises from the Philadelphia chromosome (Bcr-Abl fusion gene) abnormality. This disease is associated with a poor prognosis in adults and resistance to traditional treatment. Thus, the identification of novel therapeutic targets and drugs for Ph+ leukemia remains crucial. S-phase kinase-associated protein 2 (Skp2), a key component of the SCF ubiquitin ligase complex, is aberrantly overexpressed in various malignancies and therefore represents a potential target for anticancer therapy. This study aimed to elucidate the therapeutic mechanism of action of AAA-237, a novel Skp2 inhibitor, in Ph + leukaemia. Cellular responses to AAA-237 were evaluated using cell viability, EdU incorporation, and colony formation assays. Pyroptosis was observed by scanning electron microscopy (SEM), immunofluorescence, lactate dehydrogenase (LDH) detection, ELISA, and Western blotting. Phospholipid metabolism was evaluated through metabolomic profiling and RNA sequencing. Mechanistic findings were validated using Western blotting and quantitative real-time PCR. Mitochondrial and endoplasmic reticulum damage were evaluated using Ca2+, ATP, TMRM, and mitochondrial reactive oxygen species (ROS) assays. In vivo efficacy and safety of AAA-237 were examined in a xenograft model. The results showed that AAA-237 targeted Skp2 and inhibited Bcr-Abl phosphorylation and ubiquitination, suppressing the proliferation of Ph+ leukemia cells in a concentration-dependent manner at the cellular level. AAA-237 induced both pyroptosis and apoptosis through caspase-dependent mechanisms. Treatment with AAA-237 inhibited the PI3K/AKT signaling pathway and disrupted phospholipid metabolism, resulting in dysregulated phospholipid metabolism. AAA-237 also increased PACS2 expression, remodeled mitochondria-associated endoplasmic reticulum membranes (MAMs), and induced mitochondrial dysfunction and endoplasmic reticulum damage. In vivo, AAA-237 effectively suppressed leukemia progression. These results show that AAA-237, a novel Skp2 inhibitor, inhibits the proliferation of Ph+ leukemia cells by reducing Bcr-Abl phosphorylation and ubiquitination. AAA-237 further induces caspase-dependent pyroptosis and apoptosis by disrupting phospholipid metabolism and impairing MAM homeostasis. These results provide preliminary experimental evidence supporting the development of targeted candidate therapeutics for Ph+ leukemia.

Keywords:  AAA-237; MAMs; Ph+ leukemia; Phospholipid metabolism; Pyroptosis

DOI:  https://doi.org/10.1007/s12272-026-01634-9
Toxicology. 2026 Aug 27. pii: S0300-483X(26)00179-4. [Epub ahead of print] 154572

The role of Mfn2/PERK mediated ER-mitochondrial communication in autophagy induced by silica nanoparticles in HT22 cells.

Tiantian Tian, Yuanyuan Zhang, Xinyue Li, Jia Zhang, Ying Hao, Huiyuan Hu, Kai Ma, Mingqian Wang, Wei Quan, Haiying Du, Minghua Jin.

  Widespread application of silica nanoparticles (SiNPs) has raised concerns regarding potential neurotoxic risks, yet the complex mechanisms underlying cellular damage remain incompletely understood. Mitochondria associated endoplasmic reticulum membranes (MAMs), which are regulated by the key tethering protein Mitofusin 2 (Mfn2), serve as crucial platforms for interorgan crosstalk. However, whether ER-mitochondria communication mediated by Mfn2/PERK participate in SiNPs triggered neurotoxicity has not been elucidated. therefore, this study established an in vitro model of HT22 cells exposed to SiNPs to explore the mechanisms of the mitochondrial dynamic imbalance, ERS and autophagy. We detected cell viability, morphology and ultrastructure, antioxidant function, mtROS, Mfn2/PERK, mitochondrial dynamic, ERS, and autophagy-related proteins to investigate the role of mtROS/Mfn2/PERK in SiNPs-induced damage to HT22 cells. The results showed that the viability of HT22 cells was gradually decreased after exposure to 0-100μg/mL SiNPs for 24hours. Meanwhile, a series of cellular changes were observed, including oxidative damage, calcium overload, increased intracellular and mitochondrial ROS, decreased ATP content, broken mitochondrial cristae, swollen ER, expression of Mfn2 and PERK. Additionally, the structural and functional integrity of the Mfn2/PERK was impaired, and the expression of mitochondrial dynamics-related proteins was abnormal, thereby inducing ERS and promoting autophagy-related changes. Inhibition of mtROS or ERS and activation of Mfn2 alleviated mitochondrial dynamics imbalance and ERS, and were accompanied by attenuation of SiNPs-induced alterations in Mfn2/PERK signaling and autophagy-related proteins. This further confirms that there is a certain connection between mitochondrial function and ERS after SiNPs exposure, and that autophagy is induced through the mtROS/Mfn2/UPR signaling pathway.

Keywords:  Autophagy; Endoplasmic reticulum stress (ERS); Mitochondrial dynamics; Mitochondrial reactive oxygen species; Silica nanoparticles (SiNPs)

DOI:  https://doi.org/10.1016/j.tox.2026.154572
Sci Adv. 2026 Aug 28. 12(35): eaee8657

The molecular basis of mitochondrial crista formation by the MIC10 complex.

Chelsea M Brown, Tsjerk A Wassenaar, Zachary Freyberg, Siewert J Marrink.

Mitochondrial cristae are essential for respiration, yet the molecular basis of how the high curvature of these membrane folds is maintained remains unclear. Using structure prediction tools and multiscale simulations, we examined the role of the MIC10 subcomplex of the mitochondrial contact site and cristae organizing system (MICOS). We found that the MIC10 proteins Mic10, Mic26, and Mic27 strongly recruit cardiolipin at conserved positive loop motifs, driving oligomerization of these subunits and resulting in the stabilization of curvature in model membranes. Reconstruction of the full MIC10 complex in a realistic crista junction setup shows its capability to maintain membrane bending, while intrinsically disordered regions may form a permeability barrier between cristae and the intermembrane space. These findings provide a mechanistic model for cristae curvature formation and suggest how MICOS components cooperate with cardiolipins to maintain mitochondrial architecture.

DOI: https://doi.org/10.1126/sciadv.aee8657
Plant Physiol Biochem. 2026 Aug 26. pii: S0981-9428(26)00663-7. [Epub ahead of print]238 111677

CaMACPF1 and CaMACPF6 positively regulate hypoxia tolerance through modulating jasmonate and auxin metabolic pathways.

Yixian Guo, Sirui Ma, Yang Yu, Ziying Li, Yao Wang, Ying Zhou, Qinfang Chen, Shi Xiao, Lujun Yu.

Submergence and flooding impose severe crop losses through hypoxic stress. The Membrane Attack Complex/Perforin (MACPF) superfamily proteins function as pore-forming effectors in development and immunity across eukaryotic organisms, yet their role in plant hypoxia responses remains largely unexplored. Here, we identify two MACPF proteins in pepper (Capsicum annuum), CaMACPF1 and CaMACPF6, as positive regulators of hypoxia tolerance. CaMACPF1 and CaMACPF6 localize to endoplasmic reticulum-plasma membrane contact sites (EPCS) and the Golgi apparatus, with CaMACPF1 additionally detected in the nucleus and plasma membrane. When either protein was overexpressed, plants showed markedly better endurance under hypoxic stress and submergence, with accumulating less reactive oxygen species (ROS). Both proteins triggered jasmonic acid (JA) biosynthesis under oxygen deprivation, yet only CaMACPF6 specifically redirected auxin metabolism by converting indole-3-pyruvic acid (IPA) to indole-3-lactic acid (ILA). Taken together, these findings suggest that CaMACPF proteins may act as molecular switches linking EPCS dynamics to phytohormone signaling during hypoxic adaptation.

DOI: https://doi.org/10.1016/j.plaphy.2026.111677
J Clin Invest. 2026 Sep 01. pii: e204023. [Epub ahead of print]

Excessive EFHD1-dependent ER-mitochondrial contacts drive a maladaptive antiviral response in metabolic liver disease.

David R Eberhardt, Emma C Rekate, Yasmin B Masini, Hannah E Duron, David Mollinedo, Adrian M Velarde, Devorah Stucki, Tara R Price, Sandra Hj Lee, Enrique Balderas, Neeraj K Rai, Ashley R Bratt, Anthony M Balynas, Chris J Stubben, Ryan Bia, Sudipa Maity, Nicolas Hartel, Xue Yin, Andrea Corbin, Anshu Kumari, Dung M Nguyen, Daisuke Shimura, Vu D Nguyen, Vishaka Vinod, Kamrul H Chowdhury, Francisco Verdeguer, Joel Zvick, Patrice N Mimche, Sihem Boudina, Stavros G Drakos, Ademuyiwa S Aromolaran, Sarah Franklin, Vivek Garg, Robin M Shaw, William L Holland, Scott A Summers, Marcus G Pezzolesi, Jared Rutter, Kimberley J Evason, Dipayan Chaudhuri.

  Metabolic-associated steatohepatitis (MASH) involves hepatocyte damage that cannot be explained solely by lipid accumulation. Here, to discover injury-specific pathways, we focused on a gene of uncertain function, EF-Hand Domain Family Member D1 (EFHD1), identified in human genome-wide association studies of liver injury but not liver fat. We show that EFHD1, a Ca2+-dependent actin crosslinker, stabilizes endoplasmic reticulum-mitochondria contact sites (ERMCS), detecting spatiotemporal coincidence of inter-organellar proximity and ER Ca2+ release. During MASH, EFHD1 upregulation drives pathological mitochondrial fragmentation via excessive contact persistence. This structural failure promotes mitochondrial double-stranded RNA escape and activation of a maladaptive antiviral PKR-associated stress response, a causal relationship also supported by Mendelian randomization in humans. Consequently, inhibiting EFHD1 in human and mouse models blunts hepatocyte damage. These findings identify EFHD1 as a Ca2+-dependent ERMCS stabilizer, reveal a hepatocyte-intrinsic injury pathway, and suggest EFHD1 inhibition as a therapeutic strategy.

Keywords:  Calcium signaling; Cell biology; Cellular immune response; Hepatology; Metabolism; Mitochondria

DOI:  https://doi.org/10.1172/JCI204023
Brain Sci. 2026 Aug 21. pii: 896. [Epub ahead of print]16(8):

Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Chronic Pain.

Arun Yadawa, Sufang Liu, Feng Tao.

  Chronic pain is a major global health burden and often remains difficult to treat with current therapies, which frequently provide incomplete relief and may cause systemic side effects. As essential organelles in eukaryotic cells, mitochondria facilitate ATP synthesis and serve as key regulators of calcium homeostasis and apoptosis. Evidence points to mitochondrial dysfunction not merely as a result of trauma, but as a fundamental factor in why pain becomes persistent. On the other hand, the endoplasmic reticulum (ER) is more than just a structural component of the cell; it is a multi-functional organelle responsible for protein quality control, including folding and degradation, as well as lipid production and calcium signaling. ER dysfunction is a primary driver of various pathologies, such as cardiovascular disease, cancer, and neurodegenerative disorders. The organelle's ability to execute its vital functions is strictly dependent on sufficient levels of ATP. Because mitochondrial and ER functions are closely interconnected through calcium exchange, ATP-dependent protein homeostasis, oxidative stress, and mitochondria-associated ER membranes, their dysfunction may act together to amplify nociceptive sensitization and pain chronification. In this review, we summarize current evidence linking mitochondrial dysfunction, ER stress, and ER-mitochondrial crosstalk to the pathogenesis of chronic pain and discuss their potentials as therapeutic targets.

Keywords:  chronic pain; endoplasmic reticulum stress; mitochondrial dysfunction; neuroinflammation; nociceptive sensitization; oxidative stress

DOI:  https://doi.org/10.3390/brainsci16080896
J Mol Cell Cardiol Plus. 2026 Sep;17 100864

Organelle network dysfunction in primary cardiomyopathy: An integrated perspective on pathogenesis and therapeutics.

Shixin Pu, Pan Yang.

  Primary (genetic) cardiomyopathy comprises a heterogeneous group of predominantly monogenic (genetically determined) myocardial diseases-principally hypertrophic (HCM), dilated (DCM) and restrictive (RCM) phenotypes-and must be distinguished from secondary/acquired cardiomyopathies attributable to ischaemia, valvular disease, pressure overload, diabetes, infection or toxins. This review is restricted to primary cardiomyopathy; because organelle biology has been characterised far more extensively in secondary or acquired settings, evidence derived from such models (ischaemia-reperfusion, pressure overload, diabetes, sepsis, drug toxicity, neurodegenerative or non-cardiac injury models) is explicitly identified as such and treated as indirect, hypothesis-generating support rather than as direct evidence in primary cardiomyopathy. The pathophysiology of primary cardiomyopathy is tightly related to abnormal energy metabolism, protein homeostasis and calcium homeostasis. An increasing body of evidence suggests that organelle malfunction and abnormal inter-organelle interactions play a role in primary cardiomyopathy development. This review focuses on key organelles: mitochondrial dysfunction results in energy deprivation and oxidative imbalance; endoplasmic reticulum stress (ERS) impairs protein folding and calcium homeostasis; defects in the lysosome-mediated autophagy pathway exacerbate the accumulation of intracellular damaged material; Golgi fragmentation affects protein processing and trafficking; and cytoskeletal disruption compromises the structural integrity of myocardium. Furthermore, organelles create complex regulatory networks via structures like mitochondrial-associated ER membranes (MAMs), where imbalances such as aberrant calcium signalling and stress pathway cross-activation exacerbate pathological damage. While previous studies focus on individual proteins or organelles, the heart's high energy consumption and synchronized contraction require understanding cardiomyocytes as a dynamic, interdependent organelle ecosystem. Treating primary cardiomyopathy as a 'organelle network disease', in which organelles constitute a dynamic, interdependent ecosystem, provides a useful integrative paradigm for comprehending the causes. This review lays the groundwork for targeted therapy in primary cardiomyopathy by clarifying the functions of organelles.

Keywords:  Autophagic flux; Endoplasmic reticulum stress; Mitochondria-associated membranes; Organelle network; Primary cardiomyopathy

DOI:  https://doi.org/10.1016/j.jmccpl.2026.100864
Life Sci. 2026 Aug 26. pii: S0024-3205(26)00452-2. [Epub ahead of print] 124643

Apelin-13 drives VSMC proliferation and atherosclerosis through REEP5-dependent disruption of ER-mitochondria coupling and glycolytic shift.

Huimei Liu, Wei Chen, Hui Mao, Ruirui Lu, Xiaosi Zhou, Xueqian Ouyang, Sisi Fan, Xiaohui Huang, Xiaobo Hu, Yixuan Deng, Linxi Chen, Lanfang Li.

  Atherosclerosis is characterized by pathological vascular smooth muscle cell (VSMC) proliferation and metabolic dysregulation, yet the underlying mechanisms remain incompletely understood. Here, we identified receptor expression enhancer protein 5 (REEP5) as a potential regulator of VSMC proliferation in atherosclerosis by analyzing single-cell RNA sequencing datasets from human atherosclerotic coronary arteries and aortic tissues. REEP5 expression was markedly reduced in proliferative SMCs. In human aortic VSMCs, apelin-13 downregulated REEP5 in a time- and concentration-dependent manner. The REEP5 downregulation was associated with disrupted endoplasmic reticulum architecture, increased endoplasmic reticulum vacuolization, and impaired mitochondria-associated membrane coupling. Moreover, apelin-13 elevated mitochondrial reactive oxygen species, reduced mitochondrial membrane potential, and decreased mitochondrial Ca2+ levels, indicating mitochondrial dysfunction. Functionally, apelin-13 promoted a metabolic shift toward glycolysis, as evidenced by increased glucose consumption, lactate production, glycolytic enzyme expression and activity, and extracellular acidification rate, together with reduced oxidative phosphorylation and decreased oxygen consumption rate in vitro. REEP5 overexpression largely reversed these alterations and inhibited apelin-13-induced VSMC proliferation. Inhibition of glycolysis similarly attenuated the pro-proliferative effect of apelin-13. In ApoE-/- mice, REEP5 overexpression alleviated apelin-13-induced exacerbation of atherosclerosis, reduced lesion burden, ameliorated dyslipidemia, and reduced glycolytic marker expression in plaques. Collectively, these findings suggested that apelin-13 may promote VSMC proliferation and atherosclerotic progression, at least in part, by downregulating REEP5 and disrupting mitochondria-associated membrane coupling, thereby contributing to a glycolytic metabolic shift in VSMCs. Targeting the REEP5/mitochondria-associated membrane coupling axis may be a potential therapeutic target for atherosclerosis.

Keywords:  Apelin-13; Atherosclerosis; Glycolytic metabolic shift; MAM uncoupling; Receptor expression enhancer protein 5

DOI:  https://doi.org/10.1016/j.lfs.2026.124643