bims-miptne 2025-04-13 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2025–04–13
thirteen papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy.
TMEM65 joins the mitochondrial Ca2+ club.
MIRO1 Is Required for Dynamic Increases in Mitochondria-ER Contact Sites and Mitochondrial ATP During the Cell Cycle.
Mitochondrial dysfunction in AMI: mechanisms and therapeutic perspectives.
Induction of mitochondrial-dependent apoptosis, activation of mitochondrial ATPase and cytochrome c release by the methanol extract of Funtumia elastica stem bark.
TMEM65 regulates and is required for NCLX-dependent mitochondrial calcium efflux.
Streptomycin targets tumor-initiating cells by disrupting oxidative phosphorylation.
Ca2+/calmodulin-dependent protein kinase II regulates the inflammatory hDPSCs dentino-differentiation via BDNF/TrkB receptor signaling.
Highly dynamic and sensitive NEMOer calcium indicators for imaging ER calcium signals in excitable cells.
The Essence of Nature Can be the Simplest (1)--Warburg Effect: Transition from Intracellular ATP to Extracellular Fenton Chemistry.
Mitochondrial calcium uniporter regulates human fibroblast-like synoviocytes invasion via altering mitochondrial dynamics and dictates rheumatoid arthritis pathogenesis.
Ferroptosis as the new approach to cancer therapy.
Improving mitochondria-associated endoplasmic reticulum membranes integrity as converging therapeutic strategy for rare neurodegenerative diseases and cancer.

Sci Adv. 2025 Apr 11. 11(15): eadu5511

Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy.

James T Hagen, McLane M Montgomery, Raphael T Aruleba, Brett R Chrest, Polina Krassovskaia, Thomas D Green, Emely A Pacheco, Miki Kassai, Tonya N Zeczycki, Cameron A Schmidt, Debajit Bhowmick, Su-Fern Tan, David J Feith, Charles E Chalfant, Thomas P Loughran, Darla Liles, Mark D Minden, Aaron D Schimmer, Md Salman Shakil, Matthew J McBride, Myles C Cabot, Joseph M McClung, Kelsey H Fisher-Wellman.

OxPhos inhibitors have struggled to show a clinical benefit because of their inability to distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique to acute myeloid leukemia (AML) mitochondria. Unlike healthy cells that couple respiration to ATP synthesis, AML mitochondria support inner-membrane polarization by consuming ATP. Matrix ATP consumption allows cells to survive bioenergetic stress. Thus, we hypothesized AML cells may resist chemotherapy-induced cell death by reversing the ATP synthase reaction. In support, BCL-2 inhibition with venetoclax abolished OxPhos flux without affecting mitochondrial polarization. In surviving AML cells, sustained mitochondrial polarization depended on matrix ATP consumption. Mitochondrial ATP consumption was further enhanced in AML cells made refractory to venetoclax, consequential to down-regulations in the endogenous F1-ATPase inhibitor ATP5IF1. Knockdown of ATP5IF1 conferred venetoclax resistance, while ATP5IF1 overexpression impaired F1-ATPase activity and heightened sensitivity to venetoclax. These data identify matrix ATP consumption as a cancer cell-intrinsic bioenergetic vulnerability actionable in the context of BCL-2 targeted chemotherapy.

DOI: https://doi.org/10.1126/sciadv.adu5511
Nat Metab. 2025 Apr 08.

TMEM65 joins the mitochondrial Ca2+ club.

Yasemin Sancak.

DOI: https://doi.org/10.1038/s42255-025-01271-4
Cells. 2025 Mar 22. pii: 482. [Epub ahead of print]14(7):

MIRO1 Is Required for Dynamic Increases in Mitochondria-ER Contact Sites and Mitochondrial ATP During the Cell Cycle.

Benney T Endoni, Olha M Koval, Chantal Allamargot, Tara Kortlever, Lan Qian, Riley J Sadoski, Denise Juhr, Isabella M Grumbach.

  Mitochondria-ER contact sites (MERCS) are vital for mitochondrial dynamics, lipid exchange, Ca2+ homeostasis, and energy metabolism. We examined whether mitochondrial metabolism changes during the cell cycle depend on MERCS dynamics and are regulated by the outer mitochondrial protein mitochondrial rho GTPase 1 (MIRO1). Wound healing was assessed in mice with fibroblast-specific deletion of MIRO1. Wild-type and MIRO1-/- fibroblasts and vascular smooth muscle cells were evaluated for proliferation, cell cycle progression, number of MERCS, distance, and protein composition throughout the cell cycle. Restoration of MIRO1 mutants was used to test the role of MIRO1 domains; Ca2+ transients and mitochondrial metabolism were evaluated using biochemical, immunodetection, and fluorescence techniques. MERCS increased in number during G1/S compared with during G0, which was accompanied by a notable rise in protein-protein interactions involving VDAC1 and IP3R as well as GRP75 and MIRO1 by proximity-ligation assays. Split-GFP ER/mitochondrial contacts of 40 nm also increased. Mitochondrial Ca2+ concentration ([Ca2+]), membrane potential, and ATP levels correlated with the formation of MERCS during the cell cycle. MIRO1 deficiency blocked G1/S progression and the cell-cycle-dependent formation of MERCS and altered ER Ca2+ release and mitochondrial Ca2+ uptake. MIRO1 mutants lacking the Ca2+-sensitive EF hands or the transmembrane domain did not rescue cell proliferation or the formation of MERCS. MIRO1 controls an increase in the number of MERCS during cell cycle progression and increases mitochondrial [Ca2+], driving metabolic activity and proliferation through its EF hands.

Keywords:  Ca2+; ER; MAM; MERCS; MIRO1; cell cycle; fibroblasts; mitochondria; vascular smooth muscle cells

DOI:  https://doi.org/10.3390/cells14070482
J Transl Med. 2025 Apr 10. 23(1): 418

Mitochondrial dysfunction in AMI: mechanisms and therapeutic perspectives.

Jingle Shi, Yiding Yu, Huajing Yuan, Yan Li, Yitao Xue.

  Acute myocardial infarction (AMI) and the myocardial ischemia-reperfusion injury (MI/RI) that typically ensues represent a significant global health burden, accounting for a considerable number of deaths and disabilities. In the context of AMI, percutaneous coronary intervention (PCI) is the preferred treatment option for reducing acute ischemic damage to the heart. Despite the modernity of PCI therapy, pathological damage to cardiomyocytes due to MI/RI remains an important target for intervention that affects the long-term prognosis of patients. In recent years, mitochondrial dysfunction during AMI has been increasingly recognized as a critical factor in cardiomyocyte death. Damaged mitochondria play an active role in the formation of an inflammatory environment by triggering key signaling pathways, including those mediated by cyclic GMP-AMP synthase, NOD-like receptors and Toll-like receptors. This review emphasizes the dual role of mitochondria as both contributors to and regulators of inflammation. The aim is to explore the complex mechanisms of mitochondrial dysfunction in AMI and its profound impact on immune dysregulation. Specific interventions including mitochondrial-targeted antioxidants, membrane-stabilizing peptides, and mitochondrial transplantation therapies have demonstrated efficacy in preclinical AMI models.

Keywords:  Acute myocardial infarction; Cell death; Inflammatory response; Mitochondrial damage; Myocardial ischemia-reperfusion injury; Therapeutic strategy

DOI:  https://doi.org/10.1186/s12967-025-06406-5
J Complement Integr Med. 2025 Apr 14.

Induction of mitochondrial-dependent apoptosis, activation of mitochondrial ATPase and cytochrome c release by the methanol extract of Funtumia elastica stem bark.

Fatima B Musa, Tolulope A Oyedeji, Adeola O Olowofolahan, Hammed O Faleke, Olufunso O Olorunsogo.

   OBJECTIVES: Natural compounds that can induce the opening of the mitochondrial membrane permeability transition (MMPT) pore may be useful therapeutic agents in treating diseases associated with mitochondrial dysfunction e.g. cancer, diabetes, and neurodegenerative diseases. This pore represents a promising target for therapeutic intervention. Therefore, this study investigated the potential of the methanol extract of Funtumia elastica stem bark on the MMPT pore, mitochondrial ATPase (mATPase), cytochrome c release (cyt c), and mitochondrial lipid peroxidation (mLPO) in rat liver.
METHODS: Male Wistar rats (100-120 g) were used in this study. Differential centrifugation was used to isolate mitochondria from rat liver. MMPT pore opening, mATPase activity, cyt c, and mLPO were assayed.
RESULTS: The results indicate that the methanol extract of F. elastica induced MMPT pore opening in the absence of calcium ions. Also, in the presence of calcium ions, the extract significantly (p<0.05) reversed the opening of the MMPT pore by 21.0, 30.0, 34.0, and 38.0 % at 12, 36, 60, and 84 μg/mL, respectively. The extract activated mitochondrial ATPase activity significantly (p<0.05) compared to the control. The extract elevated cytochrome c release with increasing extract concentration relative to the control. The extract also inhibited iron-induced mitochondrial lipid peroxidation by 29.0, 38.7, 59.9, 83.0, and 87.0 % at 150, 300, 600, 1,200, and 2,400 μg/mL, respectively.
CONCLUSIONS: Our results showed that the methanol extract of F. elastica contains potent phytochemicals that can trigger MMPT pore opening, activate mATPase, cyt c, and inhibit mLPO. This extract may find use in diseases associated with apoptosis dysfunction.

Keywords:   Funtumia elastica ; apoptosis; cytochrome c release; mitochondrial ATPase; mitochondrial dysfunction

DOI:  https://doi.org/10.1515/jcim-2024-0326
Nat Metab. 2025 Apr 08.

TMEM65 regulates and is required for NCLX-dependent mitochondrial calcium efflux.

Joanne F Garbincius, Oniel Salik, Henry M Cohen, Carmen Choya-Foces, Adam S Mangold, Angelina D Makhoul, Anna E Schmidt, Dima Y Khalil, Joshua J Doolittle, Anya S Wilkinson, Emma K Murray, Michael P Lazaropoulos, Alycia N Hildebrand, Dhanendra Tomar, John W Elrod.

The balance between mitochondrial calcium (mCa2+) uptake and efflux is essential for ATP production and cellular homeostasis. The mitochondrial sodium-calcium exchanger, NCLX, is a critical route of mCa2+ efflux in excitable tissues, such as the heart and brain, and animal models support NCLX as a promising therapeutic target to limit pathogenic mCa2+ overload. However, the mechanisms that regulate NCLX activity are largely unknown. Using proximity biotinylation proteomic screening, we identify the mitochondrial inner membrane protein TMEM65 as an NCLX binding partner that enhances sodium (Na+)-dependent mCa2+ efflux. Mechanistically, acute pharmacological NCLX inhibition or genetic deletion of NCLX ablates the TMEM65-dependent increase in mCa2+ efflux, and loss-of-function studies show that TMEM65 is required for Na+-dependent mCa2+ efflux. In line with these findings, knockdown of Tmem65 in mice promotes mCa2+ overload in the heart and skeletal muscle and impairs both cardiac and neuromuscular function. Collectively, our results show that loss of TMEM65 function in excitable tissue disrupts NCLX-dependent mCa2+ efflux, causing pathogenic mCa2+ overload, cell death, and organ-level dysfunction. These findings demonstrate the essential role of TMEM65 in regulating NCLX-dependent mCa2+ efflux and suggest modulation of TMEM65 as a therapeutic strategy for a variety of diseases.

DOI: https://doi.org/10.1038/s42255-025-01250-9
Cell Chem Biol. 2025 Apr 08. pii: S2451-9456(25)00098-4. [Epub ahead of print]

Streptomycin targets tumor-initiating cells by disrupting oxidative phosphorylation.

Hélène Guillorit, Sébastien Relier, Benjamin Zagiel, Audrey Di Giorgio, Chris Planque, Bastien Felipe, Hélène Hérault, Lucile Bansard, Céline Bouclier, Béatrice Chabi, François Casas, Ornella Clara, Béatrice Bonafos, Xavier Mialhe, Chantal Cazevieille, Szimonetta Hideg, Armelle Choquet, Amandine Bastide, Julie Pannequin, Maria Duca, Françoise Macari, Alexandre David.

  Tumor initiating cells (TICs) are the roots of current shortcomings in advanced and metastatic cancer treatment. Endowed with self-renewal and multi-lineage differentiation capacity, TICs can disseminate and seed metastasis in distant organ. Our work identified streptomycin (SM), a potent bactericidal antibiotic, as a molecule capable of specifically targeting non-adherent TIC from colon and breast cancer cell lines. SM induces iron-dependent, reactive oxygen species (ROS)-mediated cell death, which is mechanistically distinct from RSL3-induced ferroptosis. SM-induced cell death is associated with profound alterations in mitochondrial morphology. This effect results from COX1 inhibition, which disrupts the regulation of the cytochrome c oxidase complex and triggers mitochondrial ROS production. SM's aldehyde group is essential, as its reduction into dihydrostreptomycin (DSM) abolishes its activity. These findings reveal a mechanism of action for streptomycin, shedding light on TIC metabolism and resistance, with potential implications for advanced cancer treatment.

Keywords:  Cytochrome C oxidase; OXPHOS activity; RSL3; aminoglycoside; mitochondria; sphere-forming ability; streptomycin; tumor initiating cells

DOI:  https://doi.org/10.1016/j.chembiol.2025.03.008
Front Cell Dev Biol. 2025 ;13 1558736

Ca2+/calmodulin-dependent protein kinase II regulates the inflammatory hDPSCs dentino-differentiation via BDNF/TrkB receptor signaling.

Ji Hyun Kim, Muhammad Irfan, Sreelekshmi Sreekumar, Kerwin Chong, Jin Hong, Satish Alapati, Seung Chung.

  CaMKII is a serine/threonine-specific protein kinase that plays a crucial role in normal and pathological conditions. However, limited information is available regarding the roles of CaMKII in dentinogenesis, particularly in an inflammatory context. Previously, we demonstrated the pivotal role of TrkB in inflammation-induced differentiation of hDPSCs into odontoblast-like cells. Here, we investigate the interaction between CaMKII and TrkB during hDPSCs odontogenic differentiation. hDPSCs were cultured and subjected to CaMKII knockdown using siRNA, followed by treatment with dentinogenic media. TNFα-stimulated cells were treated with CaMKII- inhibitor, -protein, or TrkB antagonist, CTX-B. Immunocytochemistry and ARS were used to visualize targeted proteins and calcium deposits. Real-time PCR detected expression levels of odontogenic and mineralization markers such as DSPP and DMP-1. Our data indicate that CaMKII inhibition enhances TrkB protein levels and promotes TNFα-induced transcriptional activation of genes associated with odontogenic differentiation. CaMKII knockdown via siRNA and pharmacological inhibition elevated DSPP and DMP-1 protein levels, whereas CaMKII overexpression suppressed their expression. Notably, treatment with TNF-α and a CaMKII inhibitor upregulated DSPP and DMP-1 expression, while co-treatment with CTX-B abolished this effect. Similarly, mRNA expression of DSPP and DMP-1 was reduced at day 10. Mineralization activity exhibited a similar pattern to the expression of these markers. Our findings unveil a novel mechanism underlying the role of CaMKII via TrkB in dentinogenesis, which is vital for the success of hDPSCs engineering strategies.

Keywords:  CaMKII; TNFα; TrkB; hDPSCs; inflammation; odontoblastic differentiation

DOI:  https://doi.org/10.3389/fcell.2025.1558736
Nat Commun. 2025 Apr 11. 16(1): 3472

Highly dynamic and sensitive NEMOer calcium indicators for imaging ER calcium signals in excitable cells.

Wenjia Gu, Jia-Hui Chen, Yiyin Zhang, Zhirong Wang, Jia Li, Sijia Wang, Hanhan Zhang, Amin Jiang, Ziyi Zhong, Jiaxuan Zhang, Ze Xu, Panpan Liu, Chao Xi, Tingting Hou, Donald L Gill, Dong Li, Yu Mu, Shi-Qiang Wang, Ai-Hui Tang, Youjun Wang.

The Endoplasmic/sarcoplasmic reticulum (ER/SR) is central to calcium (Ca2+) signaling, yet current genetically encoded Ca2+ indicators (GECIs) cannot detect elementary Ca2+ release events from ER/SR, particularly in muscle cells. Here, we report NEMOer, a set of organellar GECIs, to efficiently capture ER Ca2+ dynamics with increased sensitivity and responsiveness. NEMOer indicators exhibit dynamic ranges an order of magnitude larger than G-CEPIA1er, enabling 2.7-fold more sensitive detection of Ca2+ transients in both non-excitable and excitable cells. The ratiometric version further allows super-resolution monitoring of local ER Ca2+ homeostasis and dynamics. Notably, NEMOer-f enabled the inaugural detection of Ca2+ blinks, elementary Ca2+ releasing signals from the SR of cardiomyocytes, as well as in vivo spontaneous SR Ca2+ releases in zebrafish. In summary, the highly dynamic NEMOer sensors expand the repertoire of organellar Ca2+ sensors that allow real-time monitoring of intricate Ca2+ dynamics and homeostasis in live cells with high spatiotemporal resolution.

DOI: https://doi.org/10.1038/s41467-025-58705-6
Chem Biodivers. 2025 Apr 08. e202500313

The Essence of Nature Can be the Simplest (1)--Warburg Effect: Transition from Intracellular ATP to Extracellular Fenton Chemistry.

Qunfu Wu, Donglou Wang, Jiao Zhou, Xuemei Niu, Shenghong Li.

  Here we explain the energy mechanism behind the Warburg effect of aerobic glycolysis, which has been unsolved for a hundred years. We found that fungal cells that can engage in extracellular Fenton reactions share central carbon metabolism with cancer cells that can produce the Warburg effect. Fungal cells also undergo aerobic glycolysis, significantly reducing intracellular ATP levels and allocating large amounts of oxygen for the extracellular Fenton reactions. The use of aerobic glycolysis for the extracellular Fenton reaction can be a common phenomenon in nature, as glycolysis is a metabolic pathway that occurs in every cell. The development of extracellular Fenton reaction can be divided into rapid and slow formation. Rapid extracellular Fenton reactions occur predominantly in organisms that contain the key biosynthetic genes for secondary metabolite biosynthesis, while endotherms have limited capacity for slow extracellular reactions due to lack of these critical genes. Endogenous aromatic metabolites can initiate strong extracellular Fenton reactions and siderophores can sequester and recycle iron and protect the host from extracellular Fenton reactions. Most exogenous aromatics can induce an extracellular Fenton reaction reflux, thereby inhibiting cancer cells and pathogenetic microorganisms that exhibit stronger extracellular Fenton reactions than normal cells and non-pathogenetic microorganisms.

Keywords:  Warburg effect, aerobic glycolysis, thermophilic fungus, cancer cells, extracellular Fenton reaction

DOI:  https://doi.org/10.1002/cbdv.202500313
Free Radic Biol Med. 2025 Apr 04. pii: S0891-5849(25)00208-4. [Epub ahead of print]

Mitochondrial calcium uniporter regulates human fibroblast-like synoviocytes invasion via altering mitochondrial dynamics and dictates rheumatoid arthritis pathogenesis.

Lakra Promila, Kabita Sarkar, Shivika Guleria, Adrija Rakshit, Manisha Rathore, Nishakumari C Singh, Shaziya Khan, Manendra Singh Tomar, Veena Ammanathan, Manoj Kumar Barthwal, Jagavelu Kumaravelu, Ashutosh Shrivastava, Kalyan Mitra, Rajdeep Guha, Amita Aggarwal, Amit Lahiri.

  Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease that currently has no cure. Fibroblast-like synoviocytes (FLS), present in the RA synovium, play a pivotal role in RA pathogenesis. Notably, FLS in the RA patients (RA-FLS) exhibit characteristics similar to cancer cells, like enhanced migration, invasiveness, uncontrolled proliferation, resistance to apoptosis, and metabolic reprogramming. RA-FLS invasiveness is linked to radiographic joint damage in the patients, whereas inhibiting the FLS migration mitigates disease pathology. However, the molecular mechanisms underlying the migration and invasion capabilities of RA-FLS are not entirely understood. In this work, we have explored the function of mitochondrial calcium uniporter (MCU) and calcium signaling in FLS invasion. Our findings demonstrate a positive correlation between MCU expression and RA disease score. Interestingly, mitochondrial size was reduced, and peripheral localization was more pronounced in the RA-FLS when compared to the control FLS. Mitochondrial calcium import inhibition in the FLS by specific MCU inhibitor, Ruthenium-360 restored these altered mitochondrial dynamics and reduced the invasive phenotype. Through unbiased transcriptome analysis, we identified that MCU-mediated calcium signaling in RA-FLS leads to the enriched actin cytoskeleton and focal adhesion pathways responsible for the invasion phenotype, which can be effectively suppressed by inhibiting MCU. Additionally, we found that mitochondrial transport facilitator Miro1 binds to MCU in a calcium-dependent manner and regulates MCU-mediated mitochondrial dynamics and RA-FLS invasion. Experiments utilizing mice xenograft model demonstrated that MCU silencing diminishes the migration of RA-FLS toward the sites of inflammation in the immunocompromised SCID mice. Altogether, our findings highlight MCU as a promising therapeutic target to inhibit RA-FLS migration and RA progression.

Keywords:  Fibroblast-like synoviocytes; Rheumatoid arthritis; calcium; mitochondrial calcium uniporter; mitochondrial dynamics

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.04.008
Cancer Treat Res Commun. 2025 Mar 25. pii: S2468-2942(25)00050-4. [Epub ahead of print]43 100913

Ferroptosis as the new approach to cancer therapy.

Oluwafemi Adeleke Ojo, Susan Grant, Pearl Ifunanya Nwafor-Ezeh, Tobiloba Christiana Maduakolam-Aniobi, Tolulope Isaiah Akinborode, Emmanuel Henry Ezenabor, Adebola Busola Ojo.

  Cancer is characterized by unregulated cell proliferation, evasion of apoptosis, and a propensity for metastasis, making it a leading cause of morbidity and mortality globally. Major challenges in cancer treatment include drug resistance and tumor heterogeneity, which hinder the clinical efficacy of existing therapies. To enhance treatment outcomes, it is essential to integrate emerging biological insights and technological advancements with conventional therapeutic strategies. Recent research has identified various forms of cell death, which can be classified as either regulated or unregulated. Regulated cell death involves specific biochemical and signaling pathways, while unregulated cell death occurs passively and uncontrollably. Apoptosis, the most extensively studied form of regulated cell death, is primarily mediated by the activation of caspase proteases. Nevertheless, the resistance of many tumors to apoptotic pathways has shifted focus towards non-apoptotic forms of cell death, such as ferroptosis. Ferroptosis is an iron-dependent form of regulated necrosis characterized by extensive membrane damage resulting from lipid peroxidation. Numerous preclinical studies have demonstrated that inducing ferroptosis can significantly reduce tumor growth across a variety of cancer types. For instance, in a study involving breast cancer models, the use of ferroptosis inducers such as erastin and RSL3 led to a marked decrease in tumor volume and weight. This review aims to explore the potential of ferroptosis as a novel therapeutic strategy in cancer treatment.

Keywords:  Apoptosis; Cancer; Ferroptosis; Targeted therapy

DOI:  https://doi.org/10.1016/j.ctarc.2025.100913
Biochim Biophys Acta Mol Cell Res. 2025 Apr 09. pii: S0167-4889(25)00059-X. [Epub ahead of print] 119954

Improving mitochondria-associated endoplasmic reticulum membranes integrity as converging therapeutic strategy for rare neurodegenerative diseases and cancer.

Michal Cagalinec, Mohd Adnan, Silvia Borecka, Geert Bultynck, Vinay Choubey, Shira Yanovsky-Dagan, Shlomit Ezer, Daniela Gasperikova, Tamar Harel, Dana Jurkovicova, Allen Kaasik, Jean-Charles Liévens, Tangui Maurice, Marco Peviani, Elodie Marie Richard, Jan Skoda, Martina Skopkova, Pauline Tarot, Robbe Van Gorp, Liga Zvejniece, Benjamin Delprat.

  Membrane contact sites harbor a distinct set of proteins with varying biological functions, thereby emerging as hubs for localized signaling nanodomains underlying adequate cell function. Here, we will focus on mitochondria-associated endoplasmic reticulum membranes (MAMs), which serve as hotspots for Ca2+ signaling, redox regulation, lipid exchange, mitochondrial quality and unfolded protein response pathway. A network of MAM-resident proteins contributes to the structural integrity and adequate function of MAMs. Beyond endoplasmic reticulum (ER)-mitochondrial tethering proteins, MAMs contain several multi-protein complexes that mediate the transfer of or are influenced by Ca2+, reactive oxygen species and lipids. Particularly, IP3 receptors, intracellular Ca2+-release channels, and Sigma-1 receptors (S1Rs), ligand-operated chaperones, serve as important platforms that recruit different accessory proteins and intersect with these local signaling processes. Furthermore, many of these proteins are directly implicated in pathophysiological conditions, where their dysregulation or mutation is not only causing diseases such as cancer and neurodegeneration, but also rare genetic diseases, for example familial Parkinson's disease (PINK1, Parkin, DJ-1), familial Amyotrophic lateral sclerosis (TDP43), Wolfram syndrome1/2 (WFS1 and CISD2), Harel-Yoon syndrome (ATAD3A). In this review, we will discuss the current state-of-the-art regarding the molecular components, protein platforms and signaling networks underlying MAM integrity and function in cell function and how their dysregulation impacts MAMs, thereby driving pathogenesis and/or impacting disease burden. We will highlight how these insights can generate novel, potentially therapeutically relevant, strategies to tackle disease outcomes by improving the integrity of MAMs and the signaling processes occurring at these membrane contact sites.

Keywords:  ATAD3A related disorders; Amyotrophic lateral sclerosis; Calcium signaling; Endoplasmic reticulum stress; Familial Parkinson's disease; Harel-Yoon syndrome; Metabolomics; Mitochondria quality control; Mitochondria-associated endoplasmic reticulum membranes; Rare neurodegenerative diseases; Wolfram syndrome; cancer

DOI:  https://doi.org/10.1016/j.bbamcr.2025.119954