bims-mecosi 2026-06-07 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2026–06–07
thirteen papers selected by
Verena Kohler, Umeå University

TDP-43 oxidation and PP1 crosstalk at RNA granule-mitochondria contact sites.
Mitochondrial C3aR and endoplasmic reticulum C5aR orchestrate calcium imbalance during oxidative stress in retinal pigment epithelial cells.
A brief history of the human liver peroxisome.
Huoxue Qianyang Qutan Recipe limits cardiac remodeling by regulating FUNDC1/IP3R2 signaling pathway in obese hypertensive rats.
Glucose starvation signaling via nucleus-vacuole junction remodeling controls ergosterol synthesis.
Signaling lipids: An overview of emerging physiological functions.
Yiqi Huoxue Formula Promotes Post-Myocardial Infarction Angiogenesis by Modulating Mitochondria-Associated Membranes (MAMs) and Calcium Homeostasis via the cGMP/PKG Signaling Pathway.
GRP75 Chaperone-driven Mitochondria-ER Membrane Coupling Promotes Ca2+-Dependent ROS Accumulation and Ferroptosis During Hypoxic Stress.
Docosahexaenoic acid alleviates Ornidazole toxicity related to spermatogenic dysfunction by modulating PPARγ-dependent ER-mitochondrial uncoupling.
Seipin: A central lipid rheostat.
A GUV-based assay to reconstitute membrane tethering in vitro.
ATAD3A Limits Aortic Dissection via Mito-Lysosome Contacts and Lipoylation.
Plasma - Activated Medium Engages Redox Signaling to Activate a VDAC1-TRPML1 Lysosomal-Mitochondrial Ca2+ Death Pathway.

Nat Commun. 2026 Jun 05.

TDP-43 oxidation and PP1 crosstalk at RNA granule-mitochondria contact sites.

Hannah E Ball, Abby C Woods, Yvette C Wong.

Inter-organelle contact sites are key hubs for organelle bidirectional crosstalk. However, how mitochondria and RNA granules interact at contact sites and its regulation by mitochondrial oxidative phosphorylation (OXPHOS) remain unclear. Here, using Super-Resolution live microscopy, we identify RNA granule-mitochondria contact site formation in OXPHOS conditions. Reactive oxygen species (ROS) generated by mitochondrial OXPHOS promotes TDP-43 localization to cytoplasmic RNA granules via TDP-43 cysteine oxidation at Cys173/Cys175. Mechanistically, RNA granule-mitochondria contact tethering is mediated by TDP-43 on RNA granules binding to GADD34 on mitochondria, while contact untethering is regulated by TDP-43 oxidation. Functionally, this allows for GADD34 and its binding partner PP1 to regulate TDP-43 RNA granule dynamics, and conversely, for TDP-43 oxidation to regulate the ability of the phosphatase PP1 to form granules. Finally, disease-associated mutant TDP-43 misregulates this pathway, ultimately leading to PP1 granules lacking TDP-43. This dynamic crosstalk between TDP-43 oxidation and PP1 has significant consequences for TDP-43-associated diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).

DOI: https://doi.org/10.1038/s41467-026-74009-9
Mitochondrion. 2026 Jun 03. pii: S1567-7249(26)00062-0. [Epub ahead of print] 102172

Mitochondrial C3aR and endoplasmic reticulum C5aR orchestrate calcium imbalance during oxidative stress in retinal pigment epithelial cells.

Masaaki Ishii, Bärbel Rohrer.

  Although C3a and C5a are classically recognized as extracellular anaphylatoxins, we previously identified mitochondrial C3a receptors (mt-C3aR) in stressed RPE cells, where its activation enhanced Ca2+ uptake and inhibited oxidative phosphorylation (OXPHOS). Here, we demonstrate a second intracellular anaphylatoxin receptor, C5aR, localized to the endoplasmic reticulum (ER) by confocal and immuno-electron microscopy. ER-C5aR activation increased SERCA-dependent Ca2+ uptake and, together with mt-C3aR, facilitated ER-to-mitochondria Ca2+ transfer at mitochondria-endoplasmic reticulum contact sites (MERCS). Moreover, oxidative stress induced Gα16 redistribution, enabling its interaction with ER-C5aR. These findings reveal a novel mechanism by which intracellular anaphylatoxin receptors shape Ca2+ homeostasis and cellular stress responses.

Keywords:  Anaphylatoxin; Calcium; Endoplasmic reticulum; Intracellular complement signaling; mitochondria-ER contacts

DOI:  https://doi.org/10.1016/j.mito.2026.102172
Histochem Cell Biol. 2026 Jun 04. pii: 42. [Epub ahead of print]164(1):

A brief history of the human liver peroxisome.

Dirk De Craemer, Christiane Van den Branden, Frank Roels.

  The human liver peroxisome deserves a special review because it differs from peroxisomes in laboratory animals and cultured cells. We provide an overview of the historical stepping stones, with special emphasis on electron microscopy, enzyme- and immunocytochemistry, and morphometry. The contributions from several hundreds of patients, children with inherited diseases and adults with acquired illnesses are summarized. Intriguing findings such as liver peroxisomes of a patient changing over time, or the patient series with peroxisome mosaics in the liver, are highlighted. We compare our own data with the more recent discoveries, in particular the endoplasmic reticulum-peroxisome membrane contact sites and their inherited deficiencies: retinal dystrophy with leukodystrophy (RDLD). For complete diagnosis, expanded phenotyping and understanding the diseases, we urge the examination of human liver tissue.

Keywords:  Cytochemistry; Endoplasmic reticulum; Human liver; Metabolism; Morphometry; Ultrastructure

DOI:  https://doi.org/10.1007/s00418-026-02495-5
Sci Rep. 2026 Jun 04.

Huoxue Qianyang Qutan Recipe limits cardiac remodeling by regulating FUNDC1/IP3R2 signaling pathway in obese hypertensive rats.

Chunlei Hou, Yuxiu Zhao, Yulong Ma, Xunjie Zhou, Lei Yao, Jianhua Li, Mingtai Gui, Mingzhu Wang, Xiaozhe Chen, Deyu Fu, Bo Lu.

  Obese hypertension (OBH) increases cardiovascular risk through myocardial remodeling, which is associated with disrupted mitochondrial Ca²⁺ homeostasis and dysfunction of mitochondria-associated endoplasmic reticulum membranes (MAM). Huoxue Qianyang Qutan Recipe (HQQR) has been shown to lower blood pressure in OBH, but its mechanism related to MAM remains unclear. In this study, phenotypic assessments in OBH rats included blood pressure, morphological parameters, and cardiac ultrasound. Cardiomyocyte hypertrophy and mitochondrial Ca²⁺ levels were analyzed via pathological staining (assessed using fluorescence-based staining), while MAM ultrastructure was examined by electron microscopy. Additionally, the activity of mitochondrial respiratory chain Complexes I-IV was detected in vivo to evaluate mitochondrial respiratory function. In vitro, flow cytometry was used to evaluate mitochondrial Ca²⁺, mitochondrial reactive oxygen species (mitoROS), and membrane potential. Protein levels of FUNDC1 and IP3R2 were assessed. Co-immunoprecipitation revealed an interaction between FUNDC1 and IP3R2, and further experiments with FUNDC1 siRNA knockdown and overexpression were conducted to clarify the mechanism of HQQR. Results showed that HQQR significantly lowered blood pressure, reduced left ventricular mass, and alleviated cardiomyocyte hypertrophy in OBH rats. In vivo, HQQR altered MAM structure and function, facilitated mitochondrial Ca²⁺ transport, and modulated FUNDC1 and IP3R2 expression. In vitro, HQQR reduced mitoROS and preserved mitochondrial Ca²⁺ homeostasis. Both HQQR treatment and FUNDC1 knockdown attenuated angiotensin II-induced cardiomyocyte hypertrophy and mitochondrial damage, as indicated by decreased levels of ANP, BNP, β-MHC, mitochondrial Ca²⁺, and mitoROS. In contrast, FUNDC1 overexpression diminished the protective effects of HQQR. The interaction between FUNDC1 and IP3R2 was confirmed, and the decrease in IP3R2 may be associated with ubiquitination-mediated degradation. In conclusion, HQQR mitigates MAM dysfunction in OBH-induced myocardial remodeling by regulating the FUNDC1-IP3R2 interaction and promoting ubiquitin-dependent degradation of IP3R2, thereby maintaining mitochondrial Ca²⁺ homeostasis in cardiomyocytes.

Keywords:  FUNDC1; HuoXue QianYang QuTan Recipe; Hypertension; Mitochondria-associated endoplasmic reticulum membranes; Obesity

DOI:  https://doi.org/10.1038/s41598-026-56197-y
J Cell Biol. 2026 Jul 06. pii: e202506071. [Epub ahead of print]225(7):

Glucose starvation signaling via nucleus-vacuole junction remodeling controls ergosterol synthesis.

Shintaro Fujimoto, Yasushi Tamura.

Membrane contact sites, where organelle membranes come into close proximity, function as dynamic hubs for lipid metabolism in response to metabolic and stress signals. In yeast, the nucleus-vacuole junction (NVJ) expands during glucose starvation (GS) through the recruitment of stress-specific proteins; however, the underlying mechanisms and physiological significance have remained unclear. Here, we identify the aspartyl protease Ypf1 and the yeast INSIG homologs Nsg1 and Nsg2 as NVJ-localized proteins specifically recruited during GS. Ypf1 promotes the recruitment of Nsg1, Nsg2, and the HMG-CoA reductases Hmg1 and Hmg2 to the NVJ, likely in association with changes in nuclear membrane lipid composition caused by suppression of fatty acid elongases. This remodeling destabilizes Nsg1, thereby activating Hmg1, while stabilizing Nsg2, which suppresses Hmg1 to fine-tune sterol synthesis. Loss of both Nsg1 and Nsg2 leads to hyperactivation of Hmg1 and accumulation of squalene, a sterol biosynthetic intermediate. We propose that suppression of fatty acid elongases drives GS-dependent NVJ remodeling to regulate ergosterol synthesis.

DOI: https://doi.org/10.1083/jcb.202506071
Curr Opin Cell Biol. 2026 May 30. pii: S0955-0674(26)00042-6. [Epub ahead of print]101 102654

Signaling lipids: An overview of emerging physiological functions.

Ojal Saharan, Tathagata Pal, Siddhesh S Kamat.

Lipids are now recognized as central regulators of cellular signaling, extending well beyond their traditional roles in membrane structure and energy storage. As spatially confined and rapidly inducible messengers, signaling lipids integrate membrane dynamics, metabolism, and signal transduction to control processes like inflammation, immune responses, vesicular trafficking, cytoskeletal organization, and cell fate decisions. This review highlights key mechanistic principles underlying lipid signaling specificity, including localized biosynthesis, enzymatic turnover, and receptor engagement. We trace the evolution of the field from classical eicosanoids and phosphoinositides to sphingolipids, lysophospholipids, and endocannabinoids, and focus on emerging mediators such as fatty acid esters of hydroxy fatty acids, specialized pro-resolving mediators, and lysophosphatidylserines. We conclude by discussing how dysregulated lipid signaling contributes to disease and outline future directions, emphasizing membrane contact sites, signaling crosstalk, and advances in lipidomics and imaging.

DOI: https://doi.org/10.1016/j.ceb.2026.102654
J Ethnopharmacol. 2026 Jun 04. pii: S0378-8741(26)00788-9. [Epub ahead of print] 121936

Yiqi Huoxue Formula Promotes Post-Myocardial Infarction Angiogenesis by Modulating Mitochondria-Associated Membranes (MAMs) and Calcium Homeostasis via the cGMP/PKG Signaling Pathway.

Tianhui du, Yunshu Zhang, Hui Wang, Weibin Xie, Caiyu Liang, Jingyun Guo, Chenglong Zheng, Shunwen Guo.

   ETHNOPHARMACOLOGICAL RELEVANCE: Therapeutic angiogenesis represents a promising strategy for recovery following myocardial infarction (MI). Yiqi Huoxue Formula (YQHX), a well-known traditional Chinese medicinal prescription, is widely utilized in clinical practice to treat myocardial ischemia and enhance cardiac performance in patients with MI. This study aims to elucidate the regulatory role of YQHX on mitochondria-associated membranes (MAMs) via the cGMP/PKG signaling pathway in promoting post-MI angiogenesis and restoring cardiac function.
MATERIALS AND METHODS: An in vivo MI model was established via left anterior descending (LAD) coronary artery ligation in rats, and an in vitro model was developed using hypoxia-induced injury in human umbilical vein endothelial cells (HUVECs). The effects of YQHX on cardiac function and HUVEC behaviors (proliferation, migration, and tube formation) were evaluated. Myocardial histopathology and endothelial damage were assessed using HE/Masson staining and biochemical assays. Angiogenesis in the infarct border zone was visualized by platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) immunofluorescence. Ultrastructural changes in MAMs, the endoplasmic reticulum (ER), and mitochondria were observed via transmission electron microscopy (TEM). Intracellular reactive oxygen species (ROS) and calcium (Ca 2+ ) levels were detected using fluorescent probes. Transcriptomic sequencing was performed to identify key therapeutic pathways, followed by validation of the cGMP/PKG axis and MAMs-associated proteins (including cGMP, PKG, IP3R2, GRP75, FUNDC1, VDAC1, CYPD, and MCU) using ELISA, Western blotting, and immunofluorescence.
RESULTS: Echocardiography and biochemical analysis demonstrated that high-dose YQHX demonstrated comparable efficacy to the first-line clinical drug Perindopril in preserving cardiac function and mitigating myocardial injury. Immunofluorescence revealed that while the infarct border zone in the MI group exhibited disordered and dysfunctional capillary proliferation, YQHX treatment promoted the formation of organized and functional microvessels. TEM revealed significant disruption of MAMs ultrastructure post-MI. Furthermore, the colocalization of IP3R2 and VDAC1 was markedly reduced in MI tissues and hypoxic HUVECs, an effect that was reversed by YQHX. Transcriptomic analysis identified the cGMP/PKG pathway as a pivotal mechanism. Activation of this pathway by YQHX restored MAMs structural integrity and rescued impaired cytosolic Ca2+ signaling, as confirmed by TEM, Western blotting, triple-labeling immunofluorescence, and calcium assays. Consequently, YQHX-mediated MAMs repair enhanced HUVEC proliferation, migration, and angiogenic capacity.
CONCLUSION: This study demonstrates that MI/hypoxia impairs endothelial function by disrupting the structural and functional integrity of MAMs. YQHX effectively preserves MAMs architecture and restores intracellular Ca2+ signaling via the cGMP/PKG signaling axis, thereby promoting post-MI angiogenesis and improving cardiac performance. These findings identify a novel therapeutic target for MI and highlight the unique advantages of traditional Chinese medicine formulas in modulating subcellular organelle interactions.However, given the inherent variability of botanical materials, these mechanistic findings are based on a single validated batch, and future multi-batch standardizations are warranted.

Keywords:  Angiogenesis; Cytosolic Ca(2+) signaling; Mitochondria-associated membranes (MAMs); Myocardial infarction; cGMP/PKG pathway

DOI:  https://doi.org/10.1016/j.jep.2026.121936
J Biol Chem. 2026 May 30. pii: S0021-9258(26)02087-9. [Epub ahead of print] 113215

GRP75 Chaperone-driven Mitochondria-ER Membrane Coupling Promotes Ca2+-Dependent ROS Accumulation and Ferroptosis During Hypoxic Stress.

Haoxiao Yan, Penggeng Chen, Yaoyi Zhang, Qishuang He, Hao Liu, Qiao Liu, Kaige Song, Song Yang, Liulan Zhao.

  Ferroptosis is a recently identified form of regulated cell death triggered by the accumulation of iron-dependent lipid peroxides. Nevertheless, the exact function and mechanism of ferroptosis in oxidative stress injury caused by environmental challenges, especially in hypoxic stress, remains unknown. Here, we demonstrate that hypoxic stress induces an aberrant increase in mitochondria-associated ER membrane (MAM) formation both in vitro and in vivo in largemouth bass. Transcriptome analysis reveals significant upregulation of the ferroptosis pathway. Combining transcriptomics, western blot, and immunostaining results, we identify GRP75 as a key regulator of MAM formation under hypoxic conditions. Further studies demonstrate that silencing GRP75 protects hepatocytes from hypoxia-induced cellular damage hallmarked by ferroptosis. Mechanistically, the excessive formation of MAM caused by GRP75 accelerating Ca2+ transfer, mediating mitochondrial and ER dysfunction, leading to ROS accumulation. Based on these findings, MAMs are considered an essential component in the execution of ferroptosis.

Keywords:  Aquatic organisms; Ferroptosis; Hypoxic stress; IP3R1-GRP75-VDAC1 complex; Mitochondria-associated ER membranes

DOI:  https://doi.org/10.1016/j.jbc.2026.113215
Sci China Life Sci. 2026 May 27.

Docosahexaenoic acid alleviates Ornidazole toxicity related to spermatogenic dysfunction by modulating PPARγ-dependent ER-mitochondrial uncoupling.

Chuwei Li, Shanmeizi Zhao, Chongli Shi, Shanshan Sun, Zhaowanyue He, Yao Xu, Lu Zheng, Ting Tang, Shengjie Qiu, Kuan Liang, Hong Zhang, Zhichuan Zou, Yuming Feng, Min Zang, Jie Dong, Jinzhao Ma, Rujun Ma, Chuanhai Fu, Xie Ge, Yong Wang, Jun Jing, Bing Yao.

  Male infertility has been increasing globally, raising concerns for reproductive health. Ornidazole (ORN) emerges as a novel environmental pollutant and compromises male fertility. However, the protective role and underlying mechanisms of docosahexaenoic acid (DHA) against ORN-induced testicular damage remain unexplored. Our clinical data showed that elevated serum ORN levels were negatively correlated with sperm quality. In vivo, ORN exposure led to impaired spermatogenesis, including meiotic disorders. Specifically, ORN impaired redox balance and reduced the expression of mitochondrial respiratory chain proteins (Ndufs1 and SdhB) in spermatocytes. Supplementation with docosahexaenoic acid significantly restored the quantity of DDX4-positive germ cells and SYCP3-positive spermatocytes and facilitated the progression from zygotene to pachytene stage. Mechanistically, DHA restored mitochondrial function and ROS levels by stimulating peroxisome proliferator-activated receptor gamma (PPARγ) signaling. Moreover, DHA reduced the expression of mitochondria-associated endoplasmic reticulum membranes (MAMs)-tethered voltage-dependent anion channel 1 (VDAC1), restoring MAMs balance and mitochondrial calcium homeostasis in a PPARγ-dependent manner. The DHA/PPARγ/VDAC1 axis in spermatocytes functions as a critical metabolic switch for regulating MAMs and ensuring mitochondrial homeostasis during meiosis. DHA is a promising therapeutic metabolite for oligoasthenozoospermia induced by environmental pollution.

Keywords:  Ornidazole; docosahexaenoic acid; mitochondria-associated membranes; mitochondrial calcium overload; spermatogenesis

DOI:  https://doi.org/10.1007/s11427-025-3314-1
J Cell Biol. 2026 Jul 06. pii: e202602009. [Epub ahead of print]225(7):

Seipin: A central lipid rheostat.

Abdou Rachid Thiam, Maxime Carpentier.

Seipin is a conformationally flexible, oligomeric scaffold that regulates cellular lipid homeostasis beyond lipid droplet (LD) biogenesis. Seipin senses local lipid composition and membrane features to direct metabolic flux toward specific pathways and organelles. Its ring adopts multiple conformations, influenced by cofactors such as the LD assembly factor 1 and adipogenin, as well as lipid ligands including phosphatidic acid, diacylglycerol, and triacylglycerol, conferring broad functional versatility. Although seipin is an ER-resident protein primarily enriched at ER-LD junctions, a fraction relocates to mitochondria-associated membranes under specific metabolic conditions, where it regulates lipid synthesis, turnover, and local Ca2+ levels, thereby facilitating interorganelle communication and maintaining metabolic stability. Seipin dysfunction disrupts this multinodal regulation, causing lipid imbalance, organelle abnormalities, and a range of metabolic and neuronal disorders. We propose a unified model in which seipin functions as a multistate proteolipid regulatory hub: a rheostat whose structure and interactome dynamically adjust to control lipid pathway decisions in response to metabolic signals across organelle contact networks.

DOI: https://doi.org/10.1083/jcb.202602009
Mol Biol Cell. 2026 Jun 03. mbcE25110531

A GUV-based assay to reconstitute membrane tethering in vitro.

Devika Andhare, Michael J Ragusa.

Membrane tethering is essential for the generation of organelle contact sites, the catabolic process of autophagy and to anchor incoming vesicles to their target membranes before vesicle fusion. While membrane tethering is critical for cellular function, many of the current biochemical techniques to test for membrane tethering rely on indirect readouts and are limited in their ability to monitor protein localization at sites of tethering. As such, we recently developed a fluorescence microscopy-based giant unilamellar vesicle and liposome tethering assay (GLT) to study the membrane tethering properties of two autophagy proteins. In this study, we used GLT with engineered membrane tethers to demonstrate the ease of use, methods of analysis, versatility and sensitivity of the assay. We demonstrate that: 1) GLT can be used to study liposome tethering, fusion and phosphatase mediated detethering of tethered liposomes, 2) GLT detects tethering with comparable sensitivity to less direct methods for monitoring membrane tethering while allowing simultaneous monitoring of membrane and protein localization, and 3) GLT can be used to monitor the kinetics of membrane tethering in real time. Collectively, our results demonstrate GLT is a broadly useful method to study membrane tethering in vitro. [Media: see text] [Media: see text].

DOI: https://doi.org/10.1091/mbc.E25-11-0531
Circ Res. 2026 Jun 04.

ATAD3A Limits Aortic Dissection via Mito-Lysosome Contacts and Lipoylation.

Jie Lin, Shengjun Xiong, Ying An, Lin Wu, Yuxin Du, Yiran E Li, Yujie Wu, Zunhui Du, Wenjun Yu, Junbo Ge, Yingmei Zhang, Jun Ren.

   BACKGROUND: Aortic aneurysm and dissection (AAD) is a fatal vascular emergency with limited mechanism-based therapies. The mitochondrial AAA+ ATPase ATAD3A (ATPase family AAA domain-containing protein 3A), enriched at organelle contact sites, has been implicated in mitochondrial signaling, but its role in AAD remains unclear.
METHODS: AAD was induced in wild-type, ATAD3A knock-in, and vascular smooth muscle cell (VSMC)-specific knockdown (sh-ATAD3A) mice by 3-week β-aminopropionitrile monofumarate intake or 28-day AngII (angiotensin II) infusion via osmotic minipumps. Aortic dilatation, dissection incidence, rupture-related mortality, and histology were assessed. Vascular smooth muscle cells were stimulated with AngII in vitro. Mitochondrial function was evaluated using Seahorse bioenergetics, membrane potential assay, and Ca2+ imaging. ATAD3A-DLST (dihydrolipoamide S-succinyltransferase) interaction was examined by coimmunoprecipitation. Pharmacological modulation was performed with the copper chelator tetrathiomolybdate and the lipoylation inhibitor devimistat.
RESULTS: ATAD3A expression was upregulated in human thoracic aortic dissection samples and in β-aminopropionitrile monofumarate-treated mouse aortas, with early downregulation then late upregulation in VSMCs. Systemic ATAD3A overexpression mitigated β-aminopropionitrile monofumarate-induced and AngII-induced aortic dilatation, reduced dilation incidence, and improved survival, whereas VSMC-specific knockdown accelerated vascular pathology. Mechanistically, ATAD3A overexpression reduced mitochondria-lysosome contacts, limited mitochondrial Ca2+ influx, and suppressed the FDXR (ferredoxin reductase)/FDX1 (ferredoxin 1)/LIAS (lipoic acid synthetase) lipoylation pathway, decreasing DLST lipoylation and restraining cuproptosis, thereby preserving VSMC viability and delaying AAD progression. Pharmacological inhibition of cuproptosis using tetrathiomolybdate or Devimistat attenuated disease severity in vivo.
CONCLUSIONS: ATAD3A protects against AAD by coordinating organelle contact and metabolic signaling to restrain mitochondrial Ca2+ influx, NADPH flux, and DLST lipoylation-dependent cuproptosis in VSMCs. Targeting the ATAD3A-DLST-cuproptosis axis offers mechanistic insight and therapeutic potential for AAD.

Keywords:  aminopropionitrile; aortic aneurysm; calcium; dissection, thoracic aorta; mitochondria

DOI:  https://doi.org/10.1161/CIRCRESAHA.125.327965
Free Radic Biol Med. 2026 Jun 03. pii: S0891-5849(26)00848-8. [Epub ahead of print]

Plasma - Activated Medium Engages Redox Signaling to Activate a VDAC1-TRPML1 Lysosomal-Mitochondrial Ca2+ Death Pathway.

Pengpeng Huang, Yan Zheng, Chuanzan Zhou, Chengbiao Ding, Qi Zhang, Dechao Feng, Zhengwei Wu.

  Plasma-activated medium (PAM), a redox-active anticancer modality, induces cytotoxicity in multiple tumor models, but the mechanisms underlying PAM-induced tumor cell death remain incompletely understood. Here, using A549 lung cancer cells together with additional tumor models, we identify a lysosome - mitochondria Ca2+ circuit that drives a distinct form of PAM-induced tumor-selective cell death. PAM promotes the coupling of the lysosomal Ca2+ channel TRPML1 to the mitochondrial outer membrane protein VDAC1 at organelle contact sites, leading to lysosomal Ca2+ release, mitochondrial Ca2+ overload, membrane depolarization, cytochrome c release, and cell death. Mechanistically, PAM suppresses mTORC2 - SGK1 signaling, reduces VDAC1 phosphorylation at Ser104, and stabilizes VDAC1 on mitochondria. Accumulated VDAC1 then engages TRPML1 through Lys109 and Arg163 to facilitate pathological Ca2+ transfer. Disrupting this interface, or restoring phosphomimetic control of VDAC1, attenuated mitochondrial Ca2+ overload, improved cell survival, and weakened the antitumor effect of PAM in vivo. Pan-cancer analyses further suggested that although high VDAC1 expression is associated with poor prognosis, it may help stratify tumors more likely to respond to PAM. Together, these findings establish the VDAC1 - TRPML1 axis as a key mechanistic link between PAM-induced redox stress and lysosome - mitochondria Ca2+-dependent tumor cell death, and highlight this pathway as a potential therapeutic target and response biomarker.

Keywords:  Mitochondria; Mitochondrial calcium overload; Plasma Activated Medium; Ubiquitination; VDAC1-TRPML1 interaction sites; lysosome crosstalk

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.06.003