bims-miptne 2025-11-09 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2025–11–09
eight papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Cell-type-specific dysregulation of mitochondrial calcium signaling in Alzheimer's disease.
Cyclophilin D is a new non-canonical substrate of the mitochondrial intermembrane space assembly pathway.
The mitochondrial calcium uniporter regulates calcium dynamics to drive platelet function, bioenergetics, and thrombosis.
Hydroxyapatite and doxorubicin-laden nanotherapeutics for effective multimodality cancer treatment boosted via mitochondrial calcium overload.
The mitochondrial-targeted antioxidant SkQ1 prevents skeletal muscle mitochondrial-apoptotic but not necroptotic signalling during ovarian cancer.
Dexmedetomidine protects against postoperative neurocognitive disorder by mitigating mitochondrial dysfunction through regulating the IP3R-GRP75-VDAC1 complex-mediated calcium transport.
Cardioprotection via vagus nerve stimulation preconditioning: Reducing ischaemia-reperfusion injury and arrhythmic risk.
The mitochondrial nexus: Targeting metabolic vulnerabilities, oxidative stress, and immunomodulation to induce cancer cell death.

Cell Commun Signal. 2025 Nov 03. 23(1): 472

Cell-type-specific dysregulation of mitochondrial calcium signaling in Alzheimer's disease.

Shatakshi Shukla, Ashlesha A Kadam, Shanikumar Goyani, Natasha Jaiswal, Kunal Samantaray, Shiridhar Kashyap, Dhanendra Tomar, Pooja Jadiya.

   BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid plaques, tau tangles, and synaptic dysfunction. Despite decades of research, effective disease-modifying therapies remain elusive, highlighting the need for alternative therapeutic targets. While neurons have traditionally been the focus of AD studies, increasing evidence underscores critical roles for glial cells particularly microglia and astrocytes in disease progression. Mitochondrial calcium (mCa2+) dysregulation has emerged as a key contributor to neurodegeneration, yet how mCa2⁺ signaling varies across brain cell types and contributes to AD pathology remains poorly understood.
METHODS: We developed stable human SH-SY5Y (neuroblastoma-derived cells), HMC3 (microglial-like cells), and SVGp12 (astrocytic-like cells) immortalized cell lines expressing APP mutations (Swedish, Florida, and London; APPswe/F/L). We assessed mitochondrial calcium uniporter (mtCU) expression, mCa2+ flux using ratiometric calcium (Ca2+) indicators, and evaluated calcium retention capacity (mito-CRC) as a readout of mitochondrial permeability transition pore opening. Bioenergetic parameters including ATP, NADH, membrane potential, and oxygen consumption rate (OCR) were measured alongside structural mitochondrial changes, ROS levels, and cell death using imaging and biochemical assays.
RESULTS: APPswe/F/L expression induced mitochondrial dysfunction across all brain immortalized cell types, with neuroblastoma-derived cells exhibiting the highest susceptibility to mCa2+ overload, energy failure, and cell death. Compared to neuroblastoma-derived cells, glial-like cells (astrocytic-like and microglial-like cells) showed higher expression of mtCU components, elevated mCa2+ uptake at high Ca²⁺ concentrations, and greater mito-CRC. Conversely, neuroblastoma-derived cells displayed faster mCa2+ uptake at low Ca2+ levels, indicating distinct regulatory thresholds. Glial-like cells exhibited more elaborate mitochondrial networks and enhanced metabolic capacity, yet all cell types showed impaired mitochondrial structure, reduced membrane potential and respiration, and increased ROS under mutant APP expression.
CONCLUSIONS: This study reveals cell-type-specific differences in mCa2+ signaling and mitochondrial function in AD, uncovering unique vulnerabilities in neuroblastoma-derived and glial-like cells. These findings highlight the need for cell-targeted strategies to restore mCa2+ homeostasis and mitochondrial function in AD.

Keywords:  Alzheimer’s disease; Cell death; Cell-type specificity; Glial-like cells; Mitochondrial bioenergetics; Mitochondrial calcium; Neuroblastoma-derived cells; Oxidative stress

DOI:  https://doi.org/10.1186/s12964-025-02460-0
J Biol Chem. 2025 Nov 04. pii: S0021-9258(25)02735-8. [Epub ahead of print] 110883

Cyclophilin D is a new non-canonical substrate of the mitochondrial intermembrane space assembly pathway.

Mara Equisoain Redin, Veronica Bazzani, Eve Harding, Joshua McHale, Carlo Vascotto.

  Mitochondrial protein import is essential for organelle function and cellular homeostasis. While Cyclophilin D (CypD) is a well-characterized regulator of the mitochondrial permeability transition pore (MPTP) and resides in the matrix, the mechanisms underlying its import remain poorly defined. In this study, we identify CypD as a novel non-canonical substrate of the mitochondrial intermembrane space assembly (MIA) pathway mediated by the oxidoreductase Mia40. Structural analysis revealed conserved cysteine pairs in CypD that are compatible with disulfide bond formation. Using in vitro pull-down assays, we demonstrate a redox-sensitive interaction between CypD and Mia40, which was further confirmed by co-immunoprecipitation and proximity ligation assays. Expression of CypD cysteine mutants in cells revealed that residues Cys82 and Cys203 are critical for Mia40-dependent interaction and protein stability. Notably, expression of the Cys203Ala mutant significantly reduced cell viability, suggesting a key functional role for this residue. Functional experiments showed that depletion of Mia40 leads to a significant reduction in mitochondrial CypD levels, a result that was confirmed in a series of leukemia cell lines with variable Mia40 expression. Our results shed light on a previously unrecognized import mechanism for CypD and expand the known substrate repertoire of Mia40, demonstrating that the MIA pathway also contributes to the import of mitochondrial matrix proteins. This work highlights the functional versatility of the MIA pathway beyond the intermembrane space and reveals an additional regulatory level in mitochondrial proteostasis with implications for cell death signalling and mitochondrial pathophysiology.

Keywords:  Cyclophilin D; Mia40; mitochondria; protein import; redox

DOI:  https://doi.org/10.1016/j.jbc.2025.110883
J Thromb Haemost. 2025 Nov 04. pii: S1538-7836(25)00719-6. [Epub ahead of print]

The mitochondrial calcium uniporter regulates calcium dynamics to drive platelet function, bioenergetics, and thrombosis.

Madankumar Ghatge, Gagan D Flora, Rakesh B Patel, Manasa K Nayak, Mariia Kumskova, Tam Nguyen, Yuriy M Usachev, Anil K Chauhan.

   BACKGROUND: The mitochondrial calcium uniporter (MCU), a selective Ca2+ channel, mediates mitochondrial Ca2+ uptake, supporting Ca2+ homeostasis and mitochondrial bioenergetics. While cytosolic Ca2+ flux from the dense tubular system (DTS) and store-operated Ca2+ entry (SOCE) are known to drive platelet activation, the role of mitochondrial Ca2+ handling in platelet function and thrombosis is not well understood.
OBJECTIVE: To examine whether targeting MCU-dependent Ca2+ flux could attenuate platelet activation and arterial thrombosis.
METHODS: Susceptibility to arterial thrombosis was assessed using the FeCl3-induced carotid injury model in WT and MCU-/- mice. Mitochondrial and cytosolic Ca2+ levels were measured in Rhod-2- and Fura-2-loaded platelets by fluorometry, and platelet bioenergetics were analyzed using a Seahorse extracellular flux analyzer.
RESULTS: Genetic ablation of MCU inhibited agonist-induced platelet functions, including aggregation, fibrinogen binding to integrin αIIbβ3, granule secretion, and spreading on fibrinogen. MCU-/- mice were less susceptible to in vivo arterial thrombosis with unaltered tail bleeding time, suggesting normal hemostasis. Mechanistically, these effects were associated with disruption of Ca2+ homeostasis mediated by reduced mitochondrial Ca2+ uptake, altered release of Ca2+ from DTS, and impaired SOCE in agonist-stimulated MCU-/- platelets. Consistent with this, Ca2+-dependent GPVI signaling events such as PLCγ2 and PKC substrate phosphorylation were significantly reduced in collagen-stimulated MCU-/- platelets. Furthermore, disruption of mitochondrial Ca2+ uptake significantly impaired mitochondrial respiration and associated ATP production in agonist-stimulated MCU-/- platelets.
CONCLUSION: MCU facilitates platelet activation and thrombosis by regulating calcium flux (mitochondrial and cytosolic), thereby establishing its potential as a target for antithrombotic therapeutic intervention.

Keywords:  OXPHOS; aerobic glycolysis; mitochondrial calcium uniporter; platelet activation; thrombosis

DOI:  https://doi.org/10.1016/j.jtha.2025.10.019
J Control Release. 2025 Nov 02. pii: S0168-3659(25)00982-4. [Epub ahead of print]388(Pt 2): 114368

Hydroxyapatite and doxorubicin-laden nanotherapeutics for effective multimodality cancer treatment boosted via mitochondrial calcium overload.

Yi-Shou Chang, Arjun Sabu, Manoj Kandel, Chun-Liang Lo, Ekta Roy, Lakshminarayan Ramesan, You-Tien Chang, Hsin-Cheng Chiu.

  A new nanotherapeutic system comprising palladium-deposited bismuth sulfide (Pd/Bi2S3) nanoparticles (NPs) as the primary component, loaded with doxorubicin (DOX) and coated with PEG-modified hydroxyapatite/mesoporous silica (HAP/MPS) layers, was developed for the treatment of triple-negative breast cancer. In addition to chemotherapy using DOX, the nanotherapeutic system was characterized by pronounced photothermal properties through in situ Pd growth at NP interfaces and stimulus-responsive intracellular calcium release by HAP decoration. The acid-triggered calcium release from HAP of the NPs within cancer cells resulted in intracellular calcium overload, thereby inducing prolonged opening of mitochondrial permeability transition pores and mitochondrial dysfunction and sensitizing cancer cells to both chemo- and photothermal therapies. The cell viability of 4 T1 breast cancer cells, when treated by either chemotherapy or photothermal therapy in combination with calcium overload treatment, was significantly reduced compared to the single modality regimens lacking the calcium overload effect. The combined photothermal/chemotherapy efficacy was boosted with calcium overload as demonstrated by a more pronounced reduction in cell viability against 4 T1 breast cancer cells. The in vivo data indicated an almost complete eradication of orthotopic breast cancer in the 4 T1 tumor-bearing mice treated with the NP-based calcium-mediated chemo/photothermal combined therapy, along with a significant reduction in lung metastasis as compared to the appreciable tumor nodules observed in the lungs from the combined therapy in the absence of calcium aid. The results indicate that the NP-based calcium overload strategy is an effective and essential auxiliary modality for sensitizing cancer cells to both chemo- and photothermal therapies.

Keywords:  Calcium overload; Cancer therapy; Chemo/photothermal therapy; Drug delivery system; Mitochondrial damage; Pd-deposited bismuth sulfide nanoparticles

DOI:  https://doi.org/10.1016/j.jconrel.2025.114368
J Physiol. 2025 Nov 02.

The mitochondrial-targeted antioxidant SkQ1 prevents skeletal muscle mitochondrial-apoptotic but not necroptotic signalling during ovarian cancer.

Shahrzad Khajehzadehshoushtar, Luca J Delfinis, Fasih A Rahman, Madison C Garibotti, Shivam Gandhi, Aditya N Brahmbhatt, Brooke A Morris, Bianca Garlisi, Sylvia Lauks, Caroline Aitken, Leslie Ogilvie, Zhu-Xu Zhang, Jeremy A Simpson, Joe Quadrilatero, Jim Petrik, Christopher G R Perry.

  The degree to which mitochondrial-linked programmed cell death pathways contribute to skeletal muscle atrophy during cancer remains unknown. Here we combined a novel and robust mouse model of metastatic ovarian cancer with chronic administration of the mitochondrial-targeted antioxidant SkQ1 to determine the time-dependent and muscle-specific relationships of mitochondrial-linked apoptotic and necroptotic signalling to the development of muscle atrophy in the type IIB-rich gastrocnemius. Early-stage ovarian cancer reduced type IIB fibre cross-sectional area in the gastrocnemius but did not alter mitochondrial H2O2 emission despite increased activities of mitochondrial-linked caspase-9 and -3 regulators of apoptosis. During late-stage ovarian cancer sustained atrophy was associated with increased mitochondrial H2O2 emission potential in vitro, a greater probability of calcium-triggered mitochondrial permeability transition and increases in downstream caspase-9 and -3 activities. SkQ1 attenuated mitochondrial H2O2 emission and caspase-9 and -3 activities in late-stage ovarian cancer but did not prevent atrophy. Necroptosis markers were heterogeneous across time with total RIPK1 increasing during early-stage cancer, which reverted to normal levels by late stages, whereas phosphorylated RIPK3 decreased below control levels. These discoveries indicate that preventing increases in mitochondrial-linked apoptotic caspase-9 and -3 activities during late-stage ovarian cancer with SkQ1 does not prevent atrophy of type II B fibres. Furthermore necroptotic markers are inconclusive during cancer in this muscle type but are not modified by SkQ1. These results do not support a causal relationship between mitochondrial H2O2-linked apoptotic or necroptotic signalling and atrophy in type IIB fibres during ovarian cancer but do not rule out potential relationships in other muscle types. KEY POINTS: Cancer increases mitochondrial reactive oxygen species (ROS) in skeletal muscle during atrophy, but the role of ROS in regulating cell death remains unknown. We show that attenuating gastrocnemius mitochondrial ROS with the mitochondrial-targeted antioxidant SkQ1 prevented mitochondrial-linked pro-apoptotic caspase 9- and -3 activities but did not affect markers of necroptosis in a mouse model of ovarian cancer. Reductions in gastrocnemius muscle fibre cross-sectional areas and the wet weights of several muscles were not prevented by SkQ1. These findings demonstrate that mitochondrial ROS regulate apoptotic caspases but not necroptotic proteins, and neither pathway is linked to gastrocnemius atrophy in mice with ovarian cancer. The degree to which mitochondrial ROS-linked cell death pathways regulate muscle mass in other muscle types and cancer models requires further investigation.

Keywords:  apoptosis; cachexia; mitochondria; necroptosis; ovarian cancer; skeletal muscle

DOI:  https://doi.org/10.1113/JP287912
Immunol Res. 2025 Nov 06. 73(1): 156

Dexmedetomidine protects against postoperative neurocognitive disorder by mitigating mitochondrial dysfunction through regulating the IP3R-GRP75-VDAC1 complex-mediated calcium transport.

Qifan Huo, Yuming Zhang, Jianwei Guo, Yan-An Jiang, Jing Zhao.

  Dexmedetomidine (Dex), an α2 adrenergic receptor agonist, has been shown to exert protective effects against postoperative neurocognitive disorder (PND) following anesthesia and surgery. This study aimed to investigate the underlying mechanisms, with a focus on the inositol 1,4,5-triphosphate receptor (IP3R)-voltage-dependent anion channel 1 (VDAC1)-chaperone glucose-regulated protein 75 (GRP75) calcium transport protein complex-mediated mitochondrial dysfunction. An in vitro sevoflurane-induced SH-SY5Y cell injury model and an in vivo PND rat model induced by sevoflurane anesthesia plus laparotomy were established, and both models were pretreated with Dex. Subsequent assessment included cell viability, apoptosis, inflammatory cytokines, reactive oxygen species (ROS), mitochondrial calcium ion (Ca2+), mitochondrial membrane potential (MMP), mitochondrial ultrastructure, and ATP production. Cognitive functions including spatial memory, anxiety-like behavior, and recognition memory were evaluated in rats. The expression levels and interactions among IP3R, GRP75, and VDAC1 were examined to elucidate the mechanisms involved. Sevoflurane exposure reduced cell viability, increased apoptosis and inflammation, and induced mitochondrial impairments including ROS overproduction, Ca2+ overload, loss of MMP, ultrastructural damage, and reduced ATP production. Dex pretreatment effectively alleviated all these cellular injuries. Furthermore, Dex alleviated cognitive deficits in PND rats and mitigated neuronal loss, histological damage, apoptosis, neuroinflammation, and mitochondrial ultrastructural damage in hippocampal tissues. Mechanistically, Dex reversed sevoflurane-induced upregulation of IP3R, GRP75, and VDAC1 and disrupted their enhanced interaction. VDAC1 exhibited the most pronounced changes in response to both sevoflurane injury and Dex treatment. Rescue experiments suggested that VDAC1 overexpression abrogated Dex-mediated mitochondrial protection. Dex alleviates cognitive deficits in PND rats by preserving mitochondrial calcium homeostasis and mitigating mitochondrial dysfunction through regulating the IP3R-GRP75-VDAC1 complex. This study may provide critical insights into the neuroprotective mechanisms of Dex in PND and identify potential therapeutic targets.

Keywords:  Dexmedetomidine; IP3R-GRP75-VDAC1 complex; Mitochondrial calcium homeostasis; Mitochondrial dysfunction; Postoperative neurocognitive disorder; Sevoflurane

DOI:  https://doi.org/10.1007/s12026-025-09705-7
Exp Physiol. 2025 Nov 06.

Cardioprotection via vagus nerve stimulation preconditioning: Reducing ischaemia-reperfusion injury and arrhythmic risk.

Feng Hu, Yali Wang, Guangyu Li, Guangyu Wang, Qi Zhuang, Jinyao Jiang, Danfeng Hu, Lihui Zheng, Yan Yao, Minhua Zang, Jun Pu.

  Acute myocardial infarction is a leading cause of morbidity and mortality, with ischaemia-reperfusion (I/R) injury exacerbating myocardial damage. Vagus nerve stimulation (VNS) has been reported to exert cardioprotective effects, but its efficacy in preconditioning against I/R injury requires further investigation. We evaluated the cardioprotective effects of VNS preconditioning in a rat model of acute myocardial infarction with induced I/R injury. Sixty rats were randomized into Pre-VNS, Control and Sham groups. The Pre-VNS group received 1 week of low-level cervical VNS before induction of I/R injury; stimulation was deactivated 30 min before ischaemia. Survival, echocardiographic function, reperfusion arrhythmias, arrhythmia inducibility, infarct size, apoptosis and inflammatory cytokines were assessed. Survival did not differ significantly between Pre-VNS and Control groups (75.0% vs. 65.0%, p = 0.497). However, Pre-VNS animals exhibited preserved cardiac function, with higher ejection fraction and fractional shortening (p < 0.001). VNS preconditioning reduced the incidence of reperfusion arrhythmia during left anterior descending coronary artery ligature release (p = 0.006) and decreased the arrhythmia index on programmed stimulation (p = 0.003). Infarct size and cardiomyocyte apoptosis were significantly attenuated (p < 0.001), accompanied by markedly lower serum interleukin-1β, interleukin-6 and tumour necrosis factor-alpha levels (p < 0.001). VNS preconditioning effectively mitigates I/R injury by improving cardiac function, reducing infarct size and arrhythmias, and attenuating inflammatory and apoptotic responses.

Keywords:  cardiac function; ischaemia–reperfusion injury; myocardial infarction; reperfusion arrhythmias; vagus nerve stimulation

DOI:  https://doi.org/10.1113/EP092950
Biochim Biophys Acta Rev Cancer. 2025 Oct 31. pii: S0304-419X(25)00233-1. [Epub ahead of print]1880(6): 189491

The mitochondrial nexus: Targeting metabolic vulnerabilities, oxidative stress, and immunomodulation to induce cancer cell death.

Woo Hyun Park.

  Mitochondria, far from being mere cellular powerhouses, act as central command hubs dictating cell fate by integrating metabolic cues with life-or-death decisions. In cancer, these organelles undergo profound functional and structural reprogramming to support relentless proliferation, survival, and adaptation to stress. This metabolic plasticity, however, creates unique vulnerabilities exploitable for therapeutic gain. This comprehensive review synthesizes recent insights into the multifaceted roles of mitochondria in cancer, focusing on how inhibiting their core functions can trigger diverse cell death pathways and modulate the tumor microenvironment. This paper delves into the central role of mitochondria in orchestrating various forms of regulated cell death (RCD), including apoptosis, ferroptosis, necroptosis, and the newly defined cuproptosis. A primary focus is placed on the dual nature of mitochondrial reactive oxygen species (ROS), which can promote tumorigenesis but can also be pharmacologically elevated to catastrophic levels, triggering oxidative stress-induced demise. This review systematically categorizes and discusses a burgeoning pharmacopeia of mitochondrial inhibitors-targeting the electron transport chain (ETC), metabolic enzymes like glutaminase, protein homeostasis, and ion channels-and analyzes their mechanisms of action, preclinical evidence, and clinical translation status. Furthermore, this paper examines how these agents can overcome chemoresistance and synergize with existing treatments, including the exciting interface with immunotherapy, where mitochondrial fitness is paramount for robust anti-tumor T-cell responses and the induction of immunogenic cell death (ICD). By dissecting the complex interplay between mitochondrial inhibition, metabolic disruption, oxidative stress, and cell death, this review highlights the immense promise of mitochondria-targeted therapies and charts the course for future innovations in oncology.

Keywords:  Cancer metabolism; Immunotherapy; Mitochondria; Oxidative stress; Regulated cell death; Targeted therapy

DOI:  https://doi.org/10.1016/j.bbcan.2025.189491