bims-miptne 2026-01-18 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2026–01–18
eleven papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Bedaquiline inhibits the ATP synthase leak channel and prevents glutamate-induced neuronal death.
Parkin Deficiency Impairs ER-Mitochondria Associations and calcium homeostasis via IP3R-Grp75-VDAC1 Complex.
Hexokinase detachment from mitochondria drives the Warburg effect to support compartmentalized ATP production.
The myocardial ischemic cascade network and multi-target synergistic interventions: From molecular mechanisms to therapeutic innovations.
Substitution of Mg2+ cofactor with Ca2+ disrupts positive cooperativity in F1FO-ATP(hydrol)ase catalysis.
Mitochondria-ER crosstalk via MAMS: Bridging cellular homeostasis and cancer progression.
Starvation induces a transition from autophagy to apoptosis via the ER-Ca2+-calpain signaling axis in the fat body of Bombyx mori.
New mitochondrial KV1.3 conjugates are potent and specific inducers of apoptosis in cancer models.
RIPK3-driven phosphorylation of MFN2 orchestrates endoplasmic reticulum-mitochondria interaction and cardiomyocyte stress responses.
Tumor cell death by ferroptosis contributes to an immunosuppressive tumor microenvironment in syngeneic murine models of cancer.
Daily briefing: Cancer cells stay hidden using stolen mitochondria.

bioRxiv. 2026 Jan 06. pii: 2026.01.05.697836. [Epub ahead of print]

Bedaquiline inhibits the ATP synthase leak channel and prevents glutamate-induced neuronal death.

Amrendra Kumar, Erin Smith, Ikram Mezghani, Subhash Eedarapalli, Yangyu Wu, Khondoker Adeba Ferdous, Emma Amjad, Han-A Park, Nelli Mnatsakanyan.

F O F 1 -ATP synthase is one of the most abundant proteins of the mitochondrial inner membrane and the primary enzyme responsible for ATP production in eukaryotic cells. Nevertheless, it was recently reported to play a prominent role in cell death by forming a large-conductance leak channel in the mitochondrial permeability transition pore (mPTP), making it a promising therapeutic target. Bedaquiline (BDQ), a member of the diarylquinoline class of drugs, was shown to selectively inhibit the catalytic activity of Mycobacterium tuberculosis ATP synthase with no effect on the mammalian enzyme. Here, we report a new role for BDQ as a potent inhibitor of the ATP synthase c-subunit leak channel in mammals. BDQ inhibited the single-channel activity of porcine heart ATP synthase in planar lipid bilayer recordings and prevented glutamate-induced cell death in primary hippocampal neurons. These findings reveal the potential new application of BDQ for treating mPTP-related diseases by targeting the ATP synthase c-subunit leak channel.
Why it matters: Bedaquiline (BDQ) is the only FDA-approved drug to treat pulmonary multidrug-resistant tuberculosis (TB), caused by the Mycobacterium tuberculosis . BDQ cures TB by specifically targeting mycobacterial ATP synthase and inhibiting ATP production. Recently, BDQ was also reported to bind to mammalian ATP synthase at the interface between the a and c-subunits and to inhibit its catalytic activity. However, the effect of BDQ on ATP synthase leak channel activity has not been explored. Here, we report that BDQ inhibits the ATP synthase c-subunit leak channel (ACLC) activity with an IC50 of ∼24 nM and prevents glutamate-induced neuronal death, suggesting a new therapeutic repurposing of BDQ for treating ACLC-related diseases.

DOI: https://doi.org/10.64898/2026.01.05.697836
Int J Biol Sci. 2026 ;22(2): 731-749

Parkin Deficiency Impairs ER-Mitochondria Associations and calcium homeostasis via IP3R-Grp75-VDAC1 Complex.

Nai-Jia Xue, Yi Liu, Zhi-Hao Lin, Wen-Hao Huang, Feng Zhang, Ran Zheng, Xiao-Li Si, Lu-Yan Gu, Yi Fan, Jia-Li Pu, Bao-Rong Zhang.

  Disruption of mitochondria-associated endoplasmic reticulum membranes (MAMs) and calcium homeostasis has been implicated in the pathogenesis of Parkinson's disease (PD). Parkin, a PD-associated E3 ubiquitin ligase, has been shown to regulate MAM integrity and calcium dynamics. However, the mechanisms of Parkin recruitment and its substrate specificity have not been well understood. This investigation has demonstrated that loss of Parkin enhances ER-mitochondria associations and leads to excessive calcium flux in MAM, resulting in abnormal mitochondrial permeability transition pore (mPTP) opening and decreased cell viability. Further, Parkin physically interacts with IP3R-Grp75-VDAC1 complex at ER-mitochondria contact sites, where it is recruited by IP3R-mediated calcium flux and mitophagy. More importantly, Parkin deficiency leads to the accumulation of IP3R levels, particularly in MAM region. In addition, Parkin fine-tunes the stability of the complex and ubiquitinates IP3R for degradation via the ubiquitin-proteasomal system, ensuring suitable calcium transfer. Taken together, our study reveals a novel role of Parkin in regulating ER-mitochondria contacts, providing insights into PD pathogenesis and potential therapeutic strategies targeting MAMs.

Keywords:  IP3R; Parkin; calcium; mitochondria-associated ER membrane; ubiquitination

DOI:  https://doi.org/10.7150/ijbs.121759
Nat Metab. 2026 Jan 16.

Hexokinase detachment from mitochondria drives the Warburg effect to support compartmentalized ATP production.

Kimberly S Huggler, Kyle M Flickinger, Matthew H Forsberg, Carlos A Mellado Fritz, Gavin R Chang, Meghan F McGuire, Christian M Capitini, Jason R Cantor.

Hexokinase (HK) catalyses the phosphorylation of glucose to glucose 6-phosphate, marking the first step of glucose metabolism. Most cancer cells co-express two homologous HK isoforms, HK1 and HK2, which can each bind the outer mitochondrial membrane (OMM). CRISPR screens performed across hundreds of cancer cell lines indicate that both isoforms are dispensable for growth in conventional culture media. By contrast, HK2 deletion impaired cell growth in human plasma-like medium. Here we show that this conditional HK2 dependence can be traced to the subcellular distribution of HK1. Notably, OMM-detached (cytosolic) rather than OMM-docked HK supports cell growth and aerobic glycolysis (the Warburg effect), an enigmatic phenotype of most proliferating cells. We show that under conditions promoting increased translocation of HK1 to the OMM, HK2 is required for cytosolic HK activity to sustain this phenotype, thereby driving sufficient glycolytic ATP production. Our results reveal a basis for conditional HK2 essentiality and suggest that demand for compartmentalized ATP synthesis explains why cells engage in aerobic glycolysis.

DOI: https://doi.org/10.1038/s42255-025-01428-1
Biochem Pharmacol. 2026 Jan 14. pii: S0006-2952(26)00035-3. [Epub ahead of print] 117704

The myocardial ischemic cascade network and multi-target synergistic interventions: From molecular mechanisms to therapeutic innovations.

Lei Qi, Jia Yi, Yuntian Shen, Haiyan Jiang, Xinlei Yao, Bingqian Chen, Hualin Sun.

  Myocardial ischemic injury involves a multi-layered pathological cascade driven by interconnected energy metabolism disorders, calcium overload, oxidative stress, mitochondrial dysfunction, and inflammatory responses. Ischemia-hypoxia impairs mitochondrial oxidative phosphorylation, causing ATP depletion, acidosis, and calcium overload. Reperfusion exacerbates injury through ROS burst, mPTP opening, and NLRP3 inflammasome activation, leading to pro-inflammatory cytokine release. Sustained endoplasmic reticulum stress promotes apoptosis via the PERK/CHOP pathway, forming a vicious cycle with oxidative stress and inflammation. These processes collectively trigger diverse programmed cell death modalities-apoptosis, pyroptosis, ferroptosis, necroptosis, and cuproptosis-while microcirculatory disturbances cause the "no-reflow" phenomenon, culminating in irreversible damage. Therapeutic strategies are shifting from revascularization to multi-target interventions. Reperfusion injury is mitigated by ischemic conditioning (IPoC, RIC) via RISK/SAFE pathways and ALDH2-SIRT3 axis activation. Cell death is targeted using ferroptosis inhibitors (e.g., Liproxstatin-1), NLRP3/caspase-1 blockers, and autophagy regulators (e.g., Astragaloside IV). Mitochondrial/metabolic therapies include mitochondrial-targeted drugs (e.g., CsA@PLGA-PEG-SS31), metabolic modulators (Trimetazidine), and neuroendocrine agents (ARNI, SGLT2 inhibitors). Regenerative approaches employ stem cells/exosomes, gene therapy, and tissue engineering via paracrine signaling. Precision medicine integrates multi-omics and AI for risk stratification, while biomimetic nanocarriers enhance drug delivery. Future therapies should co-target the "energy-death-inflammation" network to advance myocardial ischemia treatment toward systemic repair and improved clinical outcomes.

Keywords:  Calcium overload; Inflammasome; Mitochondrial permeability transition pore; Multi-target therapy; Myocardial ischemia–reperfusion injury; Programmed cell death

DOI:  https://doi.org/10.1016/j.bcp.2026.117704
Biochim Biophys Acta Bioenerg. 2026 Jan 09. pii: S0005-2728(25)00046-5. [Epub ahead of print] 149580

Substitution of Mg2+ cofactor with Ca2+ disrupts positive cooperativity in F1FO-ATP(hydrol)ase catalysis.

Cristina Algieri, Antonia Cugliari, Fabiana Trombetti, Salvatore Nesci.

  The mitochondrial F1FO-ATPase is a dual-function enzyme that synthesizes ATP using the proton motive force and hydrolyzes ATP to reenergize the membrane. Mg2+ is the physiological cofactor of F1FO-ATPase, enabling both ATP synthesis and hydrolysis, while Ca2+ supports only ATP hydrolysis. Mg2+-dependent F1FO-ATPase exhibits positive cooperativity in ATP hydrolysis Hill coefficient (nHi) of 2.01 ± 0.21, whereas Ca2+-dependent activity shows Michaelian kinetics, nHi 1.41 ± 0.06. Ca2+ acts as an uncompetitive inhibitor on Mg2+-dependent ATP hydrolysis, suggesting distinct binding sites and conformational effects. The differential kinetic behavior underlies the enzyme's multifunctionality of F1FO-ATPase in physio-pathological conditions, depending on the cofactor.

Keywords:  Calcium; Cooperativity; Enzyme catalysis; F(1)F(O)-ATPase; Magnesium; Mitochondria

DOI:  https://doi.org/10.1016/j.bbabio.2025.149580
Apoptosis. 2026 Jan 12. 31(1): 43

Mitochondria-ER crosstalk via MAMS: Bridging cellular homeostasis and cancer progression.

Rohan Roy, Arghya Adhikary, Rudranil De, Swatilekha Ghosh.

  Mitochondria-associated endoplasmic reticulum membranes (MAMs) are dynamic contact points between the endoplasmic reticulum (ER) and mitochondria, governing essential cellular processes such as calcium (Ca²⁺) signaling, lipid metabolism, mitochondrial dynamics, and apoptosis. The effective movement of Ca²⁺ from the ER to mitochondria at MAMs is crucial for sustaining bioenergetics and controlling cell fate outcomes like survival or programmed cell death. Recent findings highlight the importance of MAMs in maintaining cellular balance and demonstrate their functional versatility in both healthy and diseased states. Disruption of MAM integrity and signaling is increasingly linked to the development of various diseases, including cancer. In cancer, MAMs demonstrate two regulatory roles- either promoting oncogenic functions or enhancing tumor-suppressive actions based on the molecular context and cellular environment. Changes in the structural framework of MAMs, such as variations in protein makeup and tethering distance between the ER and mitochondria, have been directly linked to several characteristics of tumor formation. Therefore, a deeper understanding of the molecular components and regulatory mechanisms governing MAM function may offer a promising avenue for the development of novel therapeutic strategies aimed at restoring proper organelle communication and counteracting cancer development and progression.

Keywords:  Autophagy; Calcium signaling; Endoplasmic reticulum stress; Lipid metabolism; Mitochondria-associated membranes

DOI:  https://doi.org/10.1007/s10495-025-02252-4
Insect Biochem Mol Biol. 2026 Jan 12. pii: S0965-1748(26)00018-4. [Epub ahead of print]188 104494

Starvation induces a transition from autophagy to apoptosis via the ER-Ca2+-calpain signaling axis in the fat body of Bombyx mori.

Jialu Cheng, Sheng Zhang, Haoyi Gu, Xueling Qin, Bing Li.

  Nutritional stress is a common environmental challenge for insects in nature. As a central organ of energy metabolism, the fat body plays a crucial role in maintaining energy homeostasis. However, the mechanisms by which the fat body regulates programmed cell death (PCD) during energy crises remain unclear. In this study, the fat body of Bombyx mori was used as a model to investigate the regulatory mechanisms underlying PCD transitions induced by sustained energy depletion. The results indicated that starvation caused a significant reduction in adenosine triphosphate (ATP), rapid depletion of glycogen and triglycerides, and marked inhibition of the endoplasmic reticulum (ER) calcium pump enzyme SERCA. Concurrently, it upregulated the expression of the calcium channel IP3R. These combined effects led to Ca2+ efflux from the ER calcium stores and cytoplasmic Ca2+ overload. Intracellular Ca2+ levels significantly increased, followed by a decrease during prolonged starvation, paralleling changes in calpain activity and accompanied by the upregulation of the proapoptotic protein NtATG5. Short-term starvation promoted autophagy by significantly increasing LC3-II and ATG5 expression, whereas prolonged starvation promoted calpain-mediated cleavage of ATG5 to generate NtATG5 and activated caspase-3, leading to apoptosis. Furthermore, the IP3R inhibitor 2-APB significantly suppressed starvation-induced calcium signaling, autophagy, and apoptosis. This study reveals the regulatory mechanism by which the Bombyx mori fat body modulates PCD under starvation stress via the ER-Ca2+-calpain signaling pathway, providing crucial insights into how nutritional deprivation causes physiological damage in insects.

Keywords:  Bombyx mori; Calcium signal; Calpain; Endoplasmic reticulum stress; Nutritional stress; Programmed cell death

DOI:  https://doi.org/10.1016/j.ibmb.2026.104494
Biomed Pharmacother. 2026 Jan 14. pii: S0753-3322(26)00028-4. [Epub ahead of print]195 118996

New mitochondrial KV1.3 conjugates are potent and specific inducers of apoptosis in cancer models.

Špela Gubič, Marzia Fois, Xiaoyi Shi, Ivan Džajić, Daniela Secci, Katja Kološa, Alja Štern, Joshua A Nasburg, Hai M Nguyen, Veronica Carpanese, Gayathri Viswanathan, Vanessa Checchetto, Maša Omerzel, Tim Božič, Boštjan Markelc, Tanja Jesenko, Maja Čemažar, Ildiko Szabo, Heike Wulff, Bojana Žegura, Tina Kosjek, Andrej Emanuel Cotman, Tihomir Tomašič, Luis A Pardo, Lucija Peterlin Mašič.

  Mitochondrial KV1.3 channels (mitoKV1.3) have emerged as promising targets for cancer therapy due to their role in regulating apoptosis, independent of upstream signalling pathways and Bcl-2 family protein levels. Here, we present a new non-psoralene Kv1.3 mitochondria-targeted conjugates. These conjugates, particularly cis-8 and cis-9, exhibit nanomolar affinity and high selectivity for KV1.3 while effectively inducing apoptosis in tumor cells. Unlike their parent KV1.3 inhibitors, which lack cytotoxicity, the mitoKV1.3 conjugates induce rapid mitochondrial depolarization, and caspase-3/7 activation, culminating in dose-dependent tumor cell death in both 2D and 3D models. Mechanistically, cis-8 and cis-9 disrupt mitochondrial membrane potential and selectively target cancer cells, sparing normal cells at lower concentrations. Notably, KV1.3 knockout models confirmed the dependence of cytotoxicity on mitoKV1.3 inhibition. The conjugates demonstrated robust antitumor activity in murine pancreatic intraepithelial neoplasia (PanIN)-derived organoids, with preferential action over normal pancreatic organoids, highlighting their tumor selectivity. Importantly, safety assessments showed no significant DNA damage or chromosomal aberrations at non-cytotoxic doses. This study introduces a new structural class of mitochondria-targeted KV1.3 inhibitors with enhanced solubility compared to psoralen-based analogues. The unique mechanism of action, characterized by rapid depolarization and moderate ROS dependence, underscores their potential as selective anticancer agents. These findings warrant further investigation into in vivo efficacy and potential synergy with existing therapies.

Keywords:  Apoptosis; Cancer; Mitochondrial KV1.3; Mitochondrial targeting

DOI:  https://doi.org/10.1016/j.biopha.2026.118996
Redox Biol. 2026 Jan 06. pii: S2213-2317(26)00004-2. [Epub ahead of print]90 104006

RIPK3-driven phosphorylation of MFN2 orchestrates endoplasmic reticulum-mitochondria interaction and cardiomyocyte stress responses.

Yu Wang, Tao Xu, Qi Li, Lin Ye, Peiyan Wang, Puhan Wang, Yihan Song, Xiang Ao, Jianxun Wang, Wei Ding.

   BACKGROUND: Recent studies have demonstrated that necroptosis is one of the main forms of cardiomyocyte death in heart diseases. However, the crosstalk between the death-receptor necroptosis pathway and the mitochondrial necroptosis pathway remains largely unknown. It has been reported that Mitofusin 2 (MFN2) can promote myocardial injury by inducing Endoplasmic Reticulum (ER)-mitochondria interaction. The purpose of this study was to investigate whether MFN2 promotes cardiac necroptosis and myocardial ischemia/reperfusion (I/R) injury by regulating ER-mitochondrial interactions, and whether this function of MFN2 can be regulated by the death-receptor necroptosis pathway.
METHODS: Myocardial necroptosis was induced by H2O2 in H9c2 cardiomyocytes in vitro and through left anterior descending (LAD) ligation and subsequent reperfusion in C57/BL6 mice in vivo. ER-mitochondria interaction was detected by immunofluorescence. Calcium levels were analyzed by Rhod-AM staining. The interaction between MFN2 and Receptor-interacting protein kinase 3 (RIPK3) was explored by co-immunoprecipitation and immunofluorescence. The phosphorylation site of MFN2 was examined and measured via mass spectrometry analysis. Additionally, a customized MFN2 phosphorylation-specific antibody was used to detect the role of the Threonine 130 site of MFN2 in myocardial necroptosis. In vivo, MFN2 cardiac-specific knockout mice were constructed to further explore the effect of MFN2 on myocardial I/R injury and necroptosis.
RESULTS: Our results showed that MFN2 participated in H2O2-induced cardiomyocyte necroptosis by promoting the formation of ER-mitochondrial interactions and ER-mitochondrial Ca2+ transfer, which could be regulated by RIPK3 via phosphorylating MFN2 at the Threonine 130 site. Moreover, mitochondrial Ca2+ overload induced mPTP opening and subsequent activation of Calpain1, resulting in the inhibition of mitophagy initiation. Both of these pathways could promote cardiac necroptosis. Furthermore, our results revealed that cardiac-specific knockout of MFN2 could attenuate myocardial I/R injury.
CONCLUSION: Our findings reveal that RIPK3 can mediate MFN2 phosphorylation to promote ER-mitochondria interaction and mitochondrial Ca2+ overload, leading to the induction of cardiac necroptosis.

Keywords:  Ishchemia/reperfusion injury; MFN2; Myocardium; Phosphorylation; RIPK3

DOI:  https://doi.org/10.1016/j.redox.2026.104006
bioRxiv. 2026 Jan 11. pii: 2026.01.09.698662. [Epub ahead of print]

Tumor cell death by ferroptosis contributes to an immunosuppressive tumor microenvironment in syngeneic murine models of cancer.

Nneka E Mbah, Damien Sutton, Hanna S Hong, Rashi Singhal, Rosa E Menjivar, Heather Giza, Peter Sajjakulnukit, Matthew Perricone, Zeribe C Nwosu, Jonathan Alektiar, Jason Lin, Daniel Long, Anthony C Andren, Li Zhang, Howard C Crawford, Timothy L Frankel, Marina Pasca di Magliano, Luigi Franchi, Yatrik M Shah, Costas A Lyssiotis.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by profound metabolic rewiring and a strongly immunosuppressive tumor microenvironment, both of which contribute to poor therapeutic responses. Immunogenic cell death (ICD) represents a potential strategy to overcome immune suppression by coupling tumor cell death to anti-tumor immune activation. Here, we investigated whether targeting amino acid metabolism in PDAC can induce ICD and promote tumor immunity. Through a focused metabolic screen in a panel of syngeneic mouse cancer cell lines, we identified cysteine restriction as a robust inducer of multiple damage-associated molecular patterns (DAMPs) in vitro, hallmark features of ICD. In addition to driving DAMPs, cystine-deprived tumor cells also promoted dendritic cell phagocytosis, maturation, and proinflammatory cytokine production in vitro. Because cysteine deprivation is a known trigger of ferroptosis, we further demonstrated that pharmacologic inhibition of glutathione peroxidase 4 (GPX4) similarly elicited ICD-associated features, which were reversible by the ferroptosis inhibitor Ferrostatin-1. To define additional immune-modulatory signals associated with ferroptosis, we performed metabolomic and lipidomic profiling of cells undergoing, but not yet committed to, ferroptotic death. These analyses revealed selective release of immunosuppressive metabolites and oxidized phospholipids. Consistent with this, conditioned media from ferroptotic cells impaired CD8⁺ T cell proliferation and cytotoxicity in vitro. Thus, together our results indicated that the induction of ferroptotic immunogenic cell death led to the release of both pro- and anti-inflammatory signals. Subsequent analysis in vivo revealed that ferroptotic tumor cells predominantly contributed to a tumor-protective environment. In particular, tumors inoculated with ferroptotic cells were enriched with immunosuppressive myeloid cells and exhibited reduced populations of tumor-infiltrating CD8+ T cells. Further investigation using immune compromised mice suggested that ferroptotic cells may suppress both adaptive and innate immune responses. Collectively, these results underscore the complex and highly context-dependent effects of ferroptosis on tumor immunity, highlighting the critical importance of in vivo models to determine true immunogenic potential within the tumor microenvironment.

DOI: https://doi.org/10.64898/2026.01.09.698662
Nature. 2026 Jan 15.

Daily briefing: Cancer cells stay hidden using stolen mitochondria.

Jacob Smith.

DOI: https://doi.org/10.1038/d41586-026-00181-z