bims-miptne Biomed News
on Mitochondrial permeability transition pore-dependent necrosis
Issue of 2026–10–11
nine papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool
  1. Phytochemicals differentially modulate mitochondrial bioenergetics: roles of F1FO-ATPase, respiratory complexes, and mPTP opening.
  2. Mitochondrial calcium and ROS: present understanding and future directions.
  3. Synucleins deficiency alter dopamine- and glutamate-induced calcium signal in neurons and astrocytes.
  4. SIRT7 upregulation protects against TKI-induced cardiotoxicity by inhibiting MCU-mediated mitochondrial calcium overload.
  5. Golgi-derived vesicles containing PI(3,4)P2 drive mitochondrial fusion.
  6. Immunoregulatory gene GIMAP6 suppresses lethal atherosclerotic vasculopathy and ischemic heart failure.
  7. OXR1 is a dual redox-mitochondrial checkpoint governing osteoclast differentiation and bone loss in an osteoporosis mouse model.
  8. Cis-regulatory inactivation of vitamin D signaling confers extreme calcium tolerance in Jialing fish.
  9. A second-generation "hypoxia in a pill" rescues neurodegenerative phenotypes across distinct mouse models.
  1. Biochimie. 2026 Oct 05. pii: S0300-9084(26)00238-5. [Epub ahead of print]
    Phytochemicals differentially modulate mitochondrial bioenergetics: roles of F1FO-ATPase, respiratory complexes, and mPTP opening.
    Antonia Cugliari, Cristina Algieri, Patrycja Anna Glogowski, Micaela Fabbri, Fabiana Trombetti, Salvatore Nesci.
      Phytochemicals can modulate mitochondrial function, but their specific actions on bioenergetic pathways are not fully defined. Here, isolated mitochondria were exposed to three phytocompounds, S-allyl cysteine (SAC), benzyl isothiocyanate (BITC), and epicatechin (EPC), and key mitochondrial parameters were assessed, including F1FO-ATPase activity, NADH- and succinate-driven respiration, and mitochondrial permeability transition pore (mPTP) opening. Mechanistic insights were obtained through kinetic analyses and by probing redox sensitivity using dithiothreitol-treated mitochondria. SAC increased F1FO-ATPase activity, displaying cooperative behaviour and multiple inhibitory/activating components consistent with uncompetitive and competitive interactions, while leaving respiration unchanged; it also reduced mPTP sensitivity, indicating desensitization of pore dynamics. In contrast, BITC produced mixed-type inhibition of F1FO-ATPase and significantly impaired respiration, with a stronger impact on Complex I-linked (NADH-driven) flux; BITC additionally delayed mPTP opening through a redox-dependent mechanism. EPC did not significantly alter F1FO-ATPase activity, respiration, or mPTP opening under the experimental conditions. Overall, these findings demonstrate compound-specific modulation of mitochondrial bioenergetics by phytochemicals, supporting their potential relevance for therapeutic strategies targeting oxidative stress and mitochondrial dysfunction.
    Keywords:  F(1)F(O)-ATPase; Mitochondria; Mitochondrial permebility transition pore; Phytochemicals
    DOI:  https://doi.org/10.1016/j.biochi.2026.10.001
  2. Mitochondrion. 2026 Oct 06. pii: S1567-7249(26)00112-1. [Epub ahead of print]92 102222
    Mitochondrial calcium and ROS: present understanding and future directions.
    Chloe I Roth, Alyssa C Vadovsky, Keeler J Steele, Annamaria Raftu, Skyler Shaman, Jada G Roberts, Jason N Bazil.
      This mini-review and perspective article goes over a brief history of mitochondria and their role in calcium overload and oxidative stress. Altogether, oxidative stress, calcium overload, and mitochondrial dysfunction form a pathophysiological triad, and most of the explanatory power of this triad relies on invoking the mitochondrial permeability transition pore (mPTP) as driving the pathophysiology. As such, many studies claim that calcium overload triggers oxidative stress and acts as the upstream event in mitochondrial dysfunction to explain experimental results. However, recent findings shed new light on this triad and how it affects living tissue. While the mPTP hypothesis has dominated curated explanations, emerging functional and structural data supports a distinct stable overloaded state that better accounts for graded dysfunction in the presence of low intensity chronic oxidative stress. In this stable calcium overload state, mitochondrial dysfunction is evident from the reduced oxidative metabolism impairments accompanying suppressed free radical emission rates, distinct from the effects of opening the mPTP. This refined framework has direct implications for SR/ER-mitochondrial crosstalk in disease and tunes mechanistic models that better align with the available data. While mitochondria absolutely play an important role in various pathologies, they primarily respond to exogenous driving forces that move them into compromised functional states, which in turn amplify cellular disorder. Ideally, this perspective will help refine the intriguing and complex aspects of mitochondrial function in cell death and disease.
    Keywords:  Calcium overload; Free radical; Mitochondria; Mitochondria permeability transition; Oxidative stress; Pathophysiological triad
    DOI:  https://doi.org/10.1016/j.mito.2026.102222
  3. Neurochem Int. 2026 Oct 03. pii: S0197-0186(26)00160-9. [Epub ahead of print]200 106269
    Synucleins deficiency alter dopamine- and glutamate-induced calcium signal in neurons and astrocytes.
    Anastasia A Fedulina, Artyom Y Baev, Alexey V Emelyanov, Anastasia A Khizeva, Kirill D Chaprov, Andrey Y Vinokurov, Andrey Y Abramov.
      Proteins α-, β-, and γ-synuclein in brain distributed predominantly in presynaptic terminals suggesting their role in regulating neurotransmitter release and signal transduction. Misfolded α-synuclein is involved in the pathology of Parkinson's disease which is characterized by the loss of dopaminergic neurons and the resulting dopamine deficiency. The role of synucleins in the physiology of dopamine-controlled signal transmission is still not fully understood. Using acute brain slices from transgenic mice with α-, β-, γ-synuclein knockout (KO) we studied the effect of synuclein deficiency on dopamine and glutamate-induced calcium signals in neurons and astrocytes. We have found that lack of α- or γ -synuclein decreases the dopamine-induced calcium signal in neurons while γ- or αβγ-KO were characterized by a lower calcium signal in response to glutamate. The ability of dopamine to reduce glutamate-induced calcium signal were altered by γ- and αβγ-synuclein deficiency. Monoamine oxidase-dependent dopamine-induced calcium signal in astrocytes was increased in α-synuclein KO brain slices. αβγ-synuclein deficiency had no effect on mitochondrial Ca2+-transport and only γ-synuclein KO led to decrease in the rate of mitochondrial calcium uptake and mitochondrial calcium capacity. Thus, synuclein deficiency alters dopamine- and glutamate -induced calcium signalling in neurons and astrocytes.
    Keywords:  Astrocytes; Dopamine; Glutamate; Neurons; Synuclein
    DOI:  https://doi.org/10.1016/j.neuint.2026.106269
  4. Front Pharmacol. 2026 ;17 1929231
    SIRT7 upregulation protects against TKI-induced cardiotoxicity by inhibiting MCU-mediated mitochondrial calcium overload.
    Meiling Gao, Zhe Wang, Zhiling Cheng, Suhua Qiu, Wenting Wu, Zhihan Zhang, Wei Yan, Xianying Wang, Yanfang Xu, Congxin Li.
       Background: Tyrosine kinase inhibitors (TKIs) are potent anticancer agents; however, their clinical application is often restricted because of cardiotoxic effects. The mechanisms underlying cardiotoxicity that are shared across different TKIs remain inadequately understood.
    Purpose: This study aimed to investigate the role of sirtuin 7 (SIRT7) in regulating mitochondrial calcium homeostasis during TKI-induced cardiomyocyte injury and determine whether the SIRT7-mitochondrial calcium uniporter (MCU) axis could serve as a common protective target.
    Methods: AC16 cells were treated for 72 h with three TKIs: sunitinib (4.11 µM, IC30), trametinib (12.21 µM, IC30), and imatinib (21.84 µM, IC30). Cell viability, cardiomyocyte injury markers (N-terminal pro-brain natriuretic peptide and cardiac troponin I), cytosolic and mitochondrial Ca2+ levels, mitochondrial membrane potential, adenosine triphosphate (ATP) content, and endoplasmic reticulum-mitochondria contacts assessed using transmission electron microscopy were evaluated. Proteomic analysis was performed to identify differentially expressed proteins shared across treatments. In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), contraction amplitude was measured using an impedance-based system, and mitochondrial Ca2+ overload was evaluated.
    Results: All three TKIs induced concentration-dependent injury in AC16 cells, accompanied by mitochondrial Ca2+ overload, ATP depletion exceeding 50%, and increased mitochondria-endoplasmic reticulum (ER) contacts. Proteomic analysis identified consistent SIRT7 downregulation across the three TKI treatments. SIRT7 overexpression mitigated TKI-induced cellular damage, reversed MCU upregulation and functional activation, restored mitochondrial function, and reduced excessive mitochondria-ER contacts. In hiPSC-CMs, SIRT7 overexpression reduced mitochondrial Ca2+ overload and prevented TKI-induced contraction inhibition.
    Conclusion: SIRT7 upregulation protects against TKI-induced cardiotoxicity by inhibiting MCU-mediated mitochondrial calcium overload.
    Keywords:  calcium homeostasis; cardiotoxicity; human induced pluripotent stem cell-derived cardiomyocyte; mitochondrial calcium uniporter; sirtuin 7; tyrosine kinase inhibitor
    DOI:  https://doi.org/10.3389/fphar.2026.1929231
  5. Science. 2026 Oct 08. 394(6820): eadx9628
    Golgi-derived vesicles containing PI(3,4)P2 drive mitochondrial fusion.
    Sho Aki, Mayuko Segawa, Vincent Anton, Suvagata R Chowdhury, Shun Nagashima, Isshin Shiiba, Dane M Wolf, Ikuko Koyama-Honda, Ayumu Sugiura, Joe Ganellin, Mark Johnson, Sakie Katsumura, Maki Sugaya, Yasunori Fujita, Koki Nakamura, Kazuaki Yoshioka, Hisamichi Naito, Yoh Takuwa, Ikuroh Ohsawa, Yusuke Hirabayashi, Shigeru Yanagi, Masahiro Morita, Tsuyoshi Osawa, Julien Prudent.
      Mitochondria are dynamic organelles that remodel their shape to regulate cell fate. Mitochondrial division involves interactions with the endoplasmic reticulum (ER), lysosomes, and trans-Golgi network-derived vesicles to facilitate membrane scission. How interorganelle contacts regulate mitochondrial membrane fusion remains largely unknown. Here, we identified a role for Golgi-derived vesicles enriched in phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2] in regulating mitochondrial fusion. We found that these vesicles were recruited to ER- and mitofusin-marked fusion sites. Accordingly, loss of class II PI3-kinase isoforms α and β (PI3K-C2α and PI3K-C2β), which generate PI(3,4)P2, led to mitochondrial fragmentation resulting from impaired fusion. Furthermore, cardiomyocyte-specific PI3K-C2α and PI3K-C2β double-deletion mice exhibited mitochondrial fragmentation and heart failure. Thus, subpopulations of Golgi-derived vesicles carrying different phosphoinositides control mitochondrial membrane remodeling and homeostasis.
    DOI:  https://doi.org/10.1126/science.adx9628
  6. Cell. 2026 Oct 08. pii: S0092-8674(26)01134-7. [Epub ahead of print]
    Immunoregulatory gene GIMAP6 suppresses lethal atherosclerotic vasculopathy and ischemic heart failure.
    Chen Xiang, Kaja Arusha, Danielle Springer, Sachiko Nakamori, Jing Cui, Ping Du Jiang, Zhi-Hong Yang, Yu Zhang, Huie Jing, Ann Y Park, Maria H Zhu, Sarah E Weber, Deniz Cagdas, Hassan Abolhassani, Nasrin Behniafard, Margery G Smelkinson, Qihui Liang, Elif Everest, Julia F Kun, Alyssa Grogan, Bernd J Wranik, Ngoc Vu, Bryan King, Jennifer D Treat, Nancy Asomaning, Shijinqiu Gao, Bryson D Bennett, Swee Lay Thein, Christa S Zerbe, Steven M Holland, Renu Virmani, Alan T Remaley, Helen C Su, Lixin Zheng, Michael J Lenardo.
      Controlling hyperlipidemia has reduced but not eliminated atherosclerotic cardiovascular disease (ASCVD) as a major cause of human mortality. Here, we report that loss of the immunoregulatory gene GTPase of immunity-associated protein 6 (Gimap6) in mice causes an inflammatory vasculopathy and accelerated atherosclerosis in the absence of hyperlipidemia. These vascular abnormalities cause progressive cardiac ischemia, myocardial infarction, and heart failure, culminating in early death. GIMAP6 loss precipitates early endothelial barrier failure and a mitochondrial reactive oxygen species (ROS)-PPARγ-CD36 lipid-influx cascade that lowers the threshold for foam-cell formation and induces IL-6/MCP-1/TNF-mediated inflammation. Human hypomorphic GIMAP6 variants, including the African-ancestry-enriched V65I allele, are associated with altered monocyte redox balance, increased CD36-mediated lipid uptake, and early ASCVD. Thus, GIMAP6 is a crucial safeguard for vascular integrity that restrains endothelial dysfunction, macrophage foam cell generation, and inflammation that can cause lethal ASCVD independently of systemic hyperlipidemia.
    Keywords:  CD36; cardiovascular; endothelium; lipid; macrophage; mitochondria; myocardial infarction; redox
    DOI:  https://doi.org/10.1016/j.cell.2026.09.032
  7. Nat Commun. 2026 09 05. pii: 10553. [Epub ahead of print]17(1):
    OXR1 is a dual redox-mitochondrial checkpoint governing osteoclast differentiation and bone loss in an osteoporosis mouse model.
    Xiaojun Chen, Chengyu Zhou, Xiangyun Jin, Qiongxiang Lin, Lizhen Li, Zhongxiang Wang, Buran Chen, Qiu Dong, Jianbo He, Kavishadhi Chandrasekaran, Chau Bui, Alysia Hubbard, Qunwei Dong, Lei Chen, K Swaminathan Iyer, Jiandong Yuan, Nathan J Pavlos, Haibo Jiang, Kai Chen.
      Osteoclasts are mitochondria-rich cells that rely on oxidative phosphorylation to fuel differentiation and bone resorption. Oxidative phosphorylation generates reactive oxygen species (ROS), which support signaling but can also threaten mitochondrial integrity. Oxidation Resistance 1 (OXR1) is a redox-responsive regulator involved in antioxidant defense, but its role in osteoclasts remains unclear. Here, we show that OXR1 is upregulated during mouse osteoclastogenesis and OXR1 mRNA is enriched in human osteoclasts. Knockdown of Oxr1 in mouse osteoclast precursors causes excessive ROS accumulation, mitochondrial damage, and impaired autophagic flux. Accordingly, myeloid-specific loss of Oxr1 results in defective osteoclast formation and increased bone mass in mice. Mechanistically, OXR1 binds the antioxidant response regulator KEAP1 and promotes KEAP1 association with the autophagy adaptor P62/SQSTM1, thereby supporting mitochondrial ubiquitination and mitophagic clearance. In an ovariectomy-induced osteoporosis mouse model, intraosseous AAV9-shRNA-mediated Oxr1 silencing or pharmacological OXR1 inhibition suppresses osteoclast activity and attenuates bone loss. Thus, our findings suggest OXR1 to be a dual-function regulator that buffers ROS and simultaneously orchestrates the autophagic clearance of damaged mitochondria during osteoclastogenesis, hinting at OXR1 as a potential target for preventing osteoclast‑driven bone loss.
    DOI:  https://doi.org/10.1038/s41467-026-77379-2
  8. Sci Adv. 2026 Oct 09. 12(41): eaeg8398
    Cis-regulatory inactivation of vitamin D signaling confers extreme calcium tolerance in Jialing fish.
    Nan Zhang, Yongsen Zhou, Jianbin Feng, Tianhao Yang, Huilin Liu, Yongsheng Zhang, Lingyun Chen, Weiyang Xiao, Tai Wang, Aaron J W Hsueh, Jianzhen Li.
      The turquoise karst lakes of China's Jiuzhaigou Nature Reserve harbor among the highest natural calcium concentrations known in freshwater, around threefold higher than adjacent rivers. Yet the Jialing fish (Schizopygopsis kialingensis) thrives there with serum calcium levels indistinguishable from river-dwelling conspecifics. We show that this calcium tolerance arose through evolutionary loss of vitamin D signaling. Lake and river populations diverged ∼410,000 years ago. Gill transcriptomics revealed >90% suppression of vitamin D receptor b (vdrb) and 99% reduction of its downstream calcium transporter calb2a in lake fish. Zebrafish knockout of either gene enhanced survival under hypercalcemia. We traced this suppression to specific mutations in a vdrb enhancer that reduce its activity. These findings reveal that regulatory dismantling of a canonical endocrine pathway can drive vertebrate adaptation to extreme environments, providing a clear example of how cis-regulatory evolution can drive ecological adaptation.
    DOI:  https://doi.org/10.1126/sciadv.aeg8398
  9. Proc Natl Acad Sci U S A. 2026 Oct 13. 123(41): e2618654123
    A second-generation "hypoxia in a pill" rescues neurodegenerative phenotypes across distinct mouse models.
    Hong Wang, Eizo Marutani, Luca Zazzeron, Marissa Menard, Laura Volpicelli-Daley, Fumito Ichinose, Vamsi K Mootha.
      A growing body of preclinical research is demonstrating the therapeutic potential of chronic, continuous hypoxia (11% FIO2) for rare and common diseases. However, the chronic delivery of hypoxic gas poses both practical challenges and long-term safety concerns. We previously introduced a small-molecule, "hypoxia-in-a-pill" combining a hemoglobin affinity enhancer (GBT440) to limit oxygen delivery with a HIF-2α inhibitor (PT2399) to prevent detrimental compensatory erythropoiesis. Although this small-molecule regimen extended the lifespan of the Ndufs4 knockout (KO) mouse model of mitochondrial complex I deficiency and Leigh syndrome, its efficacy did not match chronic 11% FIO2. Here we optimize this regimen using GBT601, a second-generation hemoglobin affinity enhancer with longer half-life and greater hemoglobin occupancy, and show it rescues key neurodegenerative phenotypes in multiple models. When we initiate therapy in 50 d old Ndufs4 KO mice with advanced disease, GBT601 monotherapy alleviated neurological disease phenotypes and extended median lifespan from 62 to 105 d, while dual therapy with the GBT601/PT2399 combination extended median lifespan to 158 d. When initiated after onset of advanced disease in a mouse model of Friedreich's ataxia, the combination halted further progression of motor phenotypes. In a mouse model of Parkinson's disease due to α-synuclein toxicity, initiating the GBT601/PT2399 combination after onset of motor dysfunction attenuates brain hyperoxia and lipid peroxidation and reverses motor phenotypes. Importantly, the combination maintained body weight without inducing any signs of pulmonary hypertension. Our findings motivate further preclinical and clinical evaluation of our "hypoxia in a pill" approach for diseases with high unmet need.
    Keywords:  HIF-2α; hemoglobin; hyperoxia; hypoxia; neurodegeneration
    DOI:  https://doi.org/10.1073/pnas.2618654123
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