bims-miptne Biomed News
on Mitochondrial permeability transition pore-dependent necrosis
Issue of 2026–04–05
seven papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool
  1. Mitochondrial Calcium Dysregulation and Targeted Therapies in Heart Failure.
  2. Antitumor natural products targeting mitochondrial NADH: ubiquinone oxidoreductase (complex I): a review.
  3. Membrane receptor TGR5 upregulates IP3R-induced calcium overload: Key mechanism of bile acid-induced acute pancreatitis.
  4. SARS-CoV-2 envelope protein mitochondrial localization reveals host metabolic disruption.
  5. Mechanosensory channels mediate ER Ca2+ transients to trigger assembly of autophagosome initiation sites for degradation of ER subdomains.
  6. A luminescent calcium biosensor enabling endpoint measurement of GPCR-mediated calcium signaling.
  7. Mitochondrial vulnerability underlies myocarditis from COVID-19 mRNA vaccine.
  1. Rev Cardiovasc Med. 2026 Mar;27(3): 46211
    Mitochondrial Calcium Dysregulation and Targeted Therapies in Heart Failure.
    Mengting Liu, Yunpeng Jin.
      Heart failure (HF) is steadily increasing in prevalence and poses a major global health challenge, with substantial medical and economic burdens. HF represents the terminal stage of diverse cardiac disorders and is characterized by poor prognosis despite the availability of conventional pharmacological treatments, underscoring the urgent need for novel therapeutic approaches. Accumulating evidence highlights a strong association between HF and mitochondrial dysfunction, of which dysregulated mitochondrial calcium (mCa2+) homeostasis plays a pivotal role in disease pathogenesis. Ca2+ serves as an essential signaling messenger that regulates energy metabolism and also governs cell survival and myocardial contractility. Thus, this review introduces the mechanisms of mCa2+ uptake and efflux and the association of these processes with HF and emerging therapeutic strategies. We also discuss mCa2+ uniporter (MCU) inhibitors and Elamipretide, a mitochondria-targeted peptide. Collectively, this work provides novel insights and preclinical evidence supporting mitochondria-based interventions for HF.
    Keywords:  calcium; heart failure; mitochondria; mitochondrial calcium uniporter; targeted therapy
    DOI:  https://doi.org/10.31083/RCM46211
  2. Front Pharmacol. 2026 ;17 1799383
    Antitumor natural products targeting mitochondrial NADH: ubiquinone oxidoreductase (complex I): a review.
    Jiaqi Gou, Lingdang Chen, Yuting Xu, Binbin Liao, Yuanmin Shen, Juntao Tai, Jianying Zhang, Aixue Zuo.
      Mitochondrial complex I (NADH:ubiquinone oxidoreductase) is a critical hub for bioenergetics and redox signaling. Beyond its canonical role in oxidative phosphorylation and ATP synthesis, complex I regulates the intracellular NADH/NAD+ balance and reactive oxygen species (ROS) production, both of which are vital for tumor survival. Consequently, targeting complex I has emerged as a promising therapeutic strategy. Increasing evidence shows that diverse natural products-ranging from alkaloids to annonaceous acetogenins-exert potent antitumor effects by inhibiting complex I. These compounds disrupt mitochondrial function, inducing metabolic stress and cancer cell death. However, a systematic overview linking their chemical structures to specific binding modes and antitumor mechanisms is currently lacking. In this review, we summarize recent advances in natural products targeting mitochondrial complex I. We categorize these agents based on their structural characteristics and discuss their distinct mechanisms, such as acting as "deep tunnel blockers" versus "shallow pocket binders." This work aims to provide a theoretical foundation for the rational development of novel complex I-targeted antitumor drugs.
    Keywords:  NADH; antitumor mechanisms; mitochondria; mitochondrial complex I; natural products; ubiquinone oxidoreductase
    DOI:  https://doi.org/10.3389/fphar.2026.1799383
  3. Cell Signal. 2026 Mar 30. pii: S0898-6568(26)00164-6. [Epub ahead of print]144 112512
    Membrane receptor TGR5 upregulates IP3R-induced calcium overload: Key mechanism of bile acid-induced acute pancreatitis.
    Zhi Zhong, Long Cheng, Zhiwei Jiang, Yongqiang Zhu, Chuan Zhao, Chunlin Deng, Tingyu Yang, Maolin Chen, Qianjun Yu, Chuan Xie, Xin Dai, Tao Wang.
       INTRODUCTION: Acute pancreatitis (AP) is a digestive system emergency with acomplex pathogenesis, with pathological calcium overload identified as a key driving factor. Excessive or improper exposure to bile acids (BAs) is the main pathogenic factor of AP, but the role of its membrane receptor TGR5 in AP and its downstream mechanisms has not been fully elucidated.
    METHOD: A BAs-induced rat model of AP was established. The expression of TGR5 was detected. TGR5's role in AP was evaluated by knocking down TGR5. Pathological manifestations, serum indicators, inflammatory factor expression, oxidative stress levels, cell ultrastructure, and TGR5/IP3R expression were measured in each group. In vitro, AR42J cells received TGR5/IP3R intervention. Immunofluorescence, WB, and RT-qPCR were used to evaluate the roles and interrelationships of TGR5 and IP3R in AP. Calcium imaging technology was used to detect their effects on intracellular calcium ions.
    RESULT: We found that TGR5 was widely expressed in pancreatic tissue. Its expression significantly increased in BAS-induced AP. In the AP rat model, knockdown of TGR5 can effectively alleviate pancreatic injury. It reduces serum enzymatic indicators and inflammatory factor levels, relieves oxidative stress, and improves mitochondrial structure. Cell experiments further confirmed that BAs can upregulate the expression of IP3R through TGR5. This upregulation causes intracellular calcium overload in acinar cells. Inhibiting or knocking down TGR5/IP3R expression and activity can play a protective role.
    CONCLUSION: In conclusion, our research indicates that bile acids can trigger AP through the TGR5-IP3R‑calcium overload axis. Inhibiting TGR5/IP3R can alleviate calcium overload and exert a protective effect, providing new insights into the pathogenesis of AP.
    Keywords:  Acute pancreatitis; Bile acid; Calcium overload; IP3R; TGR5
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112512
  4. J Biol Chem. 2026 Mar 31. pii: S0021-9258(26)00289-9. [Epub ahead of print] 111419
    SARS-CoV-2 envelope protein mitochondrial localization reveals host metabolic disruption.
    Emily A David, Elijah J Bass, Hannah M Woods, Daniel Stephenson, Kellyann Román-Cruz, Charles E Chalfant, Robert V Stahelin.
      Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped virus that encodes four structural proteins, including the small transmembrane envelope (E) protein. While E is known to function in viral assembly and egress, it contributes to host cell dysfunction and disease severity. We demonstrate that SARS-CoV-2 E localizes to host cell mitochondria and alters mitochondrial structure, metabolism, and redox homeostasis. Using fluorescence microscopy, we observed that E forms tubular cytoplasmic structures that colocalize with mitochondria and ceramide-rich domains. Lipidomic analysis revealed that E expression leads to reductions in cardiolipin, phosphatidylcholine, and lysophospholipids. Mitochondrial membrane potential was decreased in E-expressing cells, consistent with disrupted electron transport chain (ETC) activity, which was further supported by mitochondria stress testing via Seahorse. Despite increased mitochondrial reactive oxygen species (ROS), E did not trigger apoptosis, suggesting containment of oxidative stress within the organelle. Metabolomic profiling revealed decreased levels of key glycolytic and tricarboxylic acid (TCA) cycle intermediates, along with altered glutathione and sulfur metabolism. Notably, glutamine levels increased, potentially to compensate for reduced 2-oxoglutarate. Together, these findings suggest that E protein localizes to the mitochondria, perturbs lipid and metabolic homeostasis, and promotes ROS retention without inducing cell death. This mitochondrial dysfunction may support a shift toward aerobic glycolysis, facilitating viral replication. Our study highlights an underappreciated role for E in modulating host metabolism.
    Keywords:  SARS-CoV-2; cellular localization; envelope protein; membrane potential; metabolism; mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.jbc.2026.111419
  5. Mol Cell. 2026 Apr 02. pii: S1097-2765(26)00158-9. [Epub ahead of print]86(7): 1377-1396.e6
    Mechanosensory channels mediate ER Ca2+ transients to trigger assembly of autophagosome initiation sites for degradation of ER subdomains.
    Xiaoli Ma, Zhiyang Cheng, Hongyu Zhao, Huan Zhang, Ke Xiao, Jiali Xie, Yun Feng, Chun Yang, Yujie Feng, Xi Wang, Yaozu Xiang, Junjie Hu, Qiaoxia Zheng, Wei Ji, Hong Zhang.
      ER-phagy involves the selective autophagosomal engulfment of ER fragments, but the signaling events, selection mechanisms, and membrane source of ER-phagic autophagosomes remain elusive. Here, using state-of-the-art super-resolution multi-SIM imaging, we reveal that stresses (prolonged starvation, cholesterol dyshomeostasis, and high-Ca2+ insults) trigger the expansion of sheet ER subdomains containing high levels of luminal Ca2+ in mammalian cells, which are subsequently degraded by ER-phagy. Autophagosome formation and sequestration of ER sheets require the concerted actions of FAM134B and lipidated LC3, whereas the autophagy proteins ATG14 and ATG9 are partially dispensable. Electron microscopy and cryo-electron tomography show that the membranes of autophagosomes enclosing high-Ca2+-containing ER sheets are directly remodeled from the ER. The ER-localized cation channels PIEZO1 and TRPV1 are enriched at and mediate Ca2+ transients from high-Ca2+-containing ER sheets, triggering liquid-liquid phase separation of the autophagosome-initiating FIP200 complex to initiate ER-phagy. Thus, distinct mechanisms are employed for the formation of high-Ca2+-containing ER-enclosing autophagosomes and non-selective autophagosomes.
    Keywords:  Ca(2+); ER-phagy; FAM134B; FIP200; PIEZO1; TRPV1
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.002
  6. Commun Biol. 2026 Mar 29.
    A luminescent calcium biosensor enabling endpoint measurement of GPCR-mediated calcium signaling.
    Kosuke Doi, Ryoji Kise, Kota Shimizume, Masataka Yanagawa, Asuka Inoue.
      Gq/11-coupled GPCRs regulate critical physiological processes through calcium mobilization, making intracellular Ca2+ dynamics a key readout for drug discovery and biomarker detection. However, the transient nature of calcium signals necessitates real-time monitoring with specialized equipment, creating barriers for high-throughput screening and limiting accessibility. Here we present CalLuc-2.1, a luminescent calcium biosensor that converts brief Ca2+ spikes into persistent luminescence changes readable tens of minutes after stimulation. By eliminating the need for precisely-timed detection, CalLuc-2.1 enables endpoint measurement of GPCR activation using standard plate readers. We demonstrate robust performance (Z' > 0.88) across multiple Gq/11-coupled GPCRs in both agonist and antagonist screening formats. Furthermore, CalLuc-2.1 successfully detects endogenous GPCR ligands directly in human serum, offering a simpler alternative to immunoassays and mass spectrometry for biomarker quantification. This approach makes calcium-based GPCR assays accessible to any laboratory with basic luminescence detection capabilities, potentially accelerating both drug discovery and clinical research applications.
    DOI:  https://doi.org/10.1038/s42003-026-09920-4
  7. Nat Commun. 2026 Apr 01.
    Mitochondrial vulnerability underlies myocarditis from COVID-19 mRNA vaccine.
    Go Mori, Masayoshi Yamamoto, Kaori Ishikawa, Hiroaki Tamashiro, Hayate Suzuki, Seiya Mizuno, Kazuto Nakada, Atsushi Kawaguchi.
      mRNA vaccines against SARS-CoV-2 have been widely adopted to combat the COVID-19 pandemic. However, myocarditis has emerged as a rare but severe adverse effect, predominantly affecting young males. Here, we show that mitochondrial vulnerability is associated with mRNA vaccine-associated myocarditis. In our case-control study, patients with postvaccination myocarditis exhibited mitochondrial abnormalities. To examine the impact of mitochondrial damage, mRNA vaccines were administered to Polg+/D257A mice, which heterozygously express a proofreading-deficient mitochondrial DNA polymerase that sensitizes mitochondria to stress. mRNA vaccination in Polg+/D257A mice reduced left ventricular ejection fraction and induced cardiac immune cell infiltration. Bazedoxifene, a selective estrogen receptor modulator, prevented the reduction of cardiac function in Polg+/D257A mice, suggesting a protective role for estrogen signaling. Notably, mRNA vaccination induced mitochondrial reactive oxygen species, resulting in RIPK3 activation, a necroptosis-related kinase, in cardiomyocytes. Collectively, we propose that mitochondrial vulnerability is a potential risk factor for myocarditis following mRNA vaccination, possibly through reactive oxygen species-mediated necroptosis signaling.
    DOI:  https://doi.org/10.1038/s41467-026-71295-1
This page is being maintained by Thomas Krichel. It was last updated on 2026‒04‒06 at 21:15.