bims-miptne 2026-01-25 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2026–01–25
eight papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Mitoregulin supports mitochondrial membrane integrity and protects against cardiac ischemia-reperfusion injury.
SARS-CoV-2-infected cardiomyocytes exhibit upregulated necroptosis, but no evidence of mitochondrial permeability transition.
A small molecule VDAC ligand inhibits ERAD and induces selective cancer cell death via disruption of calcium homeostasis.
Beyond metabolism: exploring the regulatory and therapeutic implications of lactate and lactylation in cancer-regulated cell death.
The lever model of synaptotagmin-1 function.
Activation of nuclear Ca2+-dependent gene expression by CRAC channel Ca2+ nanodomains.
Lipid Metabolism in Relation to Calcium Homeostasis.
Caveolin-3 serves as a therapeutic target for myocardial ischemia-reperfusion injury in cardiac surgery patients.

Cardiovasc Res. 2026 Jan 20. pii: cvag011. [Epub ahead of print]

Mitoregulin supports mitochondrial membrane integrity and protects against cardiac ischemia-reperfusion injury.

Colleen S Stein, Xiaoming Zhang, Nathan H Witmer, Edward Ross Pennington, Scott Hahn, Adam C Straub, Saame Raza Shaikh, Ryan L Boudreau.

   AIMS: We and others discovered a highly conserved mitochondrial transmembrane microprotein, named Mitoregulin (Mtln), that supports lipid metabolism. We reported that Mtln strongly binds cardiolipin (CL), increases mitochondrial respiration and Ca2+ retention capacities, and reduces reactive oxygen species (ROS). Here we extend our observation of Mtln-CL binding and examine Mtln influence on cristae structure and mitochondrial membrane integrity during stress.
METHODS AND RESULTS: We demonstrate that mitochondria from constitutive- and inducible Mtln-knockout (KO) mice are susceptible to membrane freeze-damage and that this can be rescued by acute Mtln re-expression. In mitochondrial-simulated lipid monolayers, we show that synthetic Mtln decreases lipid packing and monolayer elasticity. Lipidomics revealed that Mtln-KO heart tissues show broad decreases in 22:6-containing lipids and increased cardiolipin damage/remodeling. Lastly, we demonstrate that Mtln-KO mice suffer worse myocardial ischemia-reperfusion injury, hinting at a translationally relevant role for Mtln in cardioprotection.
CONCLUSION: Our work supports a model in which Mtln binds cardiolipin and stabilizes mitochondrial membranes to broadly influence diverse mitochondrial functions, including lipid metabolism, while also protecting against stress.

Keywords:  Cyb5r3; cardiolipin; cardioprotection; cristae; docosahexaenoic acid; ischemia-reperfusion; mitochondria; monolysocardiolipin; permeability transition; triglycerides

DOI:  https://doi.org/10.1093/cvr/cvag011
J Mol Cell Cardiol Plus. 2026 Mar;15 100833

SARS-CoV-2-infected cardiomyocytes exhibit upregulated necroptosis, but no evidence of mitochondrial permeability transition.

C Gross, S Chatterjee, B E Nilsson-Payant, S D Stojanović, H Kefalakes, C Bär, T Thum, T Pietschmann, J Bauersachs, G Amanakis.

  Cardiac involvement in patients infected with COVID-19, in terms of myocarditis and troponin release, is associated with higher mortality. However, the underlying mechanisms are poorly understood. Infection of cardiomyocytes derived from human induced pluripotent stem cells (iPSC-CMs) with a wild-type variant of SARS-CoV-2 exhibited a cardiotoxic effect. We examined whether elevated intramitochondrial calcium causes opening of the mitochondrial permeability transition pore (mPTP) leading to cell death. The mPTP inhibitor Cyclosporine A (CsA) did not improve viability, and phosphorylation levels of pyruvate dehydrogenase (PDH) remained similar pre- and post-infection, likely suggesting no substantial alteration of the intramitochondrial calcium level. Also, the protein expression of mitochondrial respiratory complexes did not change after SARS-CoV-2 infection. Next, we examined whether cell death is related to necroptosis or pyroptosis upregulation. The phosphorylation level of receptor-interacting protein kinase 3 (RIP3) was elevated post-infection with SARS-CoV-2 while phosphorylation of mixed lineage kinase domain (MLKL)-S358 remained unaltered. This pattern may point toward an alternative regulation of necroptosis. Chemical inhibition of necroptosis (Necrostatin-1) and pyroptosis (MCC950) did not confer any protection. Notably, the phosphorylation of RIP3 under Necrostatin-1 was still elevated, suggesting that autophosphorylation of RIP3 may be a possible confounder. Our data suggest that SARS-CoV-2 compromises cell viability in iPSC-CMs and may engage in non-canonical signaling via RIP3 phosphorylation. The lack of MLKL activation and the absence of protective effects from CsA indicate that neither classical necroptosis nor mitochondrial permeability transition are likely to be central regulators of cell death.

Keywords:  COVID-19; Cardiomyocytes; Induced pluripotent stem cells; Mitochondrial permeability transition; Necroptosis; SARS-CoV-2

DOI:  https://doi.org/10.1016/j.jmccpl.2025.100833
Nat Commun. 2026 Jan 17.

A small molecule VDAC ligand inhibits ERAD and induces selective cancer cell death via disruption of calcium homeostasis.

Wenjing Yan, Daniel C Talley, Antara Syam, Carina Danchik, Yongwang Zhong, Xianzheng Zhang, Xiaoying Liu, Bolormaa Baljinnyam, Stephen C Kales, Matthew G Cyr, Yuhong Fang, Alexey V Zakharov, Xin Hu, Taylor Niehoff, Tuan Xu, Yanyan Qu, Allison Yang, Valentine V Courouble, Qin Yao, Anton Simeonov, Ruili Huang, Tatiana K Rostovtseva, Sergey M Bezrukov, Christopher A LeClair, Josephine M Egan, Hua Wang, Dingyin Tao, Ganesha Rai, Mark J Henderson, Shengyun Fang.

Endoplasmic reticulum-associated degradation (ERAD) is a critical protein quality control mechanism that also regulates lipid metabolism and calcium homeostasis. Dysregulation of ERAD and unfolded protein response underlies diseases including cancer, neurodegenerative disorders, and metabolic syndromes. Small molecule modulators of ERAD could enable mechanistic discovery and therapeutic intervention, but few have been identified. Using a high-content screening, we discovered several ERAD-modulating compounds, including NCATS-SM0225, an ERAD inhibitor that unexpectedly binds all three isoforms of VDAC, outer mitochondrial membrane proteins enriched at mitochondria-associated membranes. This led us to discover an essential role for VDACs in ERAD and ER-phagy. NCATS-SM0225 elevates cytosolic, ER, and mitochondrial calcium through calcium influx and IP3R-MCU activity. This calcium imbalance strengthens VDAC1-IP3R coupling and activates PERK, which phosphorylates STIM1 and drives degradation of key ERAD regulators. Loss of these components amplifies PERK signaling and selectively kills cancer cells while sparing normal cells. These findings uncover a cancer-specific role of VDACs in ERAD regulation and calcium signaling, highlighting a therapeutically actionable vulnerability.

DOI: https://doi.org/10.1038/s41467-025-67816-z
Cell Death Dis. 2026 Jan 22.

Beyond metabolism: exploring the regulatory and therapeutic implications of lactate and lactylation in cancer-regulated cell death.

Cong Chen, An Lin, Jiacheng Zhao, Xia Lin, Qianwei Ye, Jufeng Guo, Jian Liu, Aizhai Xiang.

Lactate, a key byproduct of glycolysis in tumor cells, has emerged as more than just a metabolic waste product. Increasing evidence reveals that lactate and its associated post-translational modification (PTM), lactylation, play multifaceted roles in regulating various forms of regulated cell death (RCD), thereby contributing to cancer proliferation, therapy resistance, and immune exclusion. Notably, evasion of RCD is a hallmark of cancer and targeting RCD may represent a promising therapeutic strategy for cancer treatment. In this review, we focus on summarizing the dual and context-dependent roles of both lactate and lactylation in modulating distinct types of RCD, including apoptosis, autophagy, ferroptosis, pyroptosis, and cuproptosis. Moreover, we further discuss how RCD processes impact lactate metabolism and highlight the therapeutic potential and current challenges of targeting the lactate-lactylation-RCD axis in cancer treatment.

DOI: https://doi.org/10.1038/s41419-026-08410-z
J Cell Sci. 2026 Jan 15. pii: jcs264345. [Epub ahead of print]139(2):

The lever model of synaptotagmin-1 function.

Josep Rizo, Yun-Zu Pan, Cyrus T Rastegar.

  Neurotransmitter release is triggered rapidly by Ca2+ binding to synaptotagmin-1 in cooperation with the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). Synaptotagmin-1 is believed to facilitate membrane fusion by inserting the Ca2+-binding loops of its two C2 domains into membranes, thus perturbing the bilayers and/or inducing curvature. However, this direct role has been questioned by the observation that when the synaptotagmin-1 C2B domain binds the SNARE complex, its Ca2+-binding loops point away from the fusion site. Recent data together with older results suggested a natural explanation for this paradox. Molecular dynamics simulations indicate that placing the Ca2+-binding loops close to the fusion site hinders SNARE-mediated membrane fusion. Electron paramagnetic resonance, nuclear magnetic resonance and fluorescence spectroscopy show that, upon Ca2+ binding, the C2B domain reorients on the membrane and can partially dissociate from the membrane-anchored SNARE complex. Electrophysiological studies strongly suggest that such reorientation of the C2B domain with respect to the SNAREs is crucial for neurotransmitter release. In this Hypothesis article, we discuss how these findings have led to a model whereby Ca2+-induced reorientation the C2B domain causes synaptotagmin-1 to act remotely as a lever, pulling the SNARE complex and facilitating SNARE conformational changes that trigger fast membrane fusion.

Keywords:  Complexin; Membrane fusion; Neurotransmitter release; SNAREs; Synaptotagmin

DOI:  https://doi.org/10.1242/jcs.264345
Cell Rep. 2026 Jan 17. pii: S2211-1247(25)01615-8. [Epub ahead of print]45(1): 116843

Activation of nuclear Ca2+-dependent gene expression by CRAC channel Ca2+ nanodomains.

Yu-Ping Lin, Abdull J Massri, Yi-Ting Huang, Sara A Grimm, Anant B Parekh.

  Oscillations in the levels of second messengers are observed throughout the phylogenetic tree, with signaling information encoded in the frequency of the spikes. Different biological targets respond to different frequencies of oscillation, leading to the concept of frequency counting. The most widely observed and best understood oscillatory second messenger is cytosolic Ca2+. Ca2+ oscillations are generated in all cell types, are seen throughout the life of a cell, and are indispensable for diverse biological processes ranging from fertilization to cell death and myriad responses in between including excitation-transcription coupling through Ca2+-dependent gene expression. The widely expressed Ca2+-dependent transcription factors nuclear factor (NF) of activated T cells (NFAT) and NF-κB are recruited by different Ca2+ oscillation frequencies, increasing the signaling bandwidth through the universal Ca2+ messenger. Here, we show that Ca2+ nanodomains near Ca2+ channels at the cell surface are central to gene expression. Cytosolic Ca2+ oscillations are not necessary for Ca2+-dependent gene expression, provided Ca2+ nanodomains near Ca2+ release-activated Ca2+ (CRAC) channels are formed. Our results establish that a fundamental unit of excitation-transcription coupling is the Ca2+ channel nanodomain at the cell surface.

Keywords:  CP: cell biology; Calcium channel; NFAT; calcium oscillations; gene expression; nanodomain; store operated

DOI:  https://doi.org/10.1016/j.celrep.2025.116843
Adv Exp Med Biol. 2026 ;1494 217-237

Lipid Metabolism in Relation to Calcium Homeostasis.

Umut Toprak.

  Calcium (Ca2+) homeostasis is a critical regulator of insect cellular functions, influencing neurotransmission, muscle contraction, hormone signaling, and lipid metabolism. This chapter explores the intricate relationship between Ca2+ signaling and lipid metabolism, emphasizing key molecular components that mediate this interaction. Store-operated calcium entry (SOCE) mechanisms, involving sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), inositol 1,4,5-trisphosphate receptor (IP3R), ryanodine receptor (RyR), stromal interaction molecule (STIM), and Orai1, coordinate intracellular Ca2+ fluxes that regulate lipid storage, mobilization, and utilization. Other Ca2+-binding proteins, such as calmodulin (CaM), calcineurin (CaN), regucalcin (RgN), calreticulin (CrT), and calnexin (CnX), further modulate Ca2+ homeostasis and impact lipid metabolism by influencing lipolysis, lipogenesis, and lipid droplet dynamics. This chapter also highlights the role of hepatocyte-like oenocytes in lipid metabolism. These cells, analogous to mammalian hepatocytes, regulate lipid processing and mobilization during fasting, forming a metabolic axis with fat body adipocytes. While Ca2+ signaling is well characterized in adipocytes, its role in oenocyte lipid metabolism remains largely unexplored. However, Ca2+-dependent regulation of lipid metabolism in mammalian hepatocytes suggests a similar involvement in insect oenocytes. A central theme is the bidirectional relationship between Ca2+ homeostasis and lipid metabolism. While Ca2+ signaling regulates lipid accumulation and hydrolysis, impaired lipid metabolism can disrupt Ca2+ homeostasis. For instance, Drosophila melanogaster seipin mutants with defective lipid storage exhibit reduced SERCA activity, leading to lower ER and mitochondrial Ca2+ levels, which impair lipogenesis. Additionally, CaN promotes lipogenesis, whereas STIM and IP3R serve as lipolytic regulators. This metabolic feedback loop is essential for maintaining energy balance. Understanding the Ca2+-lipid interplay in insects provides insights into metabolic regulation, with implications for pest management and metabolic disease research. Future studies should further investigate Ca2+-dependent mechanisms governing oenocyte function and systemic lipid homeostasis.

Keywords:  Calcium; Ip3r; Lipid; ORAI; SERCA; SOCE; STIM

DOI:  https://doi.org/10.1007/978-3-032-04842-4_875
Int J Cardiol. 2026 Jan 15. pii: S0167-5273(26)00027-6. [Epub ahead of print]449 134179

Caveolin-3 serves as a therapeutic target for myocardial ischemia-reperfusion injury in cardiac surgery patients.

Shiyun Jin, Weijun Liu, Xinyu Chen, Wenya Guo, Qijing Xing, Juan Wu, Ye Zhang.

   BACKGROUND: Caveolin-3 (Cav3) has been reported to protect both normal and failing hearts against myocardial ischemia/reperfusion (I/R) injury in rodent models. However, there is currently no evidence demonstrating its cardioprotective effects in human hearts. In this study, we investigate whether Cav3 is involved in myocardial I/R injury during cardiac surgery and the underlying mechanisms.
METHODS: Human atrial tissues were collected from cardiac surgery patients before myocardial ischemia and 30 min after reperfusion. The tissue samples were analyzed by western blot to assess the expression levels of Cav3, pro-survival kinases, and apoptosis-related proteins. Immunofluorescence assessed Cav3 distribution, and apoptosis staining evaluated cardiomyocyte death. Cardiac enzymes, lactate levels, and hospitalization data were also recorded.
RESULTS: The expression levels of cardiac Cav3 protein exhibit around 60% reduction following myocardial I/R injury in the human heart. The reduction of Cav3 showed a strong negative correlation with cardiac injury. Similarly, the phosphorylation of ERK1/2, Akt, STAT3, and GSK3β, is markedly downregulated in cardiac tissue following I/R injury. Furthermore, the pro-apoptotic protein Bax and caspase-3 shows substantial upregulation, while the anti-apoptotic protein Bcl-2 is significantly downregulated. Importantly, a strong positive correlation was observed between decreased Cav3 expression and reduced phosphorylation of survival kinases, while a negative correlation was found with cardiomyocyte apoptosis.
CONCLUSION: Our data suggest that the downregulation of Cav3 is associated with increased cardiac injury in the human heart. Targeting Cav3 may represent a promising therapeutic strategy for mitigating myocardial I/R injury in patients undergoing cardiac surgery.

Keywords:  Cardiac surgery; Cardioprotection; Cardiopulmonary bypass; Caveolin-3; Ischemia/reperfusion injury

DOI:  https://doi.org/10.1016/j.ijcard.2026.134179