bims-miptne Biomed News
on Mitochondrial permeability transition pore-dependent necrosis
Issue of 2026–03–29
eight papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool
  1. Cyclophilin D, Regulator of Mitochondrial Permeability Transition and Bioenergetics, Promotes Adipogenic Differentiation of Mesenchymal Stem Cells.
  2. Structure-based design of pyrazole derivatives targeting the human Cyclophilin D binding site.
  3. Activation of TPC2 amplifies lysosome-mitochondria calcium transfer to regulate energetic stress responses.
  4. Cytosol alkalization induces cytosolic and mitochondrial calcium elevation in human cells.
  5. Dysfunction of α2δ4 leads to photoreceptor degeneration through disrupted synaptic mitochondria and calcium crosstalk.
  6. Role of dysregulated calcium homeostasis in astrocytes in neurodegenerative disorders.
  7. Molecular Interplay of Small Molecules and Calcium Ions with α-Synuclein Revealed by NMR and Molecular Dynamics Simulations.
  8. Cancer Metabolism and Its Historical & Molecular Foundations: An Overview.
  1. Cells. 2026 Mar 13. pii: 509. [Epub ahead of print]15(6):
    Cyclophilin D, Regulator of Mitochondrial Permeability Transition and Bioenergetics, Promotes Adipogenic Differentiation of Mesenchymal Stem Cells.
    Chen Yu, Sarah E Catheline, Roman A Eliseev.
      During aging, bone marrow stromal (a.k.a. mesenchymal stem) cells (BMSCs) shift their lineage commitment away from osteogenesis and towards adipogenesis, resulting in bone loss and marrow fat accumulation. We previously reported that during osteogenesis, BMSCs activate mitochondrial oxidative phosphorylation (OXPHOS) at least in part by downregulating cyclophilin D (CypD) expression and, consequently, mitochondrial permeability transition pore (MPTP) activity. We also reported that in contrast, during adipogenesis, BMSCs upregulate CypD and MPTP, activate glycolysis and inhibit OXPHOS. To further study the role of CypD in BMSC bioenergetics, adipogenesis and bone marrow fat accumulation, we used CypD loss-of-function (LOF) or gain-of-function (GOF) models in osteo-adipoprogenitors in vitro and in vivo. We found that CypD LOF and GOF are associated with impaired and enhanced BMSC adipogenesis, respectively, both in vitro and in ectopic bone grafts in vivo. In addition, bioenergetic profiling and metabolomic analyses show evidence of corresponding metabolic reprogramming in CypD LOF and GOF cells. In summary, our study demonstrates the role of CypD-regulated mitochondrial metabolism during BMSC adipogenesis, facilitating the understanding of stem cell fate determination and the molecular mechanism of age-related bone loss as well as bone marrow fat accumulation.
    Keywords:  BMSCs; adipogenesis; cyclophilin D; marrow fat; mitochondrial permeability transition
    DOI:  https://doi.org/10.3390/cells15060509
  2. Int J Biol Macromol. 2026 Mar 23. pii: S0141-8130(26)01422-4. [Epub ahead of print] 151496
    Structure-based design of pyrazole derivatives targeting the human Cyclophilin D binding site.
    Diana O Silva, Micael C Freitas, Catarina F Malta, Madalena T Martins, Pedro M F Sousa, Pedro M Matias, Daniel Schwarz, M Rita Ventura, Ulrich Grädler, Tiago M Bandeiras.
      Mitochondrial permeability transition pore (MPTP) dysregulation can be correlated with a variety of human diseases including multiple sclerosis, cardiovascular and neurological diseases. Human Cyclophilin D is a known MPTP regulator and although devoid of deep orthosteric sites, it is believed it can be targeted to develop clinically relevant candidates. Fragment-based drug discovery is a powerful approach for such drug-targets and we revisited a panel of 52 fragment hits by X-ray crystallography, which remained structurally elusive from a previous fragment screening campaign. Using two CypD mutants in a systematic parallel approach combining co-crystallization and soaking techniques (FragInc approach - from Fragment Incubation), new high-resolution crystal structures of CypD-fragment complexes were obtained. We identified a pyrazolo[1,5-a]pyrimidin-2(1H)-one fragment binding to a cleft in-between the known CypD S1' and S2 pockets. These structural insights guided the chemical synthesis of four new molecules to address simultaneously the novel pyrazolo binding pocket and the S2 site, and their crystal structures in complex with CypD were determined. This work opens new perspectives for structure-based drug design of novel tri-vector inhibitors targeting human CypD and proposes a parallel multi-technique methodology to address low-affinity fragments by X-ray crystallography.
    Keywords:  Cyclophilin D (CypD); Fragment-based drug design (FBDD); Mitochondrial permeability transition pore (MPTP)
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.151496
  3. bioRxiv. 2026 Mar 04. pii: 2026.03.03.709381. [Epub ahead of print]
    Activation of TPC2 amplifies lysosome-mitochondria calcium transfer to regulate energetic stress responses.
    Sadia Ahmed, Namratha Javvaji, Katherine L Hammond, Kevin M Casin, John W Elrod, Paul M Holloway, Yvonne Couch, Jillian N Simon.
      Mitochondrial Ca 2+ uptake governs metabolism and cell fate, yet how signals from other organelles shape this remains incompletely defined. Although lysosomes are relatively small Ca 2+ stores, their strategic positioning at organelle contact sites suggests they may amplify Ca 2+ transfer within nanodomains. Here, we show that activation of the lysosomal Two-pore channel 2 (TPC2) initiates rapid mitochondrial Ca 2+ uptake through an endoplasmic reticulum-dependent relay requiring IP₃ receptors and the mitochondrial calcium uniporter channel. The extent of mitochondrial Ca 2+ accumulation scales with TPC2 activity without affecting global Ca 2+ responses, identifying TPC2 as a specific amplifier of lysosome-mitochondria Ca 2+ exchange. Moderate TPC2 activation transiently enhances oxidative phosphorylation, whereas sustained enhancement increases susceptibility to Ca 2+ -induced mitochondrial permeability transition. In stroke models, hyperactivation of TPC2 exacerbates injury, while acute pharmacological inhibition at reperfusion confers neuroprotection, including in human iPSC-derived neurons. Thus, lysosomal Ca 2+ release acts as an upstream regulator of mitochondrial energetic resilience under stress.
    DOI:  https://doi.org/10.64898/2026.03.03.709381
  4. Biochem Biophys Res Commun. 2026 Mar 12. pii: S0006-291X(26)00315-3. [Epub ahead of print]814 153551
    Cytosol alkalization induces cytosolic and mitochondrial calcium elevation in human cells.
    A Vlasova, S Bukhalovich, D Kravtsunova, A Gromova, D Bagaeva, A Zhilinskaya, A Bogorodskiy, N Ilyinsky, A Vlasov, A Kuklin, E Bamberg, V Gordeliy.
      Calcium ions (Ca2+) orchestrate cellular physiology as a versatile and ubiquitous second messenger, regulating a wide range of intracellular processes, including muscle contraction, secretion, metabolism, cell proliferation, and cell death. Here, we show that optogenetic cytosolic alkalization induced by the outward proton-pumping microbial rhodopsin Arch3 from Halorubrum sodomense triggers extracellular calcium influx into the cytosol of human cells. This elevation in cytosolic Ca2+ is accompanied by a subsequent increase in mitochondrial matrix Ca2+ concentration and depletion of cellular ATP. Together, these findings demonstrate how changes in cytosolic pH can modulate calcium signaling, mitochondrial physiology, and the induction of cell death. These insights are important for fundamental studies of cell physiology and may contribute to the development of improved anticancer therapeutic strategies.
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153551
  5. Cell Death Dis. 2026 Mar 23.
    Dysfunction of α2δ4 leads to photoreceptor degeneration through disrupted synaptic mitochondria and calcium crosstalk.
    Choice I Amieghemen, Trong Thuan Ung, Gillian N Huskin, James A Mobley, Melissa F Chimento, Mai Nguyen, James Fortenberry, Timothy W Kraft, Steven J Pittler, Yuchen Wang.
      Synaptic deficit has emerged as a key early hallmark for neurodegeneration in the visual pathway. The molecular pathway connecting local synaptic deficit with global cell dysfunction and death remains unclear. We have previously shown that α2δ4, an auxiliary subunit of the voltage-gated calcium channel, is targeted to photoreceptor synapses and required for their formation and function. Notably, α2δ4 mutations have been identified in patients with retinal dystrophy. However, how loss of synaptic α2δ4 leads to overall photoreceptor degeneration remains unknown. Here, we showed that α2δ4 loss in mice leads to a late onset photoreceptor degeneration around 7 months. Consistent with clinical observation, the progression of degeneration is minimal until 17 months, as supported by ERG, OCT imaging and histology. We found that Cav1.4 KO mice, where the calcium channel is missing, display an earlier degeneration onset than α2δ4 KO mice, where calcium channel is partially preserved. Proteomic studies revealed that tricarboxylic acid (TCA) cycle is significantly downregulated in the young α2δ4 KO retinas prior to degeneration. Transmission electron microscopy study demonstrated significant reduction in mitochondrial size and number in photoreceptor synaptic terminals, but not in the inner segment (IS), of the young α2δ4 KO retinas. Consistently, immunohistochemistry (IHC) studies showed significant reduction of mitochondrial proteins in the outer plexiform layer (OPL). IHC studies on ER and mitochondrial proteins revealed that ryanodine receptor (RyR2) and mitochondrial calcium uniporter (MCU) are downregulated in the OPL, but not in the IS. Together, our results propose a model where α2δ4 dysfunction impairs Cav1.4 channel activity, leading to disrupted calcium crosstalk among the plasma membrane, ER, and mitochondria, as well as mitochondrial damage and metabolic deficits. Importantly, our study underscores the critical role of synaptic calcium homeostasis and mitochondrial integrity in connecting the early stages of synaptic dysfunction with the later stages of cell degeneration.
    DOI:  https://doi.org/10.1038/s41419-026-08587-3
  6. Nat Rev Neurosci. 2026 Mar 26.
    Role of dysregulated calcium homeostasis in astrocytes in neurodegenerative disorders.
    Maria V Sanchez-Mico, Maria Calvo-Rodriguez, Brian J Bacskai.
      Calcium signalling in astrocytes is a fundamental mechanism for maintaining brain homeostasis, shaping neuronal activity, and coordinating vascular and immune responses. Once considered secondary to neuronal signalling, astrocytic Ca2+ dynamics are now recognized as highly versatile, spatially compartmentalized and essential for regulating neurotransmitter uptake, ion buffering, metabolic support and mitochondrial function. Accumulating evidence shows that these Ca2+ signalling pathways are progressively remodelled during ageing and become profoundly dysregulated in neurodegenerative diseases, including Alzheimer disease, Parkinson disease, Huntington disease and amyotrophic lateral sclerosis. Importantly, astrocyte Ca2+ alterations are heterogeneous and context-dependent, ranging from aberrant spontaneous activity to loss of signalling in specific subcellular domains, reflecting the disease stage, brain region and molecular pathology. Disruption of astrocyte Ca2+ homeostasis compromises core homeostatic functions and contributes to neuronal vulnerability, circuit dysfunction and impaired neurovascular regulation. By integrating current evidence across physiological, ageing and disease contexts, this Review highlights astrocytic Ca2+ signalling as a central node in neurodegenerative pathophysiology and underscores its potential as a target for therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41583-026-01032-6
  7. ACS Chem Neurosci. 2026 Mar 24.
    Molecular Interplay of Small Molecules and Calcium Ions with α-Synuclein Revealed by NMR and Molecular Dynamics Simulations.
    Filippo Turchi, Haydar Taylan Turan, Marco Schiavina, Giuseppe Brancato, Isabella C Felli, Roberta Pierattelli.
      Human α-synuclein is an intrinsically disordered protein concentrated at presynaptic terminals and strongly linked to Parkinson's disease and other synucleinopathies. Its dynamic C-terminal region mediates interactions with small molecules and metal ions. Here, we used high-resolution nuclear magnetic resonance spectroscopy (NMR) and molecular dynamics (MD) simulations to characterize interactions between the C-terminal α-synuclein construct, the small molecule fasudil, and calcium ions. NMR data show that fasudil and Ca2+ bind preferentially to overlapping regions enriched in alternating tyrosine and acidic residues while preserving the protein's disordered nature. Side-chain-resolved spectra indicate distinct driving forces for fasudil and calcium binding. MD simulations reveal that Ca2+ modifies the local electrostatic environment, decreasing fasudil interaction frequency through electrostatic screening and steric effects. Despite this, fasudil retains dynamic, reversible contacts with key tyrosine residues. Overall, exposed α-synuclein conformations allow simultaneous, ligand-specific interactions, highlighting side-chain hotspots governing binding in Ca2+-rich conditions.
    Keywords:  13C NMR; Amino acids side chain; Drug discovery; Intrinsically Disordered Proteins; Protein interactions; Synucleinopathies
    DOI:  https://doi.org/10.1021/acschemneuro.6c00106
  8. Drugs Drug Candidates. 2026 Mar;5(1):
    Cancer Metabolism and Its Historical & Molecular Foundations: An Overview.
    Rami A Al-Horani.
      Cancer metabolism is a cornerstone of tumor biology, characterized by profound alterations in cellular energy production and biosynthetic pathways that drive malignancy. The seminal discovery of the "Warburg effect", the preference of cancer cells for aerobic glycolysis even under oxygen-rich conditions, provided the first major insight into this field. Historically, this observation was attributed to defective mitochondria, but modern research has revealed a far more complex picture of metabolic reprogramming that is actively driven by oncogenes, tumor suppressor genes, and the tumor microenvironment (TME). This review advances a unifying framework for understanding cancer metabolism as a dynamic ecosystem defined by three interconnected adaptations: metabolic plasticity, oncometabolite-driven epigenetic remodeling, and immune-metabolic crosstalk. These adaptations extend beyond glycolysis to encompass glutamine metabolism, lipid synthesis, amino acid utilization, and mitochondrial dynamics, all coordinated to fuel rapid proliferation, promote survival, and enable metastasis. By examining the drivers, consequences, and therapeutic barriers within this framework, we highlight emerging strategies for precision intervention. Although understanding the mechanistic basis of these pathways has unveiled new therapeutic avenues, clinical translation has been limited by metabolic redundancy, microenvironmental buffering, and patient heterogeneity. Strategies such as metabolic inhibitors, dietary interventions, and immuno-metabolic combinations offer promising prospects for disrupting tumor growth when guided by biomarker-driven patient selection and emerging technologies, including spatial metabolomics and AI-driven network modeling.
    Keywords:  TME; Warburg effect; aerobic glycolysis; epigenetic regulation; metabolic reprogramming; mitochondrial dynamics; targeted therapy
    DOI:  https://doi.org/10.3390/ddc5010017
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