bims-miptne 2026-04-19 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2026–04–19
fourteen papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Extracellular Vesicle-Mediated Delivery of Mitochondrial Circular RNA MTCO2 Protects against Cerebral Ischemia by Modulating mPTP-Dependent Ferroptosis.
Loss of TMEM65 in mice causes mitochondrial disease mediated by mitochondrial Ca2.
Distinct Ca2+ pools regulate NADPH oxidase 2 activation driving Ca2+-independent mitochondrial ROS formation and mitochondrial permeability transition in arsenic trioxide-treated NB4 cells.
Mitochondrial Calcium Signaling in the Brain: From Molecular Mechanisms to Behavioral Outcomes.
Biowaste-Archetyped Hierarchical Calcium Carbonate Nanoreactors Induce Tumor Bioenergetic Crisis and Reverse Cisplatin Resistance via Mitochondrial Metabolic Reprogramming.
Mitochondrial transfer as a driver of immune microenvironment remodeling.
Therapeutic and mechanistic insights on mitochondrial transplantation in kidney disease.
Cell death in cancer.
Proteomic Profiling Reveals How Physiological Media Reshape Cancer Cell Proteomes and Signaling Networks.
Cell-type-targeted mitochondrial transplantation rescues cell degeneration.
Mitochondrial metabolism regulates the immunogenic responsiveness of dendritic cells.
Blocking ubiquitination of hnRNPA1 maintains the self-renewal of breast cancer stem cells via mutually exclusive splicing of PKM pre-mRNA.
Organelles storing Ca2+ in the brain cells: New druggable targets in neurodegenerative diseases.
Targeting VDAC1 to protect against mitochondria-linked cell death pathways: apoptosis, pyroptosis, ferroptosis, and associated diseases.

Research (Wash D C). 2026 ;9 1232

Extracellular Vesicle-Mediated Delivery of Mitochondrial Circular RNA MTCO2 Protects against Cerebral Ischemia by Modulating mPTP-Dependent Ferroptosis.

Jialei Yang, Shipo Wu, Miao He.

Ischemic stroke remains a major cause of mortality and long-term disability, with few effective neuroprotective treatments currently available. Ferroptosis, an iron-dependent form of regulated cell death marked by lipid peroxidation, is increasingly recognized as a driver of neuronal damage. However, the mitochondrial mechanisms linking ischemia to ferroptosis remain poorly defined. Here, we identify circMTCO2, a mitochondria-encoded circular RNA (circRNA), as a novel endogenous modulator of neuronal ferroptosis. circMTCO2 expression is dynamically down-regulated following cerebral ischemia/reperfusion in vitro and in vivo. Mechanistically, circMTCO2 interacts with adenine nucleotide translocase 1 (ANT1), a key regulator associated with the mitochondrial permeability transition pore (mPTP), thereby inhibiting mPTP opening and suppressing mitochondrial reactive oxygen species release. Disruption of the binding site abolishes circMTCO2-ANT1 interaction and eliminates the protective effects of circMTCO2. To restore and enhance this intrinsic defense mechanism, we developed a dual-targeting extracellular vesicle system (RVG-EVmt-RNA) capable of delivering circMTCO2 specifically to neuronal mitochondria. Systemic administration of RVG-EVmt-RNA decreased infarct volume, attenuated ferroptosis-associated injury, and improved neurological function in a mouse model of ischemic stroke, without inducing systemic toxicity. These findings establish circMTCO2 as a previously unrecognized mitochondrial circRNA that regulates ferroptosis by modulating mPTP activity and provide a proof of concept that organ-to-organelle circRNA delivery can be leveraged as a precision neuroprotective strategy for ischemic stroke.

DOI: https://doi.org/10.34133/research.1232
Nat Commun. 2026 Apr 14.

Loss of TMEM65 in mice causes mitochondrial disease mediated by mitochondrial Ca2.

Yingfan Zhang, Hailey A Parry, Laura Reyes, Alex Shamoun, Junhui Sun, Chengyu Liu, Danielle Springer, Audrey Noguchi, Sachiko Nakamori, Angel M Aponte, Jeeva Munasinghe, Raul Covian, Elizabeth Murphy, Brian Glancy.

Transmembrane protein 65 (TMEM65) depletion in a patient caused severe mitochondrial encephalomyopathy, highlighting its clinical importance. Recent studies show TMEM65 acts as a mitochondrial Na+/Ca2+ exchanger in vitro. Here, we generated conditional Tmem65 knockout mice to define its role in neuromuscular tissues in vivo. Both whole-body and nervous system-specific Tmem65 knockouts exhibited severe growth retardation and seizure-associated sudden death at ~3 weeks, establishing TMEM65 as indispensable for neuronal function. Additionally, skeletal muscle-specific knockout produced adult-onset myopathy preceded by elevated mitochondrial Ca2+. Consistently, TMEM65 ablation caused loss of Na+-dependent mitochondrial Ca2+ export. Notably, blocking mitochondrial Ca2+ entry by mitochondrial calcium uniporter (MCU) knockout rescued the early lethality of whole-body Tmem65 ablation, extending lifespan from ~3 weeks to >1 year. These data reveal an essential physiological role for TMEM65 and suggest that modulating mitochondrial Ca2+ may offer therapeutic value for TMEM65 misexpression and other mitochondrial diseases associated with Ca2+ overload.

DOI: https://doi.org/10.1038/s41467-026-71761-w
Arch Toxicol. 2026 Apr 13.

Distinct Ca2+ pools regulate NADPH oxidase 2 activation driving Ca2+-independent mitochondrial ROS formation and mitochondrial permeability transition in arsenic trioxide-treated NB4 cells.

Andrea Guidarelli, Andrea Spina, Gloria Buffi, Mara Fiorani, Orazio Cantoni.

  Clinically relevant concentrations of arsenic trioxide (ATO) induce apoptosis in NB4 cells through a complex, yet poorly defined interplay between endoplasmic reticulum-derived Ca2+ signalling and mitochondrial oxidative stress. This study enhances our understanding of these mechanisms by demonstrating that exposure to 1 µM ATO initiates a biphasic Ca2+ release: an initial flux from inositol 1,4,5-trisphosphate receptors (IP₃Rs), followed by a secondary release via ryanodine receptors (RyRs). Unlike IP3R-derived Ca2+, the fraction of the cation released through RyRs is subsequently taken up by mitochondria. Notably, IP3R-derived Ca2+ uniquely activates NADPH oxidase 2 (NOX 2), a key event leading to the downstream generation of mitochondrial superoxide (mitoO2.-). Importantly, mitochondrial Ca2+ accumulation itself is not required for mitoO2.- emission. ATO-induced genomic DNA strand breaks are mediated by NOX 2-derived reactive oxygen species (ROS), both directly and indirectly, through the subsequent induction of mitochondrial ROS formation. Furthermore, mitochondrial uptake of RyR-derived Ca2+ is essential for triggering the mitochondrial permeability transition and the ensuing apoptotic cell death. Although sodium arsenite elicited comparable effects on Ca2+ homeostasis, it promoted mitoO2.- generation via a distinct, NOX 2-independent pathway that relied on RyR-mediated mitochondrial Ca2+ accumulation. Thus, in NB4 cells, ATO exposure orchestrates a functional crosstalk between discrete Ca2+ sources to regulate a cascade of events culminating in NOX 2 activation, mitoO2.- production, and initiation of the mitochondrial apoptotic pathway.

Keywords:  Acute promyelocytic leukemia; Apoptosis; Arsenic trioxide; Inositol 1,4,5-trisphosphate receptor; Mitochondrial permeability transition; Mitochondrial superoxide; NADPH oxidase 2; Ryanodine receptor

DOI:  https://doi.org/10.1007/s00204-026-04328-9
Neuroscientist. 2026 Apr 11. 10738584261425658

Mitochondrial Calcium Signaling in the Brain: From Molecular Mechanisms to Behavioral Outcomes.

Sandrine Pouvreau, Giovanni Marsicano, Julia Welte.

  Mitochondria are multifaceted organelles positioned at the intersection of multiple signaling pathways. Beyond serving as one of the main energy providers in the brain, they play crucial roles in shaping cytosolic calcium signals across both neuronal and glial cell populations, modulating synaptic transmission and plasticity, and regulating neuronal excitability and network activity. The involvement of mitochondrial calcium handling in brain cell physiology has been explored for many years. However, by enabling in vivo cell-specific manipulations, the molecular identification of mitochondrial calcium signaling protein complexes, over the past 2 decades, has tremendously improved our understanding of how mitochondria regulate brain function and behavior.This review synthesizes current knowledge of mitochondrial calcium handling mechanisms and protein complexes in the nervous system, as well as their involvement in brain function, from cellular physiology to behavioral consequences. We discuss pharmacological and genetic evidence for a role of mitochondrial calcium handling in synaptic transmission, neuronal excitability, astrocyte functions, and circuit activity. We underline experimental differences across approaches and models, as well as show how genetic tools have challenged or confirmed earlier pharmacological results. Finally, we examine how recent advances using transgenic models have revealed complex roles for mitochondrial calcium signaling in behavioral responses and opened new research avenues.

Keywords:  astrocytes; behavior; calcium signaling; mitochondria; neuronal activity; synaptic function

DOI:  https://doi.org/10.1177/10738584261425658
ACS Appl Mater Interfaces. 2026 Apr 15.

Biowaste-Archetyped Hierarchical Calcium Carbonate Nanoreactors Induce Tumor Bioenergetic Crisis and Reverse Cisplatin Resistance via Mitochondrial Metabolic Reprogramming.

Shupeng Shi, Haicong Liu, Qingping Peng, Shenao Nan, Shuyan Liu, Linna Wei, Haoyu Wang, Kai Wang, Xiaohong Zhong, Xin Chen, Wenzhe Gao.

  The development of next-generation nanotheranostics is increasingly challenged by the dual imperatives of environmental sustainability and the urgent need to overcome complex biological barriers, particularly multidrug resistance (MDR) in hepatocellular carcinoma (HCC). Herein, we bridge the gap between circular economy principles and precision nanomedicine by upcycling discarded eggshell membranes (ESM) into a hierarchical metabolic therapeutic platform. Utilizing the protein fiber network of ESM as a natural biotemplate, we orchestrated the anisotropic growth of calcium carbonate (CaCO3) into unique yolk-shell nanostructures (YSNs) via interfacial molecular recognition. This bioinspired architecture features a high specific surface area, enabling the efficient coloading of the chemotherapeutic cisplatin (CDDP) and ultrathin vanadium carbide (V4C3) MXene nanozymes, stabilized by a biotinylated carboxymethyl chitosan (Biotin-CMCS) targeting shell. Mechanistically, this "Trojan Horse" system exploits the acidic tumor microenvironment (TME) to trigger a rapid cascade of disassembly, releasing a surge of Ca2+ ions and MXene-driven reactive oxygen species (ROS). Crucially, we demonstrate that the resulting mitochondrial calcium overload instigates a catastrophic "bioenergetic crisis," characterized by the irreversible opening of mitochondrial permeability transition pores (mPTP) and the precipitous depletion of intracellular adenosine triphosphate (ATP). This metabolic collapse effectively deactivates ATP-dependent DNA repair machineries (e.g.,poly(ADP-ribose) polymerase 1 (PARP1) and excision repair cross-complementation group 1 (ERCC1)), thereby reversing cisplatin resistance and sensitizing tumor cells to DNA damage. In vivo evaluations in HCC xenografts confirm potent tumor regression with minimal systemic toxicity, facilitated by the renal clearance of biodegradable calcium metabolites. This work presents a paradigm shift in material design, transforming biowaste into a metabolic reprogramming weapon for sustainable and effective cancer therapy.

Keywords:  biowaste upcycling; calcium overload; hepatocellular carcinoma; multidrug resistance; tumor microenvironment

DOI:  https://doi.org/10.1021/acsami.6c01369
Front Immunol. 2026 ;17 1743261

Mitochondrial transfer as a driver of immune microenvironment remodeling.

Xiaoya Zhang, Danmei Zhang, Jin Guo, Chunxia Shi, Zuojiong Gong.

  Mitochondria are central regulators of immunometabolism, and emerging evidence identifies intercellular mitochondrial transfer as a key driver of immune microenvironment remodeling. Beyond energy production, transferred mitochondria reshape immune niches by reprogramming metabolic fitness, redox balance, inflammatory tone, and immune cell interactions. Through multiple transfer routes, including tunneling nanotubes, extracellular vesicles, and gap junctions, mitochondrial exchange modulates immune activation, immunosuppression, and tolerance across diverse physiological and pathological contexts. In this review, we summarize current mechanisms of mitochondrial transfer and highlight how this process directionally remodels the immune microenvironment in inflammation, cancer, and autoimmune diseases. We further discuss therapeutic strategies aimed at modulating mitochondrial transfer to reprogram immune responses, providing new perspectives for immunomodulation and disease intervention.

Keywords:  cancer; immune cell; immune microenvironment; inflammation; mitochondria transfer

DOI:  https://doi.org/10.3389/fimmu.2026.1743261
Nat Rev Nephrol. 2026 Apr 14.

Therapeutic and mechanistic insights on mitochondrial transplantation in kidney disease.

James D McCully, Aybuke Celik, Amish Asthana, Giuseppe Orlando.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are major contributors to global morbidity and mortality, with limited treatment options beyond supportive care. Mitochondrial dysfunction is a shared feature of both conditions, driving impaired energy production, oxidative stress and cell death. Owing to its reliance on oxidative phosphorylation, the kidney is especially vulnerable to ischaemia-reperfusion injury, a leading cause of AKI and a risk factor for long-term loss of kidney function. Persistent mitochondrial damage contributes to the transition from AKI to CKD, and strategies aimed at restoring mitochondrial health, therefore, have therapeutic potential. Here, we focus on mitochondrial transplantation, a therapeutic approach that delivers viable, respiratory-competent mitochondria to injured tissue to support recovery. Mitochondria for transplantation can be isolated from a variety of sources (autologous or allogeneic) without triggering an immune, autoimmune or inflammatory response, or a reaction to damage-associated molecular patterns. Isolated mitochondria can be delivered by intra-arterial injection, and, once in the target organ, they are rapidly integrated into the cells through endocytosis. Mitochondrial transplantation supports the restoration of mitochondrial function and associated signalling pathways, promoting enhanced organ function and cellular viability. Several preclinical studies have demonstrated improved kidney function, reduced inflammation and preserved mitochondrial structure following mitochondrial therapy in models of ischaemia.

DOI: https://doi.org/10.1038/s41581-026-01072-2
Cell. 2026 Apr 16. pii: S0092-8674(26)00325-9. [Epub ahead of print]189(8): 2322-2356

Cell death in cancer.

Marcus Conrad, Andreas Strasser, Philipp J Jost, Junying Yuan, Feng Shao, Peter Vandenabeele, Adam Wahida.

"Evasion of cell death" is a hallmark of cancer, enabling transformed cells to withstand oncogenic and therapeutic stress. Restoring cancer cell death is an appealing strategy but requires a deep understanding of cell death programs. Over the past two decades, the cell death field has expanded from apoptosis to include necroptosis, pyroptosis, ferroptosis, and other emerging programs, reshaping cancer biology and revealing therapeutic opportunities. While apoptosis remains the primary radiation- and chemotherapy-induced cell death program, non-apoptotic programs can drive inflammatory responses and orchestrate the interplay among tumor, stroma, and immune components, influencing immunotherapy outcomes. Ferroptosis, an iron-dependent, lipid peroxidation-driven cell death modality, lacks a canonical induction signal and arises from perturbations in lipid, iron, and redox metabolism. This review presents a unified framework for understanding the roles of major cell death programs in cancer development, progression, and treatment response, as well as addressing resistance to cancer cell death and immune suppression. "Our bodies are made of cells that live, and just as surely, of cells that must die." -S. Brenner.

DOI: https://doi.org/10.1016/j.cell.2026.03.024
Mol Cell Proteomics. 2026 Apr 15. pii: S1535-9476(26)00065-4. [Epub ahead of print] 101569

Proteomic Profiling Reveals How Physiological Media Reshape Cancer Cell Proteomes and Signaling Networks.

Colin Zenge, Brittany Q Pham, Kihong Nam, Elana Apfelbaum, Heeseon An, Alban Ordureau.

  Altered metabolism is a hallmark of cancer, making metabolic enzymes attractive therapeutic targets. However, metabolic inhibitors have shown limited clinical success, partly due to differences between standard culture media and physiological nutrient conditions. Human plasma-like medium (HPLM) better recapitulates in vivo metabolite concentrations, yet its effects on cellular proteomes remain poorly characterized. We performed comprehensive TMTpro-based quantitative proteomics and phosphoproteomics across nine cancer cell lines cultured in DMEM or HPLM, consistently quantifying over 10,000 proteins and 24,000 phosphorylation sites across all three biological replicates with high reproducibility. Physiological media induced profound cell-type-specific remodeling of metabolic networks, mitochondrial proteomes, and signaling pathways. While decreased mTORC1 and CDK activity represented universal responses across all cell lines, metabolic enzyme expression exhibited striking heterogeneity. Enzymes in folate metabolism and pyrimidine salvage pathways showed consistent reductions across all cell types, indicating that drug responses may vary with media choice. Mitochondrial proteome composition and morphology displayed cell-type-specific adaptations. Phosphoproteomic analysis revealed kinase signaling networks underlying these metabolic changes. This dataset, accessible via an interactive web application, provides a resource for metabolic research using physiological media, highlighting substantial cell-type-specific variability in how media affect proteomes and signaling pathways.

Keywords:  CDK activity; Cancer cell metabolism; Physiological Media; Proteomics; mTORC1 signaling

DOI:  https://doi.org/10.1016/j.mcpro.2026.101569
Nature. 2026 Apr 15.

Cell-type-targeted mitochondrial transplantation rescues cell degeneration.

Temurkhan Ayupov, Verónica Moreno-Juan, Serena Curtoni, Alex Fratzl, Upnishad Sharma, Susana Posada-Céspedes, Ramona Ratiu, Rei Morikawa, Alexandra Graff Meyer, Margherita Pezzoli, Glenn Bantug, Morgan Chevalier, Yanyan Hou, Sarah A Nadeau, Álvaro Herrero-Navarro, Vikram Ayinampudi, Elizabeth Kastanaki, Natasha Whitehead, Rebecca A Siwicki, Mariana M Ribeiro, Ji Hoon Han, Annalisa Bucci, Christoph Hess, Simone Picelli, Magdalena Renner, Daniel J Müller, Cameron S Cowan, Simon Hansen, Botond Roska.

A number of currently untreatable diseases, including neurodegenerative disorders, optic nerve atrophy and heart failure, are associated with mitochondrial dysfunction. Transplantation of healthy mitochondria has been proposed as a potential therapeutic strategy1-3. However, the lack of methods to target donor mitochondria to disease-affected cell types limits treatment specificity and efficacy. Here we developed MitoCatch as a system to deliver mitochondria to specific cell types using different types of protein binders. Donor mitochondria are captured by target cells by cell-surface-displayed monospecific binders, mitochondrion-displayed monospecific binders or bispecific binders linking mitochondria to target cells. Using MitoCatch, we show that donor mitochondria are efficiently internalized, exposed to the cytosol, move, and undergo fusion and fission inside target cells. By engineering binders with different affinities, we tune the efficiency of mitochondrial delivery. We demonstrate targeted mitochondrial transplantation to retinal cell types, neurons and cardiac, endothelial and immune cells in humans and mice. Transplanted mitochondria promoted the survival of damaged neurons from an individual with optic nerve atrophy in vitro and after neuronal injury in mice in vivo. MitoCatch is a potential strategy to target disease-affected cell types with mitochondria in organs affected by diseases associated with mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s41586-026-10391-0
Cell Metab. 2026 Apr 15. pii: S1550-4131(26)00106-3. [Epub ahead of print]

Mitochondrial metabolism regulates the immunogenic responsiveness of dendritic cells.

Ignacio Heras-Murillo, Diego Mañanes, Josep Calafell-Segura, Adrián Belinchón García, Clara Borràs-Eroles, Pablo Munné, Annalaura Mastrangelo, Sarai Martínez-Cano, Pablo Hernansanz-Agustín, María A Zuriaga, José J Fuster, Marten Szibor, Ignacio Melero, José Antonio Enríquez, Navdeep S Chandel, Esteban Ballestar, Stefanie K Wculek, David Sancho.

  Activation of conventional dendritic cells (cDCs) favors increased glycolysis-driven lactic fermentation, while oxidative phosphorylation (OXPHOS) links to tolerance. Here, selective targeting of the mitochondrial electron transport chain (ETC) in cDCs uncovers a critical role for OXPHOS in regulating their immunogenicity. Disruption of ETC complex III dampens adjuvant-triggered primary human and mouse cDC1 activation and their capability to prime T cells for anti-cancer immunity, while it has a milder effect on cDC2s. Mechanistically, complex III impairment in cDC1s leads to a dysregulated redox and metabolite balance, altering DNA methylation of PU.1 and activator-protein-1 (AP-1) binding regions. These epigenetic changes hinder the rapid induction of immediate-early stimulus-induced genes in cDC1s upon stimulation. The reduced immunogenic responsiveness of ETC-impaired cDC1s can be rescued by ectopic expression of alternative oxidase and phenocopied by Tet2 deficiency. Our findings reveal that electron flow through the ETC maintains a poised activation state in cDC1s, essential for effective anti-tumor immunity.

Keywords:  DNA methylation; dendritic cells; electron transport chain; immunity; metabolites; mitochondria; redox balance

DOI:  https://doi.org/10.1016/j.cmet.2026.03.012
Oncogene. 2026 Apr 14.

Blocking ubiquitination of hnRNPA1 maintains the self-renewal of breast cancer stem cells via mutually exclusive splicing of PKM pre-mRNA.

Xuemei Lv, Li Han, Wei-Wei Tong, Xiaoyu Sun, Suying Xu, Yuanyuan Yan, Shuqi Zhou, Yangyang Zhang, Dikang Zhang, Jiaqi Wang, Jia Liu, Haishan Zhao, Weifan Yao, Ruixin Xiao, Qi Wang, Jianan Xu, Lang Gong, Minjie Wei, Bo Chen, Miao He.

PKM serves as a rate-limiting enzyme in glycolysis, which produces two isoforms depending on the inclusion of either exon 9 (PKM1) or exon 10 (PKM2). The M2 pyruvate kinase (PKM2) isoform is commonly upregulated in various cancers, where it plays a pivotal role in regulating Warburg effect. Breast cancer stem cells (BCSCs) exhibit enhanced glycolysis, which is crucial for their self-renewal. However, the specific role of PKM2 in BCSCs remains largely unexplored. Here, we report that PKM2 expression is upregulated in BCSCs. Meanwhile, we identify that LINC00887 is significantly upregulated in BRCA through a genome-wide LNCRNA microarray. Moreover, we recognize that hnRNPA1 interacts with PKM pre-mRNA and regulates its mutually exclusive splicing. Furthermore, we demonstrate that LINC00887 maintains the self-renewal of BCSCs by promoting PKM2 splicing and reprogramming glucose metabolism. Mechanistically, LINC00887 upregulates PKM2 expression by binding hnRNPA1, thereby concealing its ubiquitination site, which blocks its ubiquitination and maintains its stability. Consistently, overexpression of hnRNPA1 almost completely rescues/reverses the inhibitory effects of LINC00887 KD in BRCA. Collectively, our study characterizes the LINC00887/hnRNPA1/PKM1/2 axis in BRCA and reveals the essential role of LINC00887 in BCSCs self-renewal/maintenance through promoting hnRNPA1-mediated PKM2 splicing, highlighting the therapeutic potential of targeting cancer metabolism.

DOI: https://doi.org/10.1038/s41388-026-03776-y
Neural Regen Res. 2026 Apr 14.

Organelles storing Ca2+ in the brain cells: New druggable targets in neurodegenerative diseases.

Valentina Tedeschi, Raffaella Ciancio, Silvia Piccirillo, Alessandra Preziuso, Tiziano Serfilippi, Valentina Terenzi, Simona Magi, Vincenzo Lariccia, Pasqualina Castaldo, Antonio Vinciguerra, Ilaria Piccialli, Lorella Maria Teresa Canzoniero, Anna Pannaccione, Agnese Secondo.

  Several lines of evidence suggest that targeting dysfunctional calcium (Ca2+)-storing organelles and their defective connections may represent a promising therapeutic strategy counteracting neurodegeneration. Dysfunction in these compartments converges to promote oxidative and endoplasmic reticulum stress, energy failure, autophagy blockade or hyperactivation, and progressive neurodegeneration. Within the intracellular scenario, several dysfunctional organelles have been characterized in terms of their capability to hijack Ca2+ signaling during neurodegeneration to deadly impact on neuronal tasks in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, brain ischemia, and neonatal hypoxic injury. This review has focused on the endoplasmic reticulum, mitochondria, and lysosomes, as well as their functional interconnection able to maintain the physiological processes such as lysosomal-dependent autophagy and function, lipid trafficking, and protein quality control. Clinically, looking ahead from the already existing therapies, drugs that enhance mitochondrial Ca2+ efflux or modulate mitochondrial Ca2+ uniporter regulation at mitochondria-associated membranes-endoplasmic reticulum sites represent innovative opportunities for next-generation strategies aimed at restoring mitochondrial homeostasis and protecting dopaminergic neurons in Parkinson's disease. Furthermore, functional stabilization of the lysosomal channel transient receptor potential mucolipin 1 by the lipid-based formulation of PI(3,5)P2 may extend the lifespan of amyotrophic lateral sclerosis mice by stimulating the nuclear translocation of the master regulator of autophagy activated by lysosomal Ca2+ release, namely transcription factor EB. Moreover, dysfunction of lysosomal-dependent autophagy can cause mutant huntingtin accumulation in Huntington's disease through the repression of transcription factor EB and lysophagy induction. Collectively, this growing focus may highlight a shift toward recognizing mitochondria, lysosomes, and endoplasmic reticulum, as well as their ionic machinery and interconnections, as a unifying strategy to maintain neuronal viability and mitigate the neurodegeneration progression in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, lysosomal storage diseases, brain ischemia, and neonatal hypoxic insult.

Keywords:  ; autophagy; channels; endoplasmic reticulum; endoplasmic reticulum stress; lysosome; mitochondria; mitochondria-associated membranes; neurodegenerative diseases

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01754
Apoptosis. 2026 Apr 11. pii: 122. [Epub ahead of print]31(4):

Targeting VDAC1 to protect against mitochondria-linked cell death pathways: apoptosis, pyroptosis, ferroptosis, and associated diseases.

A Shteinfer-Kuzmine, A Karunanithi Nivedita, M Santhanam, S Trishna, R W Swerdlow, J Pan, V Shoshan-Barmatz.

  The pathways of programmed cell death (PCD), including apoptosis, pyroptosis, and ferroptosis, are interconnected. They can be activated simultaneously within tissues or cell lines and are often associated with various diseases. Thus, identifying a common player and inhibitor targeting several PCD types is essential. Here, we show that overexpression and oligomerization of the mitochondrial gatekeeper voltage-dependent anion channel 1 (VDAC1) is involved in apoptosis, pyroptosis, and ferroptosis, and specific VDAC1 oligomerization inhibitors, VBIT-4 and VBIT-12, prevented multiple forms of PCD triggered by various stimuli. In addition, they mitigated mitochondrial dysfunction, reduced reactive oxygen species production and intracellular Ca2⁺ levels, preserved mitochondrial-associated hexokinase, and inhibited assembly/activation of the NLRP3 inflammasome. In Alzheimer's disease and inflammatory bowel disease mouse models, VBIT-4 and VBIT-12, respectively, protected against apoptosis, pyroptosis, ferroptosis, and disease-associated pathologies. Thus, we show that VDAC1 oligomerization represents a prime target for VBIT-4 and VBIT-12 that can simultaneously inhibit various PCD forms and diseases associated with enhanced PCD and/or inflammation.

Keywords:  Apoptosis; Ferroptosis; Inflammation; Mitochondria; Oligomerization; Pyroptosis; VDAC1

DOI:  https://doi.org/10.1007/s10495-025-02217-7