bims-miptne 2026-05-10 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2026–05–10
eight papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Transplantation of Ru265-treated mitochondria enhances the therapeutic impact on skeletal muscle ischemia-reperfusion injury.
Novel strategies for mitigating hepatic ischemia-reperfusion injury: targeting MICU1 and calcium-glycolytic homeostasis with acteoside.
CD44-Targeting Hydroxyapatite Nanoparticles (HAP) Induce Mitochondrial Dysfunction-Driven PANoptosis and Immunogenic Cell Death (ICD) via Ca Overload in Colorectal Cancer.
Intestinal Ischemia/Reperfusion Injury: Mechanisms, Diagnosis, and Therapeutic Advances.
A century of cell death research.
Drug-Induced Liver Injury: Mitochondrial Mechanisms, Biomarkers, and Emerging Therapeutic Strategies.
Unraveling new functions of the Ca2+ sensor STIM1 in cell signaling.
The Role of Phospho-ubiquitin in Mitochondrial Health and Diseases.

Mol Cell Biochem. 2026 May 04.

Transplantation of Ru265-treated mitochondria enhances the therapeutic impact on skeletal muscle ischemia-reperfusion injury.

Saima Barki, Fazal Wahid, Shafia Khan, Laiba Tariq Abbasi, Zarrish Rubab, Ameer Hamza, Farman Ullah, Khadeeja Ahsan, Durre Shehwar, Muhammad Rizwan Alam.

  Mitochondrial transplantation (MT) is a promising therapeutic approach for the treatment of several pathologies, including ischemia-reperfusion injury (IRI). However, its efficacy remains limited by the high calcium concentration of the transplantation milieu. Elevated extracellular calcium induces MCU-mediated matrix calcium overload, leading to the opening of the permeability transition pore and metabolic collapse of the transplanted organelles. We hypothesized that shielding mitochondria from the adverse effects of high calcium using the reversible MCU inhibitor, Ru265, would increase the efficacy of MT therapy. An acute, non-invasive hindlimb skeletal muscle IRI model was established in BALB/c mice using orthodontic rubber bands to mimic peripheral artery disease. Isolated liver mitochondria were treated with Ru265 and evaluated for their responsiveness to calcium using the mitochondrial swelling assay. Mice subjected to hindlimb IRI received either standard MT (Mitochondria alone) or Ru265-treated mitochondria (Mito + Ru), and treatment efficacy was evaluated using various parameters. IRI induced significant changes in mouse body weight, musculoskeletal dysfunction, systemic inflammation, lipid peroxidation, and skeletal muscle damage. While standard MT therapy provided baseline recovery, the Mito + Ru group demonstrated superior outcomes, including significant body weight recovery, reduced infarct size, and attenuated oxidative stress. Thus, reversible shielding of exogenous mitochondria from calcium stress using Ru265 enhances the efficacy of MT therapy in rodent skeletal muscle IRI.

Keywords:  Ischemia Reperfusion Injury (IRI); Mitochondrial Calcium Uniporter (MCU); Mitochondrial Transplantation (MT); Ru265; Skeletal Muscle IRI

DOI:  https://doi.org/10.1007/s11010-026-05563-5
Int J Biol Sci. 2026 ;22(8): 4074-4094

Novel strategies for mitigating hepatic ischemia-reperfusion injury: targeting MICU1 and calcium-glycolytic homeostasis with acteoside.

Yinhao Zhang, Runping Liu, Yun Yang, Huayao Lu, Mengyu Guo, Hong Wang, Ranyi Luo, Xiaoyong Xue, Guifang Fan, Kaihong Xie, Jia Liu, Xiaojiaoyang Li.

  Hepatic ischemia-reperfusion injury (HIRI) contributes to metabolic disorders within hepatic sinusoid and frequently occurs during liver transplantation, yet its underlying mechanisms and intervention strategies remain obscure. This study aimed to elucidate whether acteoside (ACT) improved HIRI by repairing mitochondrial calcium uptake 1 (MICU1)-mediated Ca2+ dysregulation and facilitating glycolytic reprogramming. Using RNA sequencing, cleavage under targets & tagmentation (CUT&Tag) analysis, liver sinusoidal endothelial cells (LSECs)-specific overexpression virus or siMicu1 lipid nanoparticles and ACT derivatives, we explored the hepatoprotective mechanisms of ACT in vivo in HIRI mice and in vitro in hypoxia-reoxygenation or lactate-stimulated LSECs. ACT enhanced endoplasmic reticulum function and restored mitochondrial homeostasis, thereby alleviating LSECs damage and HIRI. Mechanistically, ACT directly bound to MICU1 and inhibited the overflow of Ca2+ from endoplasmic reticulum (ER) to mitochondria and subsequent mitochondrial Ca2+ overload. This competitive binding mode also suppressed MICU1-dependent glycolysis by blocking Ca2+-stimulated lactate production and histone H3K18 lactylation, which epigenetically regulated MICU1 transcription. Notably, ACT synergized with lactate inhibitors or siMicu1 lipid nanoparticles to enhance its anti-HIRI effects, while LSECs-specific Micu1 overexpression abolished these benefits. Structural analysis revealed that the C26/C27/C40/C41 hydroxyl groups determined ACT's MICU1-binding and hepatoprotective activities. This study identifies MICU1 as a central regulator of HIRI and reveals ACT as a targeted therapy by restoring Ca2+ balance and metabolic homeostasis.

Keywords:  HIRI; LSEC; acteoside; calcium ion; lactylation; lipid nanoparticles

DOI:  https://doi.org/10.7150/ijbs.126332
Adv Sci (Weinh). 2026 May 06. e75559

CD44-Targeting Hydroxyapatite Nanoparticles (HAP) Induce Mitochondrial Dysfunction-Driven PANoptosis and Immunogenic Cell Death (ICD) via Ca Overload in Colorectal Cancer.

Yao Xiao, Yuxuan Yang, Haosen Qiu, Jia Yang, Hao Liang, Zhaojun Jiang, Xiao Tong, Yongying Li, Qunfeng Huang, Jiaming Wu, Tian Lin, Jiang Yu, Min Liang.

  Colorectal cancer (CRC) remains therapeutically challenging due to high metastasis, recurrence, and immunotherapy resistance driven by tumor microenvironment-mediated immune evasion. Immunogenic cell death (ICD) offers a promising strategy to reshape the immune microenvironment, yet existing ICD inducers suffer from poor targeting efficiency and insufficient death signal release. Here, we constructed a calcium overload-based smart nanosystem, HA-HAP@CUR, to achieve highly efficient ICD induction via a triple-effect mechanism: hyaluronic acid (HA)-mediated CD44 targeting enables tumor-selective accumulation; pH-responsive hydroxyapatite (HAP) degradation releases Ca2+ in the acidic tumor microenvironment; and curcumin (CUR) amplifies intracellular calcium overload by promoting endoplasmic reticulum Ca2+ release, collectively establishing a positive feedback loop disrupting calcium homeostasis. Mechanistically, calcium overload induces mitochondrial membrane potential dissipation and sustained mPTP opening, triggering mitochondrial oxidative stress and energy metabolic disorders. This mitochondrial crisis concurrently activates caspase-3, GSDMD, and RIPK1, synergistically initiating apoptosis, pyroptosis, and necroptosis, ultimately converging into PANoptosis with potent immunostimulatory potential. This strategy, encompassing targeted accumulation, calcium storm activation, and multi-modal cell death synergy, provides a biologically precise approach to overcoming immunotherapy resistance in CRC.

Keywords:  PANoptosis; calcium overload; colorectal cancer; immunogenic cell death; immunotherapy

DOI:  https://doi.org/10.1002/advs.75559
Int J Biol Sci. 2026 ;22(8): 4059-4073

Intestinal Ischemia/Reperfusion Injury: Mechanisms, Diagnosis, and Therapeutic Advances.

Fan Deng, Qi-Shun Sun, Sun Xie, Ling Wu, Shi-Ying He, Bo-Wei Zhou, Zhen Hu, Wan-Yi Lian, Bing-Jie Li, Cai Li, Wei-Feng Liu, Jing-Juan Hu, Ke-Xuan Liu.

  Intestinal ischemia/reperfusion (I/R) injury is a critical clinical syndrome precipitated by the restoration of blood flow following intestinal ischemia, a common occurrence in perioperative settings such as abdominal aortic surgery, hemorrhagic shock, and cardiopulmonary bypass. This injury extends beyond the local gut, as the disruption of the intestinal mucosal barrier facilitates bacterial and endotoxin translocation into the systemic circulation, triggering a systemic inflammatory response that can progress to sepsis and multiple organ dysfunction syndrome (MODS). Despite advances in critical care, the mortality rate associated with severe intestinal I/R injury remains formidable. The microcirculatory disturbances and organ damage following intestinal I/R involve complex pathological processes, including metabolic injury and oxidative stress. In recent years, rapid developments in the understanding of cell death mechanisms, gut microbiota, microRNAs, and fundamental medical technologies have significantly advanced research on the prevention and treatment of I/R injury. This review aims to comprehensively summarize the occurrence and progression of intestinal I/R, its impact on extraintestinal organ injury, diagnostic strategies and biomarkers, as well as current treatment methods, thereby providing guidance for the future prediction, diagnosis, and treatment of intestinal I/R injury.

Keywords:  biomarkers; diagnostic strategies; extraintestinal organs injury; intestinal ischemia-reperfusion; therapeutic approaches

DOI:  https://doi.org/10.7150/ijbs.130025
J Cell Sci. 2026 May 01. pii: jcs264578. [Epub ahead of print]139(9):

A century of cell death research.

Douglas R Green.

  The fact that cells die during development, metamorphosis and tissue homeostasis was recognized well over a century ago. However, aside from noting and classifying such cell death events, research into the mechanisms of regulated cell death did not 'take off' until about 35 years ago. Since then, our understanding of the different ways that cells die and how this comes about has blossomed. In celebration of the 100-year anniversary of the Journal of Cell Science's publisher The Company of Biologists, this Perspective article presents an overview of the past 100-plus years of cell death research, touching on the history of apoptosis, necroptosis and other forms of cell death.

Keywords:  Apoptosis; Ferroptosis; Necroptosis; Pyroptosis

DOI:  https://doi.org/10.1242/jcs.264578
Chem Res Toxicol. 2026 May 07.

Drug-Induced Liver Injury: Mitochondrial Mechanisms, Biomarkers, and Emerging Therapeutic Strategies.

Brijesh Kumar Verma, Drashti Bhalgama, Pooja Thakur, Debashis Banerjee.

Drug-induced liver injury (DILI) remains a major challenge in drug development and clinical pharmacology, contributing significantly to late-stage attrition and regulatory failure. Growing experimental evidence implicates mitochondrial dysfunction as a central mechanism underlying chemically induced hepatotoxicity. This review provides an integrated analysis of mitochondrial pathways involved in DILI, including disruption of oxidative phosphorylation, inhibition of fatty acid β-oxidation, mitochondrial permeability transition, and mitochondrial DNA damage. We synthesize data from in vitro systems, animal models, and human studies to illustrate how diverse xenobiotics converge on mitochondrial targets to trigger hepatocellular injury. Emerging mitochondrial biomarkers, such as glutamate dehydrogenase, circulating mitochondrial DNA, and microRNAs, are discussed in the context of mechanistic relevance and translational utility. In addition, advances in experimental models including humanized mice and liver organoids are evaluated for their predictive value in drug safety assessment. The review further highlights mitochondria-centered intervention strategies as mechanistic tools to validate injury pathways and inform pharmacological risk mitigation. By integrating mitochondrial biology with applied toxicology, this review provides a mechanistic framework to improve early detection, mechanistic understanding, and prevention of drug-induced liver injury during drug development.

DOI: https://doi.org/10.1021/acs.chemrestox.6c00030
Biochem Soc Trans. 2026 05 27. 54(5): 437-447

Unraveling new functions of the Ca2+ sensor STIM1 in cell signaling.

Irene Sanchez-Lopez, Yolanda Orantos-Aguilera, Aida M Lopez-Guerrero, Eulalia Pozo-Guisado, Francisco Javier Martin-Romero.

  Calcium (Ca2+) signaling is a fundamental regulator of virtually all aspects of eukaryotic cell physiology, including gene expression, secretion, metabolism, motility, and cell fate decisions. The spatial and temporal control of cytosolic Ca2+ signals relies on a coordinated interplay between intracellular Ca2+ stores and plasma membrane (PM) Ca2+ channels. A critical advance in this field over the past two decades was the molecular identification of stromal interaction molecule 1 (STIM1) as the long-sought Ca2+ sensor that couples depletion of endoplasmic reticulum Ca2+ stores to Ca2+ influx across the PM. STIM1 has been established as a core component of store-operated Ca2+ entry, acting through direct activation of ORAI Ca2+ channels. However, accumulating evidence now indicates that STIM1 functions extend beyond this canonical role. STIM1 participates in the regulation of multiple classes of ion channels, contributes to the organization of membrane contact sites, and acts as a signaling scaffold influencing cellular processes independently of classical store depletion. This review summarizes the discovery and canonical functions of STIM1 and focuses on its emerging non-canonical roles, highlighting how STIM1 has evolved from an ER Ca2+ sensor into a multifunctional signaling hub.

Keywords:  DNA damage response; calcium signalling; endoplasmic reticulum; immune response; mitochondria; mitochondrial dysfunction

DOI:  https://doi.org/10.1042/BST20250458
J Biol Chem. 2026 May 06. pii: S0021-9258(26)02000-4. [Epub ahead of print] 113128

The Role of Phospho-ubiquitin in Mitochondrial Health and Diseases.

Kumar Suresh, Christopher Rainvillee, David E Sterner, Matthew S Goldberg, Tauseef R Butt.

  Mitochondria play a major role in cellular health, yet their contribution to chronic diseases has been underestimated. Mitochondria are essential for all tissues, and a major source of ATP in high-energy-demand organs such as brain and heart being vulnerable to mitochondrial dysfunction. Failure to repair or remove damaged mitochondria contributes to aging and chronic diseases. Cells have evolved quality control mechanisms, including mitophagy to eliminate damaged mitochondria and mitobiogenesis to replenish them. The ubiquitin-proteasome system (UPS) is responsible for removing misfolded proteins, a process that is highly ATP dependent and therefore reliant on mitochondrial function. In turn, damaged mitochondria are eliminated through coordinated actions of the UPS and lysosomal degradation through mitophagy. Many neurodegenerative diseases are characterized by the presence of disease-specific protein aggregates, such as α-synuclein aggregates in Parkinson's disease and tau neurofibrillary tangles in Alzheimer's disease. These aggregates impair mitochondrial function, while dysfunctional mitochondria generate reactive oxygen species that further exacerbate proteotoxic stress, creating a pathogenic cycle. This highlights the functional interplay between mitochondria and the UPS. Recent studies have uncovered phosphorylation of ubiquitin at Serine 65 by the mitochondrial kinase PINK1 as a key signal of mitochondrial dysfunction. Phospho-Ser65-Ubiquitin (pUb) has emerged as an indicator of mitochondrial health and a potential biomarker for aging and neurodegenerative disease. However, due largely to a lack of tools, little is known about the role of pUb in cellular physiology. Here we review the current landscape of pUb biology, the phospho-ubiquitome, and its role as biomarker for mitochondrial health, and neurodegeneration.

Keywords:  (10): mitochondria; PINK1; Parkin; aging; autophagy; biomarker; mitophagy; neurodegeneration; phospho-ubiquitin; proteasome

DOI:  https://doi.org/10.1016/j.jbc.2026.113128