bims-miptne 2025-08-03 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2025–08–03
seven papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Role of mitochondrial Ca2+ in stroke: From molecular mechanism to treatment strategy (Review).
Extracellular vesicle-mediated delivery of circp53 suppresses the progression of multiple cancers by activating the CypD/TRAP/HSP90 pathway.
Mitochondrial dysfunction mediated by ER-calcium dysregulation in neurons derived from Alzheimer's disease patients.
Development of a Mitochondrial Permeability Transition-Driven Necrosis-Related Prognostic Signature in Cervical Cancer: Integrating Bulk Transcriptomic and Single-Cell Data.
Network Pharmacology Approaches to Myocardial Infarction Reperfusion Injury: Exploring Mechanisms, Pathophysiology, and Novel Therapies.
Oligomer-based functions of mitochondrial porin.
Repurposing BCL2 inhibitors: Venetoclax protects against acinar cell necrosis in acute pancreatitis by promoting apoptosis.

Mol Med Rep. 2025 Oct;pii: 271. [Epub ahead of print]32(4):

Role of mitochondrial Ca2+ in stroke: From molecular mechanism to treatment strategy (Review).

Yanlin Liu, Wenjie Jin, Huixin Zhou, Xiaomei Wang, Hongbin Ren, Xibing Yang, Kaitao Luo, Xiaobing Dou.

  Mitochondria serve a pivotal role in the pathological mechanisms of stroke, particularly in the regulation of intracellular calcium homeostasis. Stroke‑induced ischemia and reperfusion injury frequently result in disruptions of mitochondrial calcium ion (Ca2+) transport, characterized by Ca2+ overload. This imbalance directly impairs mitochondrial function and triggers neuronal death. Mitochondrial Ca2+ transport involves calcium influx, primarily mediated by the mitochondrial calcium uniporter (MCU) complex, and efflux, primarily through the sodium‑calcium exchanger (NCLX), making this mechanism a critical therapeutic target in stroke. The present review systematically explores the central role of mitochondrial Ca2+ transport in ischemia/reperfusion injury, with an in‑depth analysis of its pathological mechanisms in cellular energy metabolism, oxidative stress and apoptotic signaling pathways. Additionally, this review summarizes recent advancements in therapeutic strategies targeting mitochondrial Ca2+ transport, including MCU inhibitors, NCLX activators, antioxidant therapies and combination treatments. It also highlights the potential of Ca2+ signaling for early stroke diagnosis and reviews progress in dynamic monitoring technologies for mitochondrial Ca2+, such as fluorescence probes and super‑resolution microscopy. Despite significant progress in basic research, challenges remain in translating these findings into clinical applications. Future efforts should focus on elucidating the regulatory mechanisms of mitochondrial Ca2+, developing diagnostic tools and optimizing therapeutic interventions to improve stroke prognosis and enhance the quality of life of patients.

Keywords:  calcium homeostasis; diagnosis; dynamic monitoring; ischemia/reperfusion injury; mitochondrial calcium transport; stroke

DOI:  https://doi.org/10.3892/mmr.2025.13636
Exp Mol Med. 2025 Aug 01.

Extracellular vesicle-mediated delivery of circp53 suppresses the progression of multiple cancers by activating the CypD/TRAP/HSP90 pathway.

Xichao Yu, Pinggang Ding, Mengjie Guo, Xiaozhu Tang, Ze Wang, Yuanjiao Zhang, Lianxin Zhou, Xinyu Lv, Hui Shi, Hongming Huang, Jialei Mao, Zhancheng Gu, Chunyan Gu, Ye Yang.

The majority of cancers remain incurable due to limited therapeutic responses in malignancies with high-risk genetic mutations such as TP53. Building on the success of mRNA vaccine technology, we investigated circular RNA (circRNA) therapeutics and identified hsa_circp53_0041947, a TP53-derived circRNA in multiple myeloma (MM). The hsa_circp53_0041947 encodes a functional peptide (circp53-209aa) demonstrating p53 mutation-independent anti-MM effects through CypD/TRAP1/HSP90 complex-mediated mechanisms. Specifically, circp53-209aa activated cyclophilin D (CypD) isomerase activity at the circp53-209aa-R175 site, triggering mitochondrial permeability transition pore opening and subsequent mitochondrial apoptosis. To enable targeted delivery, we engineered extracellular vesicle (EV) systems, E7-Lamp2b-EVs and Her2-Lamp2b-EVs, for MM and colorectal cancer, respectively. Circp53-EVs administration achieved tumor-selective growth inhibition in both malignancies. Our study establishes engineered circp53-EVs as a versatile therapeutic platform, demonstrating the translational potential of circRNA-based strategies for refractory cancers with TP53 pathway alterations.

DOI: https://doi.org/10.1038/s12276-025-01506-0
Acta Neuropathol Commun. 2025 Jul 29. 13(1): 165

Mitochondrial dysfunction mediated by ER-calcium dysregulation in neurons derived from Alzheimer's disease patients.

Sarah Mustaly-Kalimi, Wacey Gallegos, Daniel Steinbrenner, Smriti Gupta, Aiden J Houcek, David A Bennett, Robert A Marr, Daniel A Peterson, Israel Sekler, Grace E Stutzmann.

  Tight regulation of mitochondrial Ca2+ is essential for neuronal bioenergetics and cellular metabolism. Ca2+ transfer from ER-localized ryanodine receptors (RyR) and inositol triphosphate receptors (IP3R) to the mitochondria maintains a steady Ca2+ source that fuels oxidative phosphorylation and ATP production. In Alzheimer's disease (AD), RyR-evoked Ca2+ release is markedly increased, contributing to synaptic deficits, protein mishandling, and memory impairment. Here, we demonstrate dysregulated RyR-Ca2+ release in neurons from familial and sporadic AD patients, and this directly compromises mitochondrial activity and contributes to AD cellular pathology. We measured an array of mitochondrial functions using fluorescent biosensors and optical imaging in RyR2-expressing HEK cells and neurons derived from AD and nonAD individuals. In neurons from AD patients, resting mitochondrial Ca2+ levels were elevated alongside increased free radical production and higher caspase-3 activity relative to nonAD neurons. RyR-evoked Ca2+ release further potentiated pathogenic mitochondrial responses in AD neurons, with increased Ca2+ uptake and exaggerated mitochondrial membrane depolarization. Additionally, clearance of damaged mitochondria was impaired in AD neurons, demonstrating consequences from dysfunctional lysosomes. Notably, impairments to mitochondria in AD neurons were largely prevented with the RyR negative allosteric modulator, Ryanodex. These findings highlight how excess RyR-Ca2+ release broadly contributes to early cellular pathology in AD which includes a cascade of ER, lysosomal, and mitochondrial deficits culminating in neuronal decline and degeneration. Additionally, pharmacological suppression of RyR-Ca2+ release preserves mitochondrial, ER and lysosomal function, thus providing a novel and effective therapeutic strategy.

Keywords:  Alzheimer’s disease; Calcium dysregulation; Mitochondria; Ryanodine receptor; iPSC-derived neurons

DOI:  https://doi.org/10.1186/s40478-025-02023-x
Cancer Med. 2025 Aug;14(15): e71094

Development of a Mitochondrial Permeability Transition-Driven Necrosis-Related Prognostic Signature in Cervical Cancer: Integrating Bulk Transcriptomic and Single-Cell Data.

Jiaojiao Niu, Sreenivasan Sasidharan.

   BACKGROUND: Cervical cancer (CC) is a prevalent gynecological malignancy with notable heterogeneity. The role of mitochondrial permeability transition (MPT)-driven necrosis, a form of cell death due to mitochondrial dysfunction, in CC progression and prognosis is poorly understood and represents a promising therapeutic target for cancers. This study aimed to create a new prognostic signature linked to MPT-driven necrosis, improving CC prediction and prognosis.
METHODS: This study utilized the GSE63514, TCGA-CESC, CGCI-HTMCP-CC, and GSE197641 transcriptome datasets. Firstly, the GSE63514 dataset was utilized to identify differentially expressed genes (DEGs). Differentially expressed MPT-driven necrosis-related genes (DE-MRGs) were obtained by intersecting DEGs with MRGs. Regression analyses were performed to identify genes significantly associated with prognosis. A prognostic model was established in TCGA-CESC, followed by independent validation and nomogram construction. Additional analyses included immune infiltration, enrichment analysis, and drug susceptibility based on high- and low-risk groups. Finally, cell communication analysis was performed to investigate interactions between key cell types.
RESULTS: A total of 156 DE-MRGs were identified. Regression analyses identified three prognostic genes (ICOS, MMP3, and POSTN) to construct a prognostic risk signature. Then, risk score was an independent prognostic factor for CC, and a nomogram demonstrated effective predictive accuracy for CC survival outcomes. The risk signature was linked to immune-associated processes such "Antigen processing and presentation" and immune cell infiltration, especially M0 macrophages and CD8 T cells. Cell communication analysis uncovered a strong interaction between endothelial cells and monocytes. To validate the molecular mechanisms, qRT-PCR, cell proliferation, and wound healing assays were performed. Functional tests showed that MMP3 and POSTN knockdown drastically reduced CC cell growth and migration.
CONCLUSION: This study developed a novel prognostic risk signature based on ICOS, MMP3, and POSTN. MMP3 and POSTN knockdown significantly decrease CC cell growth and migration, highlighting their potential as therapeutic targets.

Keywords:  cell communication; cervical carcinoma; nomogram; prognostic genes; regulator network

DOI:  https://doi.org/10.1002/cam4.71094
Biomedicines. 2025 Jun 23. pii: 1532. [Epub ahead of print]13(7):

Network Pharmacology Approaches to Myocardial Infarction Reperfusion Injury: Exploring Mechanisms, Pathophysiology, and Novel Therapies.

Joy Das, Ashok Kumar Sah, Ranjay Kumar Choudhary, Rabab H Elshaikh, Utpal Bhui, Shreya Chowdhury, Anass M Abbas, Manar G Shalabi, Nadeem Ahmad Siddique, Raji Rubayyi Alshammari, Navjyot Trivedi, Khoula Salim Ali Buwaiqi, Said Al Ghenaimi, Pranav Kumar Prabhakar.

  Myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide. While timely reperfusion therapies such as percutaneous coronary intervention (PCI) and thrombolysis are essential for salvaging ischemic myocardium, they can paradoxically exacerbate tissue injury through a process known as myocardial infarction reperfusion injury (MIRI). MIRI can contribute to up to 50% of the final infarct size, significantly diminishing the benefits of revascularization and leading to worsened cardiac outcomes. The pathophysiology of MIRI involves complex, interrelated mechanisms including oxidative stress, calcium overload, mitochondrial dysfunction, inflammatory responses, apoptosis, and dysregulated autophagy. Post-reperfusion recovery is further complicated by structural and functional abnormalities such as microvascular obstruction, endothelial dysfunction, and myocardial stunning. Clinically, distinguishing reperfusion injury from ischemic damage is challenging and often requires the use of sensitive biomarkers, such as cardiac troponins, alongside advanced imaging modalities. Although a range of pharmacological (e.g., antioxidants, calcium channel blockers, mitochondrial stabilizers, anti-inflammatory agents) and non-pharmacological (e.g., hypothermia, gene therapy, stem cell-based therapies) interventions have shown promise in preclinical studies, their clinical translation remains limited. This is largely due to the multifactorial and dynamic nature of MIRI. In this context, network pharmacology offers a systems-level approach to understanding the complex biological interactions involved in MIRI, facilitating the identification of multi-target therapeutic strategies. Integrating network pharmacology with omics technologies and precision medicine holds potential for advancing cardioprotective therapies. This review provides a comprehensive analysis of the molecular mechanisms underlying MIRI, examines the current clinical challenges, and explores emerging therapeutic strategies. Emphasis is placed on bridging the translational gap through validated, multi-target approaches and large-scale, multicenter clinical trials. Ultimately, this work aims to support the development of innovative and effective interventions for improving outcomes in patients with myocardial infarction.

Keywords:  KEGG pathway analysis; calcium overload; cardiac reperfusion injury; mitochondrial dysfunction; molecular target; myocardial infarction; oxidative stress

DOI:  https://doi.org/10.3390/biomedicines13071532
Nat Commun. 2025 Jul 25. 16(1): 6854

Oligomer-based functions of mitochondrial porin.

Hironori Takeda, Saori Shinoda, Chiho Goto, Akihisa Tsutsumi, Haruka Sakaue, Chunming Zhang, Takashi Hirashima, Yuta Konishi, Haruka Ono, Yu Yamamori, Kentaro Tomii, Hiroya Shiino, Yasushi Tamura, Solène Zuttion, Bruno Senger, Sylvie Friant, Hubert D Becker, Yuhei Araiso, Nanako Kobayashi, Noriyuki Kodera, Masahide Kikkawa, Toshiya Endo.

Porin, or the voltage-dependent anion channel (VDAC), is a primary β-barrel channel in the mitochondrial outer membrane. It transports small metabolites and ions through its β-barrel pore and plays key roles in apoptosis and inflammatory response. Here we report the cryo-electron microscopy structure of yeast porin (Por1) in its hexameric form at 3.2 Å resolution. This structure allows us to introduce various mutations at the protomer interfaces, uncovering three critical functions of Por1 assembly beyond transport. Por1 binds unassembled Tom22, a subunit of the mitochondrial protein import gate (the TOM complex), to facilitate protein import into the intermembrane space, maintains proper mitochondrial lipid composition in the outer membrane through lipid scramblase activity, and contributes to the retention and regulated loss of mitochondrial DNA, in cooperation with nucleases identified through screening enabled by the obtained Por1 mutant.

DOI: https://doi.org/10.1038/s41467-025-62021-4
Cell Death Dis. 2025 Jul 27. 16(1): 566

Repurposing BCL2 inhibitors: Venetoclax protects against acinar cell necrosis in acute pancreatitis by promoting apoptosis.

Jacek J Litewka, Mateusz D Szopa, Katarzyna Fryt, Monika A Jakubowska, Urszula Jankowska, Bozena Skupien-Rabian, Karolina Hajduk, Ewa Werner, Kinga B Stopa, Agnieszka A Kusiak, Daria Krzysztofik, Zbigniew Madeja, Pawel E Ferdek.

Acute pancreatitis (AP), a severe inflammatory disorder of the pancreas, lacks effective pharmacological treatment. The disease is primarily driven by necrosis of pancreatic acinar cells (PACs), which intensifies inflammation and organ injury. This study explores the potential of BCL2 inhibitors, specifically Navitoclax and Venetoclax, to shift cell death pathways from necrosis to apoptosis and thereby mitigate disease severity. Ex vivo models using cerulein or ethanol/palmitoleic acid (EtOH/POA) showed that both inhibitors significantly reduced necrosis, increased apoptosis, and improved PAC viability and ATP levels. In mouse models of AP, both drugs promoted apoptosis and decreased tissue necrosis, with Venetoclax showing superior efficacy and safety. Venetoclax markedly reduced disease severity in two AP models without affecting healthy tissue or inducing thrombocytopenia. In contrast, Navitoclax caused apoptosis even in healthy tissue and triggered thrombocytopenia. Additionally, both drugs attenuated pathological Ca2+ responses in PACs and upregulated the expression of Ca²⁺-binding proteins S100A8/A9 and the chemokine CCL8. The latter may mediate enhanced apoptotic clearance and limit secondary necrosis, supporting the therapeutic shift from necrosis to apoptosis. Proteomic analyses revealed extensive drug-induced remodeling. In the short-term AP model, both inhibitors altered expression of proteins linked to intracellular compartments and extracellular signaling, reflecting cellular adaptation. In CP, Navitoclax upregulated ECM and lysosomal proteins while downregulating ribosomal components-indicating intensified fibrosis and suppressed protein synthesis. Venetoclax had milder effects and did not worsen fibrosis. Despite Navitoclax's efficacy toward activated pancreatic stellate cells in vitro, it exacerbated fibrosis and tissue atrophy in CP in vivo, likely due to ongoing parenchymal damage and stellate cell activation. Together, these findings demonstrate that selective BCL2 inhibition with Venetoclax promotes apoptosis, reduces necrosis, and improves outcomes in AP, supporting its repurposing as a therapeutic strategy. However, BCL2 inhibition does not benefit CP and may aggravate fibrosis, underscoring the need for context-specific approaches.

DOI: https://doi.org/10.1038/s41419-025-07881-w