bims-miptne 2025-10-19 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2025–10–19
seven papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Nynrin enhances cardiac function by inhibiting mitochondrial permeability transition pore opening upon myocardial ischemia/reperfusion injury.
Impaired Atrial Mitochondrial Calcium Handling in Patients With Atrial Fibrillation.
Fluoride Induces Spermatogonial Apoptosis via IP3R-MCU-Mediated Mitochondrial Calcium Overload.
The role of mitochondria-endoplasmic reticulum crosstalk in colorectal cancer.
Quercetin ameliorates oxidative stress in BMP15-deficient oocytes by regulating the ERK1/2-GSK3β-CypD pathway.
Effects of different reperfusion durations on neuronal mitochondrial ultrastructure following cerebral ischemia in diabetic rats: a transmission electron microscopy study.
The Sirt3-CD38 axis induces mitochondrial dysfunction in hypertrophied heart by regulating mitochondrial calcium overload.

J Mol Cell Cardiol. 2025 Oct 10. pii: S0022-2828(25)00180-4. [Epub ahead of print]

Nynrin enhances cardiac function by inhibiting mitochondrial permeability transition pore opening upon myocardial ischemia/reperfusion injury.

Yuhan Wang, Yujing Li, Yanan Zhou, Hao Zhang, Jingyi Zang, Chaofan Yang, Zeyu Gao, Yu Hou, Moshi Song.

  Acute myocardial infarction (AMI) is a leading cause of cardiovascular disease-related death. Reperfusion therapies, although essential, can exacerbate damage through myocardial ischemia/reperfusion (I/R) injury. Cyclophilin D (CypD) and mitochondrial permeability transition pore (mPTP) opening have been identified as potential therapeutic targets for I/R injury. However, clinical trials with cyclosporin A (CsA) have shown mixed results, highlighting the urgent need for alternative strategies to suppress CypD expression or activity. In this study, we explored the role of Nynrin, a newly identified transcriptional repressor of peptidylprolyl isomerase F (Ppif) that encodes CypD, in mitigating I/R injury by regulating mPTP opening. We first observed that Nynrin was downregulated in adult mouse hearts subjected to I/R and in primary adult mouse cardiomyocytes upon oxygen-glucose deprivation/reperfusion (OGD/R). Subsequently, we generated a tamoxifen-inducible cardiomyocyte-specific Nynrin-knockout (Nynrin-cKO) mouse model, which was well-tolerated in otherwise normal adult mouse hearts. Notably, Nynrin-cKO mice exhibited exacerbated contractile dysfunction and cardiac injury, characterized by enhanced Ppif transcription, CypD expression, mPTP opening, and cardiomyocyte death when subjected to I/R. Furthermore, the exacerbated I/R-induced cardiac dysfunction in Nynrin-cKO mice was significantly reversed by CsA, an mPTP inhibitor that targets CypD, indicating that the intensified pathological manifestations in Nynrin-cKO mice during I/R injury were dependent on CypD and mPTP. Conversely, Nynrin overexpression in primary adult mouse cardiomyocytes blunted Ppif/CypD upregulation and restrained mPTP opening, thus reducing cardiomyocyte damage upon OGD/R. Taken together, our findings highlight the critical role of Nynrin in regulating CypD and mPTP in I/R injury and suggest that targeting Nynrin may be a promising therapeutic strategy for mitigating cardiac dysfunction in managing I/R injury.

Keywords:  CypD; Myocardial ischemia/reperfusion injury; Nynrin; mPTP

DOI:  https://doi.org/10.1016/j.yjmcc.2025.10.002
Circ Res. 2025 Oct 15.

Impaired Atrial Mitochondrial Calcium Handling in Patients With Atrial Fibrillation.

Julius Ryan D Pronto, Fleur E Mason, Eva A Rog-Zielinska, Funsho E Fakuade, Donata Bülow, Marcell Tóth, Khaled Machwart, Paulina Brandes, Felix Wiedmann, Michael Kohlhaas, Alexander Nickel, Matthias Wolf, Julian Mustroph, Kim-Chi Vu, Sören Brandenburg, Tri Q Do, Peter Joshua Siedler, Katharina Ritzenhoff, Zongqian Xue, Xiaobo Zhou, Stefanie Kestel, Olga Dschun, Oksana Kyshynska, George Kensah, Robyn T Rebbeck, Aschraf El-Essawi, Ahmad Fawad Jebran, Bernhard C Danner, Hassina Baraki, Johann Schredelseker, Ivan Bogeski, Bianca J J M Brundel, Stephan E Lehnart, Constanze Bening, Ingo Kutschka, Felix Bremmer, Stefan Kallenberger, Silvio O Rizzoli, Björn C Knollmann, Stefan Neef, Katrin Streckfuss-Bömeke, Constanze Schmidt, Christoph Maack, Niels Voigt.

   BACKGROUND: Mitochondrial calcium (Ca2+) is a key regulator of cardiac energetics by stimulating the tricarboxylic acid cycle during elevated workload. Atrial fibrillation (AF) is associated with a reduction in cytosolic Ca2+ transient amplitude, but its effect on mitochondrial Ca2+ handling and cellular redox state has not been explored in AF.
METHODS: Cardiac myocytes isolated from patient-derived right atrial biopsies were subjected to workload transitions using patch-clamp stimulation and β-adrenergic stimulation (isoproterenol). In conjunction, NAD(P)H/flavin adenine dinucleotide autofluorescence, cytosolic and mitochondrial [Ca2+] were monitored using epifluorescence microscopy. Sarcoplasmic reticulum and mitochondria were imaged using electron tomography and stimulated emission depletion microscopy. The effects of the mitochondrial Ca2+ uptake enhancer ezetimibe on proarrhythmic activity in atrial myocytes and on AF burden in patients were investigated.
RESULTS: Mitochondrial Ca2+ accumulation during increased workload was blunted in AF, and was associated with impaired regeneration of nicotinamide adenine dinucleotide and flavin adenine dinucleotide. Nanoscale imaging revealed spatial disorganization of sarcoplasmic reticulum and mitochondria, associated with microtubule destabilization. This was confirmed in human induced pluripotent stem cell-derived myocytes, where nocodazole treatment displaces mitochondria and increases proarrhythmic Ca2+ sparks, which were rescued by MitoTEMPO. Ezetimibe also reduced the occurrence of arrhythmogenic Ca2+ release events both in AF myocytes and nocodazole-treated human induced pluripotent stem cell-derived cardiac myocytes. Retrospective patient analysis also revealed a reduced AF burden in patients on ezetimibe treatment.
CONCLUSIONS: Mitochondrial Ca2+ uptake and accumulation are impaired in atrial myocytes from patients with AF. The disturbed spatial association between sarcoplasmic reticulum and mitochondria driven by destabilized microtubules may underlie impaired Ca2+ transfer in AF. Enhancing mitochondrial Ca2+ uptake potentially protects against arrhythmogenic events.

Keywords:  atrial fibrillation; calcium; ezetimibe; microtubules; mitochondria

DOI:  https://doi.org/10.1161/CIRCRESAHA.124.325658
Biol Trace Elem Res. 2025 Oct 18.

Fluoride Induces Spermatogonial Apoptosis via IP3R-MCU-Mediated Mitochondrial Calcium Overload.

Rong Wang, Han Wang, Wenjing Gong, Xiaoqian Chen, Mengli Zheng, Ya Cui, Chunmei Liang, Jiayue Hu, Yuanhua Chen, Yanli Ji.

  Excessive fluoride exposure is associated with male reproductive dysfunction, but the underlying mechanisms remain poorly understood. This study investigated the role of Inositol 1,4,5-trisphosphate receptor (IP3R)-mitochondrial calcium uniporter (MCU)-mediated mitochondrial calcium (Ca2+) overload in fluoride-triggered apoptosis in spermatogonia. The results demonstrated that fluoride induced oxidative stress, decreased mitochondrial membrane potential, and triggered apoptosis in spermatogonia. Furthermore, we observed that fluoride exposure induced calcium transfer from the endoplasmic reticulum (ER) to the mitochondria, leading to excessive mitochondrial Ca2+ accumulation. Mechanistic studies revealed that fluoride activated the IP3R-MCU signaling pathway, a key regulator of Ca2+ release from the ER. Notably, treatment with the calcium chelator BAPTA-AM significantly inhibited mitochondrial Ca2+ overload and protected spermatogonia against fluoride-induced apoptosis. In conclusion, the findings indicated that fluoride activated the IP3R-MCU pathway, promoted Ca2+ release from the ER, and led to mitochondrial calcium overload, inducing oxidative stress and apoptotic factor release, ultimately triggering apoptosis in spermatogonia. These findings offer potential therapeutic targets for mitigating fluoride-induced reproductive toxicity.

Keywords:  Apoptosis; Fluoride; IP3R-MCU pathway; Mitochondrial calcium overload; Spermatogonia

DOI:  https://doi.org/10.1007/s12011-025-04860-2
Genes Dis. 2026 Jan;13(1): 101766

The role of mitochondria-endoplasmic reticulum crosstalk in colorectal cancer.

Lanshu Xiao, Yao Wei, Yiping Qin, Bianqin Guo.

  Colorectal cancer (CRC) is a significant health burden globally, with the third highest incidence and the second highest mortality among all types of cancer. Understanding the mechanisms underlying CRC progression is crucial for advancing therapeutic strategies. Organelles are essential components of cells and play a critical role in the initiation and progression of cancer. Over the past decades, numerous studies have demonstrated that mitochondria and the endoplasmic reticulum (ER) can communicate through signaling pathways, thereby regulating cellular homeostasis and function in both normal and cancer cells. This interaction primarily occurs through mitochondria-associated endoplasmic reticulum membranes (MAMs). MAMs, as key nodes in cancer initiation and progression, are also potential vulnerabilities of cancer cells, offering promising opportunities for cancer treatment. Recent research further emphasizes the close association between MAMs and CRC in terms of proliferation, apoptosis, and invasion. To deepen our understanding of the interactions and mechanisms between mitochondria and the ER in CRC, this review, for the first time, synthesizes the research advancements concerning the crosstalk between these organelles in CRC. It innovatively identifies potential targets associated with MAMs, aiming to uncover novel therapeutic strategies for CRC.

Keywords:  CRC; ER; MAMs; Mitochondria; Therapeutic strategy

DOI:  https://doi.org/10.1016/j.gendis.2025.101766
Redox Biol. 2025 Oct 08. pii: S2213-2317(25)00399-4. [Epub ahead of print]87 103886

Quercetin ameliorates oxidative stress in BMP15-deficient oocytes by regulating the ERK1/2-GSK3β-CypD pathway.

Yafei Jiao, Xinran Li, Jinming Guo, Chang Bei, Xintong Jiang, Houwu Jiang, Bingqian Mi, Tiantuan Jiang, Xiaohong Liu, Yaosheng Chen, Peiqing Cong, Zuyong He.

  Bone morphogenetic protein 15 (BMP15) is an oocyte-secreted growth factor, which interacts with ovarian follicular somatic cells and in turn promotes oocyte maturation. Disrupting BMP15 by CRISPR-ctRNP has been found to severely impair in vitro maturation (IVM) of porcine oocytes, accompanied with mitochondrial dysfunction and increased accumulation of reactive oxygen species (ROS). To investigate whether the plant-derived antioxidant quercetin (QUE) is able to rescue the IVM of BMP15-deficient oocytes, porcine oocytes microinjected with CRISPR-ctRNP targeting BMP15 were treated with 10 μM QUE, and we found that QUE can effectively rescue the impaired IVM of BMP15-deficient oocytes by restoring the impaired mitochondrial functions and reducing ROS through activating extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Activated ERK1/2 in turn inactivated glycogen synthase kinase-3β (GSK3β), which subsequently reduced Cyclophilin D (CypD) levels, and probably modulated the status of the permeability transition pore (PTP) of mitochondria, contributing to the reduced oxidative stress and apoptosis in porcine oocytes, and thus the improved oocyte quality and IVM. Our study further revealed the molecular mechanisms of QUE on alleviating oxidative stress of BMP15-deficient oocytes, suggesting that QUE may be a promising candidate for improving quality of oocytes with BMP15 mutations.

Keywords:  BMP15-Deficiency; ERK1/2 signaling pathway; Mitochondrial function; Quercetin; ROS

DOI:  https://doi.org/10.1016/j.redox.2025.103886
Eur J Med Res. 2025 Oct 15. 30(1): 979

Effects of different reperfusion durations on neuronal mitochondrial ultrastructure following cerebral ischemia in diabetic rats: a transmission electron microscopy study.

Dan Wang, Gui-Sheng Chen.

   OBJECTIVE: This study employed transmission electron microscopy (TEM) to characterize the temporal dynamics of neuronal mitochondrial ultrastructural alterations following cerebral ischemia-reperfusion (I/R) in diabetic rats.
METHODS: Male Wistar rats were divided into four groups: hyperglycemic, normoglycemic, hyperglycemic cerebral ischemia, and normoglycemic cerebral ischemia. Diabetic rat models were established via streptozotocin (STZ) induction. Cerebral ischemia was induced by bilateral common carotid artery occlusion combined with hypotension for 10 min, followed by reperfusion for 5 h, 1 day, or 7 days. Neurological deficits were evaluated using the Longa scoring criteria, and mitochondrial damage in the cortical region was assessed by TEM. Transmission electron micrographs were analyzed using ImageJ software (National Institutes of Health, USA).
RESULTS: (1) Diabetic rats exhibited exacerbated neuronal and mitochondrial damage compared with normoglycemic controls after I/R, with the most severe injury observed at 5 h of reperfusion. (2) Quantitative analysis revealed significantly greater mitochondrial swelling and cristae disruption in the hyperglycemic I/R group at all time points (p < 0.01). (3) Although prolonged reperfusion time correlated with gradual recovery of mitochondrial integrity, this recovery was significantly delayed and incomplete in diabetic rats compared with normoglycemic controls.
CONCLUSIONS: (1) A diabetic cerebral I/R injury model was successfully established using STZ combined with bilateral carotid artery occlusion and hypotension. (2) Diabetes markedly exacerbates and prolongs mitochondrial damage following cerebral I/R. Impaired recovery of mitochondrial ultrastructure represents a critical determinant of stroke prognosis in diabetic patients, providing a well-defined therapeutic target for subsequent fundamental research and intervention strategies.

Keywords:  Cerebral ischemia–reperfusion; Diabetes mellitus; Electron microscopy; Mitochondria

DOI:  https://doi.org/10.1186/s40001-025-03273-0
Eur J Med Res. 2025 Oct 14. 30(1): 967

The Sirt3-CD38 axis induces mitochondrial dysfunction in hypertrophied heart by regulating mitochondrial calcium overload.

Jia Liu, Ning Liu, Chao Qi, Delu Dong, Bin Liu.

  Mitochondrial dysfunction driven by calcium overload is a hallmark of cardiac hypertrophy, yet the role of Sirtuin-3 (Sirt3) in regulating this process remains incompletely defined. Specifically, the mechanism by which CD38-mediated NAD depletion links Sirt3 deficiency to mitochondrial calcium dysregulation remains incompletely elucidated. Therefore, 12 week-old Sirt3-deficient mice were used as cardiac hypertrophy model. The morphological changes of cardiac muscle fibers and the ultra-structure changes of mitochondria were detected by hematoxylin and eosin (HE) staining and transmission electron microscopy (TEM). Then, multi-omics approach was used to analyze the differently expressed genes and different metabolites. Key genes and metabolites were scrutinized through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG). Finally, in vitro studies examining the effects of Sirt3 knockdown on H9C2 cells, including intracelluler and mitochondrial reactive oxygen species (ROS) and calcium, and mitochondrial membrane potential (MMP). Western blot and qPCR were used to verify the differently expressed genes. The hearts of Sirt3-deficient mice increased myofiber thickness, and altered mitochondrial morphology. Sirt3 deficiency induced mitochondrial dysfunction was promoted by an inhibition of the translation of oxidative phosphorylation (OXPHOS) complex subunits. Multi-omics profiling implicated CD38 as a major NAD consumer and linked the metabolites of CD38 to cAMP signaling pathways. Furthermore, in vitro studies examining H9C2 Sirt3 knockdown showed an increase in intracellular and mitochondrial ROS levels, a decrease in MMP, and promoted MCU expression and mitochondrial calcium overload. However, CD38 inhibitors effectively attenuated Sirt3 knockdown-induced elevations in intracellular and mitochondrial ROS levels, dissipation of mitochondrial membrane potential, and mitochondrial calcium overload, thereby restoring mitochondrial function. In summary, the Sirt3-CD38 axis induces mitochondrial dysfunction in hypertrophied heart by regulating mitochondrial calcium overload. These findings will aid in providing new ideas for the prevention and treatment of age-related cardiac hypertrophy.

Keywords:  CD384 ; Cardiac hypertrophy1 ; Mitochondria5 ; ROS3 ; Sirt32

DOI:  https://doi.org/10.1186/s40001-025-03211-0