bims-miptne 2025-12-28 papers

Biochemistry (Mosc). 2025 Dec;90(12): 1789-1810

Ca2+-Dependent Mitochondrial Permeability Transition Pore: Structure, Properties, and Role in Cellular Pathophysiology.

Konstantin N Belosludtsev, Mikhail V Dubinin, Natalia V Belosludtseva.

The Mitochondrial Permeability Transition pore (MPT pore) activated by Ca2+ ions is a phenomenon that has long been the subject of intense study. Cyclophilin D-dependent opening of the MPT pore in mitochondria in response to calcium overload and oxidative stress leads to swelling of the mitochondrial matrix, depolarization of the inner membrane and dysregulation of ion homeostasis. These processes are accompanied by damage to mitochondrial membranes and, ultimately, to cell death. Despite decades of research, the molecular identity of the MPT pore remains unclear. Currently, the inner membrane proteins - ATP synthase and adenine nucleotide translocator (ANT) - are considered to be its key structural components, along with the regulatory protein cyclophilin D. The involvement of the MPT pore in the progression of various pathological conditions and diseases, as well as in a number of physiological processes, such as the regulation of cellular bioenergetics and rapid release of Ca2+, is widely discussed. This review summarizes modern molecular genetic data on the putative structure of the MPT pore, traces the evolution of views on its functioning - from interpreting it as a simple experimental artifact to its recognition as a putative key regulator of energy metabolism - and also considers the mechanisms of its regulation and its multifaceted pathophysiological role.

Keywords: Ca2+; F0F1–ATP synthase; MPT pore; adenine nucleotide translocator; cell death; cyclophilin D; diabetes mellitus; mitochondria; neurodegenerative diseases; neuromuscular diseases

DOI: https://doi.org/10.1134/S0006297925602369

Front Endocrinol (Lausanne). 2025 ;16 1696344

Metabolic-stress-induced mitochondrial calcium dysregulation: a central hub in diabetic cardiomyopathy pathogenesis and treatment.

Siqi Deng, Fatemeh Tayefi, Yunpeng Jin.

Diabetic cardiomyopathy (DCM), as a devastating complication of diabetes mellitus (DM), arises from a complex interplay between systemic metabolic derangements and myocardial vulnerability. While hyperglycemia, lipotoxicity, and insulin resistance are established drivers of cardiac dysfunction, the precise mechanisms linking these metabolic insults to cardiac dysfunction remain elusive. Recent evidence suggests that the dysregulation of mitochondrial calcium homeostasis plays a critical role in integrating diabetic metabolic stress and cardiomyocyte fate. This review synthesizes recent advances in understanding how mitochondrial calcium mishandling-encompassing impaired uptake, excessive release, and buffering failure-orchestrates the pathological triad of bioenergetic deficit, oxidative stress, and cell death in DCM. We delve into the molecular mechanisms underpinning this dysregulation, highlighting its interplay with the diabetic metabolic milieu. Furthermore, we critically evaluate novel therapeutic strategies targeting mitochondrial calcium fluxes, including the inhibition of the mitochondrial calcium uniporter (MCU), the activation of the mitochondrial Na+/Ca2+/Li+ exchanger (NCLX), and the modulation of the mitochondrial permeability transition pore (mPTP), discussing their clinical translation potential and existing challenges. By reframing DCM through the lens of mitochondrial calcium homeostasis, this review not only synthesizes current knowledge but also provides a critical comparison of emerging therapeutic strategies and evaluates the formidable challenges in their clinical translation, thereby bridging the gap between endocrine metabolism and cardiac pathophysiology and offering nuanced perspectives for biomarker discovery and stage-specific interventions.

Keywords: calcium homeostasis; diabetic cardiomyopathy; heart failure; mitochondrial calcium; mitochondrial dysfunction; therapeutic targets

DOI: https://doi.org/10.3389/fendo.2025.1696344

Cell Commun Signal. 2025 Dec 24.

Mitochondrial DNA release via mPTP and BAX/BAK drives inflammatory injury in intestinal ischemia reperfusion.

Yixin Jing, Yiguo Zhang, Tulanisa Kadier, Ke Ding, Rong Chen, Qingtao Meng.

BACKGROUND: Intestinal ischemia reperfusion (IIR) is a challenging and life-threatening clinical condition, with disease progression closely linked to excessive inflammatory responses. As a potent activator of innate immunity, the mechanism underlying mitochondrial DNA (mtDNA) release across the mitochondrial membrane remains incompletely elucidated.
METHODS: In this study, an in vivo IIR model was established by clamping the superior mesenteric artery in male mice, and an in vitro hypoxia reoxygenation (HR) model was constructed using Caco-2 cells. Combining multiple techniques including RNA sequencing, subcellular organelle isolation, laser confocal imaging, siRNA transfection, protein cross-linking, Western blotting, enzyme-linked immunosorbent assay (ELISA), and quantitative real-time PCR (qPCR), the regulatory mechanisms of mtDNA release and its biological effects in IIR were systematically verified.
RESULTS: We found that IIR significantly induced an increase in cytosolic and circulating mtDNA levels, correlating with inflammatory cytokine production. Mechanistic studies revealed that calcium overload mediated by the mitochondrial calcium uniporter (MCU) triggered the opening of the mitochondrial permeability transition pore (mPTP). Meanwhile, the pro-apoptotic protein BAX was recruited to mitochondria and interacted with BAK to form outer mitochondrial membrane oligomeric pores. Notably, although mPTP opening was independent of the BAX/BAK pathway, the two pathways exhibited sequential synergistic effects during mtDNA release. Inhibition of either pathway significantly reduced mtDNA release, decreased inflammatory cytokine levels, and alleviated intestinal tissue injury caused by IIR.
CONCLUSIONS: These findings identify mtDNA as a potential biomarker for IIR and highlight the MCU-mPTP-BAX/BAK axis as a therapeutic target.

Keywords: BAX/BAK; IIR; MCU; mPTP; mtDNA

DOI: https://doi.org/10.1186/s12964-025-02603-3

Front Genet. 2025 ;16 1615167

Development of a prognostic model related to mitochondria and programmed cell death-related genes in bladder cancer.

Xuwei Zhao, Hongyao Liu, Chao Wang, Fuyu Guo, Bin Yang.

Background: Various forms of programmed cell death (PCD) play a crucial role in regulating the development and spread of cancer, with mitochondria serving as key organelles involved in executing PCD. In this study, mitochondrial and PCD-related prognostic genes in bladder cancer (BLCA) were explored, and prognostic models were constructed.
Methods: The GSE32894, GSE13507, and The Cancer Genome Atlas (TCGA)-BLCA datasets related to BLCA were retrieved. The intersection genes of differentially expressed genes (DEGs) between BLCA and control samples in TCGA-BLCA, mitochondrial-related genes (MRGs), and PCD-related genes (PCD-RGs) were obtained for univariate and multivariate Cox regression analysis. Prognostic genes were selected, and a prognostic model was developed. Then, the validity of the model was evaluated and subsequently validated in the GSE32894 dataset. To enhance the clinical precision of the model, a nomogram was developed and combined with clinical traits. Enrichment analysis, immune infiltration analysis, and drug sensitivity analysis were employed. Finally, the expressions of prognostic genes were verified in the GSE13507 and TCGA-BLCA datasets and by real-time quantitative polymerase chain reaction (RT-qPCR).
Results: Based on the above analysis, five prognostic genes (POLB, FASN, CASP9, VDAC2, and RHOT2) were selected, and a prognostic model was constructed, which revealed a strong predictive capability for sample survival in both the TCGA-BLCA and GSE32894 datasets. Meanwhile, the risk scores of BLCA samples in TCGA-BLCA were calculated, and samples were divided into high- and low-risk categories based on the optimal threshold. Further analysis found that risk score, stage, and age were independent prognostic factors, and they were used to construct the nomogram. Thereafter, we observed that pathways (e.g., epithelial-mesenchymal transition (EMT) and inflammatory response) related to BLCA were markedly enriched in the high-risk patients, and the response to immunotherapy in high-risk patients was suboptimal. Importantly, the expression trends of FASN, VDAC2, and RHOT2 in the BLCA and control groups within the TCGA-BLCA and GSE13507 datasets, as well as in clinical samples, were consistent and significant.
Conclusion: In this study, a novel prognostic model for bladder cancer was constructed based on POLB, FASN, CASP9, VDAC2, and RHOT2, which provided preliminary references for the prognostic evaluation of bladder cancer and subsequent studies related to its diagnosis and treatment.

Keywords: bladder cancer; immune infiltration; mitochondrial; prognosis; programmed cell death

DOI: https://doi.org/10.3389/fgene.2025.1615167

iScience. 2025 Dec 19. 28(12): 113985

Developing therapeutic strategies to target MCL1 and BCLXL in lethal prostate cancer.

Targeting anti-apoptotic BCL2 family proteins is an attractive therapeutic strategy to drive prostate cancer (PCa) cell death. Here, we show that MCL1 is highly expressed in castration-resistant PCa, associating with worse clinical outcome. We demonstrate that targeting MCL1 with BH3 mimetics triggers apoptotic cell death in a subset of PCa cell line models. Furthermore, siRNA targeting of UCHL3, a deubiquitinating enzyme, downregulates MCL1 expression to synergize with BCLXL blockade; however, its impact on MCL1 is driven through an off-target effect, raising an important methodological consideration when studying MCL1 biology. Finally, we demonstrate that co-targeting MCL1 and BCLXL in patient-derived and mouse PCa models drives apoptotic PCa cell death. Taken together, targeting the intrinsic apoptosis pathway remains an attractive therapeutic strategy for lethal PCa. Future studies should focus on identifying strategies and technologies that can deliver cancer specific kill, to improve the outcome for men with this lethal disease.

Keywords: Pharmacology; cancer; molecular biology

DOI: https://doi.org/10.1016/j.isci.2025.113985