bims-miptne 2025-06-29 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2025–06–29
seven papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Influence of Tariquidar, an ABC Transporter Inhibitor, on the Ca2+-Dependent Mitochondrial Permeability Transition Pore.
TGEV-M up-regulates ATP5D to promote mPTP opening via inhibiting BIRC6-236aa encoded by circBIRC6-2.
Cannabidiol Prevents Heart Failure Dysfunction and Remodeling Through Preservation of Mitochondrial Function and Calcium Handling.
Inhibition of the ATP synthase c subunit ameliorates HDM/LPS-induced inflammatory responses in asthmatic bronchial epithelial cells by blocking the mPTP-mtDNA-cGAS-STING axis.
The Multifaceted Role of Calcium Signaling in Regulated Necrosis.
Mitochondrial proteome landscape unveils key insights into melanoma severity and treatment strategies.
"Therapeutic Transplantation of Mitochondria and Extracellular Vesicles: Mechanistic Insights into mitochondria bioenergetics, redox signaling, and organelle dynamics in preclinical models".

Pharmaceuticals (Basel). 2025 Jun 19. pii: 924. [Epub ahead of print]18(6):

Influence of Tariquidar, an ABC Transporter Inhibitor, on the Ca2+-Dependent Mitochondrial Permeability Transition Pore.

Tatiana A Fedotcheva, Alexey G Kruglov, Nadezhda I Fedotcheva.

  Background: Tariquidar (Tq) is an inhibitor of the multidrug resistance (MDR) proteins relevant to ATP-binding cassette transporters (ABC transporters), which suppresses the ATP-dependent efflux of a variety of hydrophilic and amphipathic compounds, including anticancer drugs. Tq is a representative of a new generation of MDR inhibitors with high affinity to ABC proteins. However, there are still no data on the possible effect of Tq on mitochondria as an important target in the regulation of cell death or survival. Methods: We investigated the influence of Tq on the Ca2+-dependent mitochondrial permeability transition pore (mPTP). The effect of Tq was assessed using several parameters, including the calcium load, membrane potential, and mitochondrial swelling. To evaluate the specific targets of Tq, selective inhibitors of components of the mitochondrial pore were used, including adenine nucleotides, carboxyatractylozide (Catr) and bongkrekic acid (BA), oligomycin, and cyclosporine A. Results: Tq decreased the calcium retention capacity, activated mitochondrial swelling, and lowered the influence of ADP and ATP, the inhibitors of the Ca2+-induced pore opening, at their low concentrations. These effects of Tq were observed in both calcium-load and swelling assays, thus mimicking the effect of Catr, a selective inhibitor of adenine nucleotide translocase (ANT). Tq also decreased the protective effect of BA, an inhibitor of ANT and mPTP, on the calcium retention capacity of mitochondria. Further, Tq dose-dependently decreased the inhibitory effect of a low ATP concentration but not of high concentrations, at which the effect of Tq was activated by oligomycin, an inhibitor of F-ATP synthase. Conclusions: The influence of Tq extends to mitochondria, specifically to the regulation of membrane permeability, promoting the activation of pore opening, probably through an interaction with ANT, a component of the pore-forming complex. The effect of Tq on the opening of mPTP is strongly dependent on the concentrations of adenine nucleotides and, consequently, on the functional state of mitochondria. The direct influence of Tq on mitochondria can be considered as a new activity that promotes the sensitization of cells to various treatments and stimuli.

Keywords:  adenine nucleotide translocase; mitochondria; mitochondrial permeability transition pore; multidrug resistance; tariquidar

DOI:  https://doi.org/10.3390/ph18060924
Vet Microbiol. 2025 Jun 13. pii: S0378-1135(25)00241-X. [Epub ahead of print]307 110606

TGEV-M up-regulates ATP5D to promote mPTP opening via inhibiting BIRC6-236aa encoded by circBIRC6-2.

Jianxiong Guo, Lingling Chang, Fengxi Zhang, Xingyi Dang, Xiangyin Zhang, Fenli Zhang, Xiaomin Zhao, Dewen Tong.

  Transmissible gastroenteritis virus (TGEV) infection can down-regulate circBIRC6-2 expression and induce mitochondrial permeability transition pore (mPTP) opening abnormally. BIRC6-236aa, encoded by circBIRC6-2, can suppress mPTP opening by interacting with VDAC1. However, the molecular mechanism of circBIRC6-2 downregulation by TGEV infection is unsuspected, and it is unclear that whether BIRC6-236aa can inhibit mPTP opening by post translational modifications (PTM) and downstream regulatory proteins. In this study, we found that TGEV membrane protein (TGEV-M) can suppress circBIRC6-2 expression by interacting with heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) and inhibiting the translocation of hnRNPA1, which can bind to baculoviral IAP repeat containing 6 (birc6) pre-mRNA to promote the formation of circBIRC6-2. In addition, glycogen synthase kinase-3 beta (GSK-3β) can phosphorylate Ser180 of BIRC6-236aa, and phosphorylated-BIRC6-236aa (p-BIRC6-236aa) can inhibit mPTP opening. 271 differential expression proteins (DEPs) were identified after overexpression of BIRC6-236aa. ATP synthase, H+ transporting, mitochondrial F1 complex, delta subunit (ATP5D, also named ATP5F1D), one of the DEPs was down-regulated in response to BIRC6-236aa, and ATP5D can promote mPTP opening induced by TGEV. In conclusion, TGEV-M can suppress the expression of circBIRC6-2 through targeting hnRNPA1. The Ser180 of BIRC6-236aa encoded by circBIRC6-2 can be phosphorylated by GSK-3β, and p-BIRC6-236aa can inhibit mPTP opening by down-regulating ATP5D expression.

Keywords:  ATP5D; BIRC6-236aa; HnRNPA1; MPTP; TGEV

DOI:  https://doi.org/10.1016/j.vetmic.2025.110606
JACC Basic Transl Sci. 2025 Jun;pii: S2452-302X(24)00459-5. [Epub ahead of print]10(6): 800-821

Cannabidiol Prevents Heart Failure Dysfunction and Remodeling Through Preservation of Mitochondrial Function and Calcium Handling.

Gerardo García-Rivas, Omar Lozano, Judith Bernal-Ramírez, Christian Silva-Platas, Felipe Salazar-Ramírez, Abraham Méndez-Fernández, Carolina Morales-Ochoa, Hugo Alves-Figueiredo, Martín Rogelio Ramos-González, Nestor Rubio-Infante, Eduardo Vázquez-Garza, Luis A Luévano-Martínez, Silvia López-Morán, Héctor Chapoy-Villanueva, James Bolton, José-Luis Velasco-Bolom, Paola Mendoza-Espinosa, Flavio F Contreras-Torres, Carlos Jerjes-Sánchez, Guillermo Torre-Amione.

  Heart failure (HF) is characterized by energy deprivation, calcium (Ca2+) handling alterations, and inflammation: effects associated with mitochondrial dysfunction. Cannabidiol previously prevented mitochondrial dysfunction. Thus, it may prevent HF progression. In mice with HF, subcutaneous cannabidiol attenuated cardiac fibrosis, hypertrophy, loss of ejection fraction, and inflammation; isolated cardiomyocytes preserved cell shortening, Ca2+ handling, mitochondrial function and redox balance. Hypertrophied ventricular cardiomyoblasts suggested cannabidiol-mediated effects through peroxisome proliferator-activated gamma receptors. Therefore, cannabidiol in HF limited cardiac hypertrophy and preserved contractile function by sustaining cardiomyocyte and mitochondrial function through redox balance maintenance, supporting cannabidiol role as a cardioprotective therapy in HF.

Keywords:  Ca(2+) dynamics; PPAR-γ; cannabidiol; heart failure; mitochondrial energetics; oxidative stress

DOI:  https://doi.org/10.1016/j.jacbts.2024.12.009
Respir Res. 2025 Jun 21. 26(1): 219

Inhibition of the ATP synthase c subunit ameliorates HDM/LPS-induced inflammatory responses in asthmatic bronchial epithelial cells by blocking the mPTP-mtDNA-cGAS-STING axis.

Decai Wang, Chao Liu, Chen Bao, Jiannan Hu, Ziling Li, Xinyue Ma, Yunfei Zhu, Shuyun Xu.

  The ATP synthase c subunit (c subunit) constitutes the mitochondrial permeability transition pore (mPTP). The extended opening of the mPTP is crucial in the development of various human illnesses. Nevertheless, it remains unclear whether the c subunit regulates the prolonged opening of the mPTP to attenuate inflammatory responses in asthma. This study sought to clarify the impact of the c subunit on inflammatory responses and to examine the therapeutic effects of 1,3,8-triazaspiro [4.5] decane derivatives (PP10), a c subunit inhibitor, in human bronchial epithelial (HBE) cells induced by house dust mite (HDM) and lipopolysaccharide (LPS), as well as in a mouse model. The findings indicated that the expression of the c subunit is elevated in asthmatic patients, HDM/LPS-induced HBE cells, and asthmatic mice. The inhibition of the c subunit by PP10 alleviated the prolonged opening of mPTP, then blocked the release of mitochondrial DNA (mtDNA) and cyclic GMP-AMP synthase (cGAS)-interferon response cGAMP interactor (STING) pathway activation in HDM/LPS-induced HBE cells. Furthermore, PP10 decreased the secretion of inflammatory cytokines and ameliorated airway inflammation in HDM/LPS-induced HBE cells and asthmatic animals, respectively. The data collectively suggest that the c subunit triggers an inflammatory response by promoting the sustained opening of mPTP, leading to the activation of the mtDNA-GAS-STING pathway in HDM/LPS-induced HBE cells. Inhibition of the c-subunit attenuates inflammatory responses in HDM/LPS-induced cells or mouse models. Clinical trial number Not applicable.

Keywords:  ATP synthase c subunit; Airway epithelial cells; Asthma; Inflammatory responses; Mitochondria; Mitochondrial permeability transition pore

DOI:  https://doi.org/10.1186/s12931-025-03299-2
Biomolecules. 2025 Jun 11. pii: 854. [Epub ahead of print]15(6):

The Multifaceted Role of Calcium Signaling in Regulated Necrosis.

Eric Perez-Rivera, Claudia Plasencia, Uris Ros.

  Calcium is a versatile ion that regulates diverse intracellular processes, including cell death and survival, cytokine and chemokine production, lipid scrambling, and immune cell activation. In regulated necrosis, an early increase in cytosolic calcium is a hallmark of pathways such as pyroptosis, necroptosis, and ferroptosis, and resembles the calcium surge triggered by pore-forming toxins. The complexity of calcium signaling is orchestrated by specialized channels in various cellular compartments and calcium-binding proteins that respond to localized calcium concentrations. However, the coordination of this intricate code during regulated necrosis and its connections to other calcium-driven processes remains poorly understood. This review provides an overview of the molecular mechanisms of calcium signaling in regulated necrosis, analyzing parallels with pore-forming toxin-mediated membrane damage to uncover nodes that are shared by these seemingly independent pathways. We also discuss advanced techniques for studying calcium dynamics, with high precision, that can be applied to study regulated necrosis. Calcium signaling emerges as a central hub where necrotic cell death pathways converge, shaping the unique signatures of dying cells and influencing their communication with the immune system. This integrated perspective highlights the complex and multifaceted role of calcium in cells and its implications for fundamental cellular processes.

Keywords:  calcium signaling; cell death; immune response; membrane damage; necrosis

DOI:  https://doi.org/10.3390/biom15060854
Cancer. 2025 Jul 01. 131(13): e35897

Mitochondrial proteome landscape unveils key insights into melanoma severity and treatment strategies.

Yonghyo Kim, Viktória Doma, Uğur Çakır, Magdalena Kuras, Lazaro Hiram Betancourt, Indira Pla, Aniel Sanchez, Yutaka Sugihara, Roger Appelqvist, Henriett Oskolas, Boram Lee, Jéssica Guedes, Gustavo Monnerat, Gabriel Reis Alves Carneiro, Fábio C S Nogueira, Gilberto B Domont, Johan Malm, Bo Baldetorp, Elisabet Wieslander, István Balázs Németh, A Marcell Szász, Runyu Hong, Krzysztof Pawłowski, Melinda Rezeli, Ho Jeong Kwon, Jozsef Timar, David Fenyö, Sarolta Kárpáti, György Marko-Varga, Jeovanis Gil.

   BACKGROUND: Melanoma, the deadliest form of skin cancer, exhibits resistance to conventional therapies, particularly in advanced and metastatic stages. Mitochondrial pathways, including oxidative phosphorylation and mitochondrial translation, have emerged as critical drivers of melanoma progression and therapy resistance. This study investigates the mitochondrial proteome in melanoma to uncover novel therapeutic vulnerabilities.
METHODS: Quantitative proteomics was performed on 151 melanoma-related samples from a prospective cohort and postmortem tissues. Differential expression analysis identified mitochondrial proteins linked to disease aggression and treatment resistance. Functional enrichment analyses and in vitro validation using mitochondrial inhibitors were conducted to evaluate therapeutic potential.
RESULTS: Mitochondrial translation and oxidative phosphorylation (OXPHOS) were significantly upregulated in aggressive melanomas, particularly in BRAF-mutant and metastatic tumors. Inhibition of mitochondrial pathways using antibiotics (doxycycline, tigecycline, and azithromycin) and OXPHOS inhibitors (VLX600, IACS-010759, and BAY 87-2243) demonstrated dose-dependent antiproliferative effects in melanoma cell lines, sparing noncancerous melanocytes. These treatments disrupted mitochondrial function, suppressed key metabolic pathways, and induced apoptosis, highlighting the clinical relevance of targeting these pathways.
CONCLUSIONS: This study reveals mitochondrial pathways as critical drivers of melanoma progression and resistance, providing a rationale for targeting mitochondrial translation and OXPHOS in advanced melanoma. Combining mitochondrial inhibitors with existing therapies could overcome treatment resistance and improve patient outcomes.

Keywords:  BRAF mutation; MCM complex; melanoma; mitochondrial metabolism; mitochondrial proteome; mitoribosomes; oxidative phosphorylation; proteomics

DOI:  https://doi.org/10.1002/cncr.35897
Free Radic Biol Med. 2025 Jun 24. pii: S0891-5849(25)00789-0. [Epub ahead of print]

"Therapeutic Transplantation of Mitochondria and Extracellular Vesicles: Mechanistic Insights into mitochondria bioenergetics, redox signaling, and organelle dynamics in preclinical models".

Quentin Perrier, Veronica Lisi, Kelsey Fisherwellman, Sandrine Lablanche, Amish Asthana, Giuseppe Orlando, Sophie Maiocchi.

  Mitochondrial and extracellular vesicles (EV) transplantation have emerged as promising therapeutic strategies targeting mitochondrial dysfunction, a central feature of numerous pathologies. This review synthesizes preclinical data on artificial mitochondrial and EV transfer, emphasizing their therapeutic potential and underlying mechanisms. A systematic analysis of 123 animal studies revealed consistent benefits across diverse models, including ischemia-reperfusion injury (IRI), neurological disorders, drug-induced toxicities, and sepsis. Mitochondrial transfer improved organ function, reduced inflammation and apoptosis, and enhanced survival. Mechanistic insights revealed restored bioenergetics, increased oxidative phosphorylation, redox balance through activation of specific pathways, and modulation of mitochondrial dynamics via fusion/fission proteins. Mitochondrial homeostasis was supported through elevated mitophagy and biogenesis, alongside the preservation of mitochondrial-associated membranes. EV demonstrated similar effects, offering a potentially more targeted therapeutic alternative. Although pre-clinical studies have demonstrated safety and feasibility, broader application is limited by variability in isolation methods, lack of mechanistic clarity, and minimal human data. Standardization and mechanistic validation are critical to advance clinical translation. This review underscores the therapeutic promise of mitochondrial and EV transfer while highlighting the need for continued research to refine these interventions and unlock their full potential in regenerative medicine.

Keywords:  Artificial Mitochondrial transfer; Extracellular vesicles; Microvesicles; Mitochondrial Transplantation; Pre-clinical data; Therapeutic; Treatment

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.06.040