bims-miptne 2025-07-27 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2025–07–27
nine papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Pseudohypoxic stabilization of HIF1α via cyclophilin D suppression promotes melanoma metastasis.
Perturbing the mitochondrial pores using inhibitors of bax and bid along with cyclosporine-A could prevent cell death due to secondary injury after contusion spinal cord injury.
Development of novel mitochondrial pyruvate carrier inhibitors for breast cancer treatment.
The peculiar properties of mitochondrial carriers of the SLC25 family.
Cytochrome c-mediated mitochondrial apoptosis activation underpins THz wave-induced melanoma cell death.
Mitochondrial ROS inhibition prevents doxorubicin-induced breast cancer cell migration and invasion.
ATP Supply from Cytosol to Mitochondria Is an Additional Role of Aerobic Glycolysis to Prevent Programmed Cell Death by Maintenance of Mitochondrial Membrane Potential.
LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes.
Metabolic Effects of Succinate Dehydrogenase Loss in Cancer.

Signal Transduct Target Ther. 2025 Jul 24. 10(1): 231

Pseudohypoxic stabilization of HIF1α via cyclophilin D suppression promotes melanoma metastasis.

Hye-Kyung Park, Sung Hu, So Yeon Kim, Sora Yoon, Nam Gu Yoon, Ji Hye Lee, Wonyoung Choi, Sun-Young Kong, Jong Heon Kim, Dougu Nam, Byoung Heon Kang.

Stabilization of hypoxia-inducible factor 1 alpha (HIF1α), which plays a pivotal role in regulating cellular responses to insufficient oxygen, is implicated in cancer progression, particularly epithelial-mesenchymal transition and metastatic dissemination. Despite its crucial role in tumorigenesis, the precise mechanisms governing HIF1α stabilization under varying tumor microenvironmental conditions are not fully understood. In this study, we show that stabilization of HIF1α in metastasizing melanoma under mild hypoxia is regulated primarily by mitochondrial reactive oxygen species (ROS) rather than by reduced oxygen levels. Activated HIF1α suppresses the expression of cyclophilin D (CypD), a regulator of the mitochondrial permeability transition pore (mPTP), as a reciprocal regulatory mechanism to sustain HIF1 signaling via upregulation of microRNAs miR-23a and miR-27a. Reduced expression of CypD leads to mPTP closure, resulting in elevated mitochondrial calcium accumulation and enhanced oxidative phosphorylation, which in turn increases mitochondrial ROS levels. The ROS then inhibits a prolyl hydroxylase, establishing a pseudohypoxic state that stabilizes HIF1α even in the presence of oxygen. This HIF1-reinforced and mitochondria-driven pseudohypoxic induction is essential for maintaining HIF1 signaling under conditions of mild hypoxia or transient increases in oxygen levels during melanoma metastasis. Overexpression of CypD reversed the pseudohypoxic state and potently inhibited melanoma metastasis. Thus, mitochondria-driven pseudohypoxic induction is critical for sustaining HIF1 signaling in metastasizing cancer cells and can be exploited to develop anti-metastatic therapies.

DOI: https://doi.org/10.1038/s41392-025-02314-8
Biochem Biophys Res Commun. 2025 Jul 16. pii: S0006-291X(25)01088-5. [Epub ahead of print]778 152373

Perturbing the mitochondrial pores using inhibitors of bax and bid along with cyclosporine-A could prevent cell death due to secondary injury after contusion spinal cord injury.

Preeja Chandran, Khaviyaa Chandramohan, Krithika Iyer, Sreelakshmi Kokkatt Balachandran, Felicia Mary Michael, Sankar Venkatachalam.

  Delayed cell death following contusion spinal cord injury (SCI) is mediated through multiple, overlapping apoptotic pathways, including intrinsic, extrinsic, and granzyme-mediated cascades. Mitochondrial permeability transition pore (mPTP) opening plays a central role in the intrinsic pathway by compromising mitochondrial membrane integrity and enabling the release of cytochrome C and apoptosis-inducing factor (AIF), which activate caspase-dependent and -independent mechanisms. In this study, a holistic approach to preventing the intrinsic pathway of apoptosis was undertaken by inhibiting mPTP gating through targeting the responsible proteins, namely, both BAX and BID, key pro-apoptotic Bcl-2 family proteins, along with cyclosporine A, a known inhibitor of the VDAC-ANT-Cyp-D pore complex. In a rodent model of thoracic contusion SCI, intraparenchymal administration of these inhibitors was followed by Western blot analysis of pathway-specific apoptotic markers at 3 and 7 days post-injury. The results demonstrated effective attenuation of intrinsic apoptosis, accompanied by a collateral reduction in extrinsic and granzyme-mediated pathways. Importantly, this inhibition of apoptosis did not exacerbate necrotic progression, indicating a selective and beneficial modulation of secondary cell death mechanisms. These findings provide initial evidence supporting mitochondrial pore-targeted strategies as a promising therapeutic avenue to mitigate apoptosis-driven secondary damage following SCI. Interestingly, it appears targeting just one pathway of apoptosis itself can produce more beneficial effects by collateral inhibition of other pathways as well. Further studies would be required to validate whether the molecular level benefits observed transulate into systemic improvement in functional recovery after contusion SCI.

Keywords:  Apoptosis; Cyclosporine A; Mitochondrial permeability transition pore; Protein inhibitors; Spinal cord injury

DOI:  https://doi.org/10.1016/j.bbrc.2025.152373
J Biol Chem. 2025 Jul 16. pii: S0021-9258(25)02336-1. [Epub ahead of print] 110486

Development of novel mitochondrial pyruvate carrier inhibitors for breast cancer treatment.

Tanner J Schumacher, Zachary S Gardner, Jon Rumbley, Conor T Ronayne, Venkatram R Mereddy.

  Reprogrammed metabolism of cancer cells offers a unique target for pharmacological intervention. The mitochondrial pyruvate carrier (MPC) plays important roles in cancer progression by transporting cytosolic pyruvate into the mitochondria for use in the TCA cycle. In the current study, a series of novel fluoro-substituted aminocarboxycoumarin derivatives have been evaluated for their mitochondrial pyruvate carrier (MPC) inhibition properties. Our studies indicate that the aminocarboxycoumarin template elicits potent MPC inhibitory characteristics, and specifically, structure activity relationship studies show that the N-methyl-N-benzyl structural template provides the optimal inhibitory capacity. Further respiratory experiments demonstrate that candidate compounds specifically inhibit pyruvate driven respiration without substantially affecting other metabolic fuels, consistent with MPC inhibition. Further, computational inhibitor docking studies illustrate that aminocarboxycoumarin binding characteristics are nearly identical to that of classical MPC inhibitor UK5099 bound to human MPC, recently determined by cryoEM. The lead candidate C5 elicits cancer cell proliferation inhibition specifically in monocarboxylate transporter 1 (MCT1) expressing murine breast cancer cells 4T1 and 67NR, consistent with its ability to accumulate intracellular lactate. In vivo tumor growth studies illustrate that C5 significantly reduces the tumor burden in two syngeneic murine tumor models with 4T1 and 67NR cells. These studies provide novel MPC inhibitors with potential for anticancer applications in MCT1 expressing breast cancer tumor models.

Keywords:  aminocarboxycoumarin; breast cancer; mitochondrial pyruvate carrier; tumor metabolism

DOI:  https://doi.org/10.1016/j.jbc.2025.110486
Biochem J. 2025 Jul 23. pii: BCJ20253171. [Epub ahead of print]482(15):

The peculiar properties of mitochondrial carriers of the SLC25 family.

Edmund R S Kunji, Vasiliki Mavridou, Martin S King, Camila Cimadamore-Werthein, Stephany Jaiquel Baron, Scott A Jones, Alannah C King, Roger Springett, Deepak Chand, Shane M Palmer, Denis Lacabanne, Sotiria Tavoulari, Jonathan J Ruprecht.

  With 53 members, the SLC25 mitochondrial carriers form the largest solute carrier family in humans. They transport a wide variety of substrates across the mitochondrial inner membrane to generate chemical energy and to supply molecules and ions for growth and maintenance of cells. They are among the smallest transporters in nature, yet they translocate some of the largest molecules without proton leak. With one exception, they are monomeric and have an unusual three-fold pseudo-symmetric structure. These carriers also have a unique transport mechanism, which is facilitated by six structural elements, meaning that all transmembrane helices move separately, but in a co-ordinated way. In addition, there are three functional elements that are an integral part of the alternating access mechanism, which opens and closes the carrier to the mitochondrial matrix or the intermembrane space. The first is a matrix gate, comprising the matrix salt bridge network and glutamine braces on transmembrane helices H1, H3 and H5. The second is a cytoplasmic gate, containing the cytoplasmic salt bridge network and tyrosine braces on transmembrane helices H2, H4 and H6. The third functional element is a single central substrate-binding site, the access to which is controlled by the opening and closing of the two gates in an alternating way. The electrostatic properties of the binding site facilitate the exchange of charged substrates across the inner membrane in the presence of a high membrane potential. Here, we discuss the extraordinary features of mitochondrial carriers, providing new insights into one of the most complex and dynamic transport mechanisms in nature.

Keywords:  bioenergetics; mitochondria; oxidative phosphorylation; translocases; translocators; transport mechanism

DOI:  https://doi.org/10.1042/BCJ20253171
Int J Biol Macromol. 2025 Jul 17. pii: S0141-8130(25)06630-9. [Epub ahead of print] 146073

Cytochrome c-mediated mitochondrial apoptosis activation underpins THz wave-induced melanoma cell death.

Liu Sun, Lei Wang, Shuocheng She, Jiachen Zuo, Mingxia He.

  Cutaneous melanoma, a malignancy with a rising global incidence, remains a therapeutic challenge due to drug resistance despite advances in immunotherapies. We identified 0.1 THz (THz) waves as a precise therapeutic modality that induced melanoma-specific apoptosis via a caspase-independent pathway, while preserving the viability, proliferation, and migratory capacity of normal fibroblasts. Proteomics revealed that mitochondria were the main target of THz radiation and Cytochrome c1 (Cyc1) was the most significantly altered molecule, closely related to Cytochrome c (Cyt c). Notably, molecular dynamics simulations showed that THz radiation did not induce significant structural changes in Cyt c, but could lead to the release of Cyt c by causing mitochondrial perforation. Experimental studies further showed that melanoma cells could trigger the release of Cyt c and the apoptosis inducing factor (AIF) by synergistically opening mitochondrial permeability transition pores (mPTP) and mitochondrial apoptosis inducing channels (MAC), thereby initiating the apoptosis program. Further validation using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases confirmed that AIF was a critical determinant in the prognosis of melanoma. In summary, the mechanism by which THz waves specifically activate the cascade of mitochondrial apoptosis through the Cyt c-AIF-dependent pathway provides theoretical support for their use as a highly targeted and novel therapeutic strategy.

Keywords:  AIF; Cutaneous melanoma cells; Cyt c; MAC; THz waves; mPTP

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.146073
iScience. 2025 Aug 15. 28(8): 113031

Mitochondrial ROS inhibition prevents doxorubicin-induced breast cancer cell migration and invasion.

Tania Capeloa, Justine A Van de Velde, Erica Pranzini, Luigi Ippolito, Luca X Zampieri, Morgane Tardy, Thibaut Vazeille, Alan Provito, Giovanna Carrà, Alfonso Scalera, Valéry L Payen, Paolo E Porporato, Pierre Sonveaux.

  For cancer patients, metastasis is a life-threatening event limiting therapeutic options. Molecularly, the metastatic phenotype can be conferred by mitochondrial reactive oxygen species (mtROS) generated upon metabolic stress. Mitochondrial damage can also trigger mtROS production, which is particularly well illustrated for anthracyclines. Here, we tested in mouse models of murine and human breast cancer whether this type of chemotherapy can trigger metastasis. We report that subcytotoxic doses of doxorubicin mimicking the clinical situation in poorly perfused tumor areas sequential trigger mtROS production, activate TGFβ pathway effector Pyk2, and increase cancer cell migration and invasion. Fortunately, the metastatic switch was incompletely induced, and doxorubicin did not promote breast cancer metastasis in immunocompetent mice. Yet, MitoTEMPO fully prevented metastatic dissemination and did not interfere with doxorubicin cytotoxicity, making it attractive to combine anthracyclines with mitochondria-targeted antioxidants.

Keywords:  Cancer systems biology; Molecular network; Therapeutic procedure

DOI:  https://doi.org/10.1016/j.isci.2025.113031
Metabolites. 2025 Jul 07. pii: 461. [Epub ahead of print]15(7):

ATP Supply from Cytosol to Mitochondria Is an Additional Role of Aerobic Glycolysis to Prevent Programmed Cell Death by Maintenance of Mitochondrial Membrane Potential.

Akane Sawai, Takeo Taniguchi, Kohsuke Noguchi, Taisuke Seike, Nobuyuki Okahashi, Masak Takaine, Fumio Matsuda.

  Eukaryotic cells generate ATP primarily via oxidative and substrate-level phosphorylation. Despite the superior efficiency of oxidative phosphorylation, eukaryotic cells often use both pathways as aerobic glycolysis, even in the presence of oxygen. However, its role in cell survival remains poorly understood. Objectives: In this study, aerobic glycolysis was compared between the Warburg effect in breast cancer cells (MCF7) and the Crabtree effect in a laboratory strain of Saccharomyces cerevisiae (S288C). Methods: The metabolic adaptations of MCF7 and S288C cells were compared following treatment with electron transport chain inhibitors, including FCCP, antimycin A, and oligomycin. Results: MCF7 and S288C cells exhibited strikingly similar metabolic rewiring toward substrate-level phosphorylation upon inhibitor treatment, suggesting that mitochondrial oxidative phosphorylation and cytosolic substrate-level phosphorylation communicate through a common mechanism. Measurement of mitochondrial membrane potential (MMP) and ATP concentrations further indicated that cytosolic ATP was transported into the mitochondria under conditions of reduced electron transport chain activity. This ATP was likely utilized in the reverse mode of H+/ATPase to maintain MMP, which contributed to the avoidance of programmed cell death. Conclusions: These results suggest that the ATP supply to mitochondria plays a conserved role in aerobic glycolysis in yeast and mammalian cancer cells. This mechanism likely contributes to cell survival under conditions of fluctuating oxygen availability.

Keywords:  Saccharomyces cerevisiae; aerobic glycolysis; breast cancer cells; metabolic rewiring; mitochondrial membrane potential; programmed cell death; reverse mode of H+/ATPase

DOI:  https://doi.org/10.3390/metabo15070461
Nat Metab. 2025 Jul 21.

LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes.

Jin Li, Yamei Deng, Marie Gasser, Jie Zhu, Emily M Walker, Vaibhav Sidarala, Emma C Reck, Dre L Hubers, Mabelle B Pasmooij, Chun-Shik Shin, Khushdeep Bandesh, Eftyhmios Motakis, Siddhi Nargund, Romy Kursawe, Venkatesha Basrur, Alexey I Nesvizhskii, Michael L Stitzel, David C Chan, Guy A Rutter, Scott A Soleimanpour.

Protein misfolding is a contributor to the development of type 2 diabetes (T2D), but the specific role of impaired proteostasis is unclear. Here we show a robust accumulation of misfolded proteins in the mitochondria of human pancreatic islets from patients with T2D and elucidate its impact on β cell viability through the mitochondrial matrix protease LONP1. Quantitative proteomics studies of protein aggregates reveal that islets from donors with T2D have a signature resembling mitochondrial rather than endoplasmic reticulum protein misfolding. Loss of LONP1, a vital component of the mitochondrial proteostatic machinery, with reduced expression in the β cells of donors with T2D, yields mitochondrial protein misfolding and reduced respiratory function, leading to β cell apoptosis and hyperglycaemia. LONP1 gain of function ameliorates mitochondrial protein misfolding and restores human β cell survival after glucolipotoxicity via a protease-independent effect requiring LONP1-mitochondrial HSP70 chaperone activity. Thus, LONP1 promotes β cell survival and prevents hyperglycaemia by facilitating mitochondrial protein folding. These observations provide insights into the nature of proteotoxicity that promotes β cell loss during the pathogenesis of T2D, which could be considered as future therapeutic targets.

DOI: https://doi.org/10.1038/s42255-025-01333-7
J Cell Physiol. 2025 Jul;240(7): e70066

Metabolic Effects of Succinate Dehydrogenase Loss in Cancer.

Adam Chatoff, Daniel S Kantner, Nathaniel W Snyder, Lori Rink.

  Succinate dehydrogenase (SDH) is both Complex II in the electron transport chain (ETC) and a key metabolic enzyme in the tricarboxylic acid cycle. SDH is a heterotetrameric enzyme consisting of four subunits SDHA, SDHB, SDHC, and SDHD, all encoded in the nuclear genome. In addition, the SDH complex requires two assembly factors, SDHAF1 and SDHAF2, which are required for assembly of SDHA and SDHB onto the inner mitochondrial-embedded subunits SDHC and SDHD. Once assembled, SDH catalyzes the conversion of succinate to fumarate coupled to the reduction of ubiquinone to ubiquinol via FAD/FADH2 and ultimately the generation of ATP via ATP synthase through a functioning ETC. Given the unique dual metabolic role of SDH, loss of activity results in major metabolic rewiring, potentially uncovering metabolic vulnerabilities that could be targeted for pharmacological manipulation in disease states. SDH is a tumor suppressor and SDH-loss is a driver of oncogenesis for cancers including pheochromocytomas, paragangliomas, gastrointestinal stromal tumors, and clear cell renal cell carcinomas. SDH deficiency also plays a role in the pathogenesis in non-neoplastic diseases, including Leigh syndrome and other neurometabolic disorders. Considering the implications of SDH function in both normal physiology and disease, understanding SDH function has fundamental and translational implications. This review seeks to summarize SDH deficiency, focusing on the role SDH plays in metabolism, the metabolic consequences of SDH deficiency, the proteomic consequences of SDH loss, thereby highlight potential therapeutic vulnerabilities in SDH-deficient cells.

Keywords:  Complex II; clear cell renal cell carcinoma; electron transport chain; gastrointestinal stromal tumors; leigh syndrome; pheochromocytomas/paragangliomas; succinate dehydrogenase; tricarboxylic acid cycle

DOI:  https://doi.org/10.1002/jcp.70066