bims-miptne 2025-01-19 papers

J Physiol. 2025 Jan 14.

Adenine nucleotide translocator and ATP synthase cooperate in mediating the mitochondrial permeability transition.

Ludovica Tommasin, Andrea Carrer, Federica Boscolo Nata, Elena Frigo, Federico Fogolari, Giovanna Lippe, Michela Carraro, Paolo Bernardi.

The permeability transition (PT) is a permeability increase of the mitochondrial inner membrane causing mitochondrial swelling in response to matrix Ca2+. The PT is mediated by regulated channel(s), the PT pore(s) (PTP), which can be generated by at least two components, adenine nucleotide translocator (ANT) and ATP synthase. Whether these provide independent permeation pathways remains to be established. Here, we assessed the contribution of ANT to the PT based on the effects of the selective ANT inhibitors atractylate (ATR) and bongkrekate (BKA), which trigger and inhibit channel formation by ANT, respectively. BKA partially inhibited Ca2+-dependent PT and did not prevent the inducing effect of phenylarsine oxide, which was still present in mouse embryonic fibroblasts deleted for all ANT isoforms. The contribution of ANT to the PT emerged at pH 6.5 (a condition that inhibits ATP synthase channel opening) in the presence of ATR, which triggered mitochondrial swelling and elicited currents in patch-clamped mitoplasts. Unexpectedly, ANT-dependent PT at pH 6.5 could also be stimulated by benzodiazepine-423 [a selective ligand of the oligomycin sensitivity conferral protein (OSCP) subunit of ATP synthase], suggesting that the ANT channel is regulated by the peripheral stalk of ATP synthase. In keeping with docking simulations, ANT could be co-immunoprecipitated with ATP synthase subunits c and g, and oligomycin (which binds adjacent c subunits) decreased the association of ANT with subunit c. These results reveal a close cooperation between ANT and ATP synthase in the PT and open new perspectives in the study of this process. KEY POINTS: We have assessed the relative role of adenine nucleotide translocator (ANT) and ATP synthase in generating the mitochondrial permeability transition (PT). At pH 7.4, bongkrekate had little effect on Ca2+-dependent PT, and did not prevent the inducing effect of phenylarsine oxide, which was still present in mouse embryonic fibroblasts deleted for all ANT isoforms. The contribution of ANT emerged at pH 6.5 (which inhibits ATP synthase channel opening) in the presence of atractylate, which triggered mitochondrial swelling and elicited currents in patch-clamped mitoplasts. Benzodiazepine-423, a selective ligand of the oligomycin sensitivity conferral protein subunit of ATP synthase, stimulated ANT-dependent PT at pH 6.5, suggesting that the ANT channel is regulated by the peripheral stalk of ATP synthase. ANT could be co-immunoprecipitated with ATP synthase subunits c and g; oligomycin, which binds adjacent c subunits, decreased the association with subunit c, in keeping with docking simulations.

Keywords: ATP synthase; adenine nucleotide translocator; calcium; mitochondria; permeability transition

DOI: https://doi.org/10.1113/JP287147

Neuro Oncol. 2025 Jan 11. pii: noaf008. [Epub ahead of print]

Disease stage-specific role of the mitochondrial pyruvate carrier suppresses differentiation in temozolomide and radiation-treated glioblastoma.

Emma Martell, Helgi Kuzmychova, Harshal Senthil, Ujala Chawla, Esha Kaul, Akaljot Grewal, Versha Banerji, Christopher M Anderson, Chitra Venugopal, Donald Miller, Tamra E Werbowetski-Ogilvie, Sheila K Singh, Tanveer Sharif.

BACKGROUND: The mitochondrial pyruvate carrier (MPC), a central metabolic conduit linking glycolysis and mitochondrial metabolism, is instrumental in energy production. However, the role of the MPC in cancer is controversial. In particular, the importance of the MPC in glioblastoma (GBM) disease progression following standard temozolomide (TMZ) and radiation therapy (RT) remains unexplored.
METHODS: Leveraging in vitro and in vivo patient-derived models of TMZ-RT treatment in GBM, we characterize the temporal dynamics of MPC abundance and downstream metabolic consequences using state-of-the-art molecular, metabolic, and functional assays.
RESULTS: Our findings unveil a disease stage-specific role for the MPC, where in post-treatment GBM, but not therapy-naïve tumors, the MPC acts as a central metabolic regulator that suppresses differentiation. Temporal profiling reveals a dynamic metabolic rewiring where a steady increase in MPC abundance favors a shift towards enhanced mitochondrial metabolic activity across patient GBM samples. Intriguingly, while overall mitochondrial metabolism is increased, acetyl-CoA production is reduced in post-treatment GBM cells, hindering histone acetylation and silencing neural differentiation genes in an MPC-dependent manner. Finally, the therapeutic translations of these findings are highlighted by the successful pre-clinical patient-derived orthotopic xenograft (PDOX) trials utilizing a blood-brain-barrier (BBB) permeable MPC inhibitor, MSDC-0160, which augments standard TMZ-RT therapy to mitigate disease relapse and prolong animal survival.
CONCLUSION: Our findings demonstrate the critical role of the MPC in mediating GBM aggressiveness and molecular evolution following standard TMZ-RT treatment, illuminating a therapeutically-relevant metabolic vulnerability to potentially improve survival outcomes for GBM patients.

Keywords: Glioblastoma; differentiation; metabolism; mitochondrial pyruvate carrier; tumor recurrence

DOI: https://doi.org/10.1093/neuonc/noaf008

PLoS Pathog. 2025 Jan 13. 21(1): e1012872

Calcium-mediated mitochondrial fission and mitophagy drive glycolysis to facilitate arterivirus proliferation.

Zhe Sun, Zicheng Ma, Wandi Cao, Chenlong Jiang, Lei Guo, Kesen Liu, Yanni Gao, Juan Bai, Jiang Pi, Ping Jiang, Xing Liu.

Mitochondria, recognized as the "powerhouse" of cells, play a vital role in generating cellular energy through dynamic processes such as fission and fusion. Viruses have evolved mechanisms to hijack mitochondrial function for their survival and proliferation. Here, we report that infection with the swine arterivirus porcine reproductive and respiratory syndrome virus (PRRSV), manipulates mitochondria calcium ions (Ca2+) to induce mitochondrial fission and mitophagy, thereby reprogramming cellular energy metabolism to facilitate its own replication. Mechanistically, PRRSV-induced mitochondrial fission is caused by elevated levels of mitochondria Ca2+, derived from the endoplasmic reticulum (ER) through inositol 1,4,5-triphosphate receptor (IP3R)-voltage-dependent anion channel 1 (VDAC1)-mitochondrial calcium uniporter (MCU) channels. This process is associated with increased mitochondria-associated membranes (MAMs), mediated by the upregulated expression of sigma non-opioid intracellular receptor 1 (SIGMAR1). Elevated mitochondria Ca2+ further activates the Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ)-AMP-activated protein kinase (AMPK)-dynamin-related protein 1 (DRP1) signaling pathway, which interacts with mitochondrial fission protein 1 (FIS1) and mitochondrial dynamics proteins of 49 kDa (MiD49) to promote mitochondrial fission. PRRSV infection, alongside mitochondrial fission, triggers mitophagy via the PTEN-induced putative kinase 1 (PINK1)-Parkin RBR E3 ubiquitin (Parkin) pathway, promoting cellular glycolysis and excessive lactate production to facilitate its own replication. This study reveals the mechanism by which mitochondrial Ca2+ regulates mitochondrial function during PRRSV infection, providing new insights into the interplay between the virus and host cell metabolism.

DOI: https://doi.org/10.1371/journal.ppat.1012872

Adv Exp Med Biol. 2025 ;1464 347-370

Metabolic Reprogramming and Adaption in Breast Cancer Progression and Metastasis.

Qianying Zuo, Yibin Kang.

Recent evidence has revealed that cancer is not solely driven by genetic abnormalities but also by significant metabolic dysregulation. Cancer cells exhibit altered metabolic demands and rewiring of cellular metabolism to sustain their malignant characteristics. Metabolic reprogramming has emerged as a hallmark of cancer, playing a complex role in breast cancer initiation, progression, and metastasis. The different molecular subtypes of breast cancer exhibit distinct metabolic genotypes and phenotypes, offering opportunities for subtype-specific therapeutic approaches. Cancer-associated metabolic phenotypes encompass dysregulated nutrient uptake, opportunistic nutrient acquisition strategies, altered utilization of glycolysis and TCA cycle intermediates, increased nitrogen demand, metabolite-driven gene regulation, and metabolic interactions with the microenvironment. The tumor microenvironment, consisting of stromal cells, immune cells, blood vessels, and extracellular matrix components, influences metabolic adaptations through modulating nutrient availability, oxygen levels, and signaling pathways. Metastasis, the process of cancer spread, involves intricate steps that present unique metabolic challenges at each stage. Successful metastasis requires cancer cells to navigate varying nutrient and oxygen availability, endure oxidative stress, and adapt their metabolic processes accordingly. The metabolic reprogramming observed in breast cancer is regulated by oncogenes, tumor suppressor genes, and signaling pathways that integrate cellular signaling with metabolic processes. Understanding the metabolic adaptations associated with metastasis holds promise for identifying therapeutic targets to disrupt the metastatic process and improve patient outcomes. This chapter explores the metabolic alterations linked to breast cancer metastasis and highlights the potential for targeted interventions in this context.

Keywords: Breast cancer; Circulating tumor cells (CTCs); Epithelial-mesenchymal transition (EMT); Metabolism; Metastasis; Metastatic colonization

DOI: https://doi.org/10.1007/978-3-031-70875-6_17

Cell Rep. 2025 Jan 10. pii: S2211-1247(24)01534-1. [Epub ahead of print]44(1): 115183

Deletion of AMP-activated protein kinase impairs metastasis and is rescued by ROS scavenging or ectopic CD36 expression.

Gopalakrishnan Ramakrishnan, Alexander R Terry, Veronique Nogueira, Ahmed Magdy, Nissim Hay.

AMPK's role in tumor initiation and progression is controversial. Here, we provide genetic evidence that AMPK is required for metastasis in mouse models of breast cancer. In a mouse model of spontaneous breast cancer metastasis, the deletion of AMPK before and after tumor onset decreased breast cancer metastasis, and similar results were obtained after AMPK deletion in breast cancer cell lines. The deletion of AMPK induces reactive oxygen species (ROS) levels in vitro and lipid oxidation in vivo, which likely impede metastasis. Indeed, antioxidants restore the ability of AMPK-deficient tumors to metastasize. By inhibiting acetyl-coenzyme A (CoA) carboxylases 1 and 2, AMPK maintains NADPH levels by reducing NADPH consumption in fatty acid synthesis and increasing NADPH generation via fatty acid oxidation, thus increasing the dependency on auxotrophic fatty acids. Consistently, AMPK is required for the expression of the fatty acid transporter CD36 in tumors, and ectopic expression of CD36 in AMPK-deficient cells restored their ability to metastasize.

Keywords: AMPK; CD36; CP: Cancer; CP: Metabolism; ROS; breast cancer metastasis

DOI: https://doi.org/10.1016/j.celrep.2024.115183

J Transl Med. 2025 Jan 15. 23(1): 70

A review of the pathogenesis of mitochondria in breast cancer and progress of targeting mitochondria for breast cancer treatment.

Aoling Huang, Haochen Xue, Ting Xie, Lingyan Xiang, Zhengzhuo Chen, Aolong Ma, Honglin Yan, Jingping Yuan.

With breast cancer being the most common tumor among women in the world today, it is also the leading cause of cancer-related deaths. Standard treatments include chemotherapy, surgery, endocrine therapy, and targeted therapy. However, the heterogeneity, drug resistance, and poor prognosis of breast cancer highlight an urgent need for further exploration of its underlying mechanisms. Mitochondria, highly dynamic intracellular organelles, play a pivotal role in maintaining cellular energy metabolism. Altered mitochondrial function plays a critical role in various diseases, and recent studies have elucidated its pathophysiological mechanisms in breast carcinogenesis. This review explores the role of mitochondrial dysfunction in breast cancer pathogenesis and assesses potential mitochondria-targeted therapies.

Keywords: Apoptosis; Breast cancer; Mitochondria; Mitochondrial dynamics; Mitochondrial metabolism

DOI: https://doi.org/10.1186/s12967-025-06077-2