bims-mibica 2024-05-19 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2024‒05‒19
nine papers selected by
Kelsey Fisher-Wellman, East Carolina University

NADPH composite index analysis quantifies the relationship between compartmentalized NADPH dynamics and growth rates in cancer cells.
Mitochondrial F0F1-ATP synthase governs the induction of mitochondrial fission.
Unraveling ETC complex I function in ferroptosis reveals a potential ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.
Residual OXPHOS is required to drive primary and metastatic lung tumours in an orthotopic breast cancer model.
Peptides Targeting the IF1-ATP Synthase Complex Modulate the Permeability Transition Pore in Cancer HeLa Cells.
Ophiobolin A Covalently Targets Mitochondrial Complex IV Leading to Metabolic Collapse in Cancer Cells.
HIF2α-dependent inhibition of mitochondrial clustering of glutaminase suppresses clear cell renal cell carcinoma.
mTORC1 regulates cell survival under glucose starvation through 4EBP1/2-mediated translational reprogramming of fatty acid metabolism.
The clinical significance of mitochondrial calcium uniporter in gastric cancer patients and its preliminary exploration of the impact on mitochondrial function and metabolism.

bioRxiv. 2024 Apr 29. pii: 2024.04.27.591477. [Epub ahead of print]

NADPH composite index analysis quantifies the relationship between compartmentalized NADPH dynamics and growth rates in cancer cells.

Sun Jin Moon, Anush Chiappino-Pepe, Wentao Dong, Joanne K Kelleher, Matthew Vander Heiden, Gregory Stephanopoulos, Hadley D Sikes.

NADPH, a highly compartmentalized electron donor in mammalian cells, plays essential roles in cell metabolism. However, little is known about how cytosolic and mitochondrial NADPH dynamics relate to cancer cell growth rates in response to varying nutrient conditions. To address this issue, we present NADPH composite index analysis, which quantifies the relationship between compartmentalized NADPH dynamics and growth rates using genetically encoded NADPH sensors, automated image analysis pipeline, and correlation analysis. Through this analysis, we demonstrated that compartmentalized NADPH dynamics patterns were cancer cell-type dependent. Specifically, cytosolic and mitochondrial NADPH dynamics of MDA-MB-231 decreased in response to serine deprivation, while those of HCT-116 increased in response to serine or glutamine deprivation. Furthermore, by introducing a fractional contribution parameter, we correlated cytosolic and mitochondrial NADPH dynamics to growth rates. Using this parameter, we identified cancer cell lines whose growth rates were selectively inhibited by targeting cytosolic or mitochondrial NADPH metabolism. Mechanistically, we identified citrate transporter as a key mitochondrial transporter that maintains compartmentalized NADPH dynamics and growth rates. Altogether, our results present a significant advance in quantifying the relationship between compartmentalized NADPH dynamics and cancer cell growth rates, highlighting a potential of targeting compartmentalized NADPH metabolism for selective cancer cell growth inhibitions.

DOI: https://doi.org/10.1101/2024.04.27.591477
iScience. 2024 May 17. 27(5): 109808

Mitochondrial F0F1-ATP synthase governs the induction of mitochondrial fission.

Charlène Lhuissier, Valérie Desquiret-Dumas, Anaïs Girona, Jennifer Alban, Justine Faure, Julien Cassereau, Philippe Codron, Guy Lenaers, Olivier R Baris, Naïg Gueguen, Arnaud Chevrollier.

  Mitochondrial dynamics is a process that balances fusion and fission events, the latter providing a mechanism for segregating dysfunctional mitochondria. Fission is controlled by the mitochondrial membrane potential (ΔΨm), optic atrophy 1 (OPA1) cleavage, and DRP1 recruitment. It is thought that this process is closely linked to the activity of the mitochondrial respiratory chain (MRC). However, we report here that MRC inhibition does not decrease ΔΨm nor increase fission, as evidenced by hyperconnected mitochondria. Conversely, blocking F0F1-ATP synthase activity induces fragmentation. We show that the F0F1-ATP synthase is sensing the inhibition of MRC activity by immediately promoting its reverse mode of action to hydrolyze matrix ATP and restoring ΔΨm, thus preventing fission. While this reverse mode is expected to be inhibited by the ATPase inhibitor ATPIF1, we show that this sensing is independent of this factor. We have unraveled an unexpected role of F0F1-ATP synthase in controlling the induction of fission by sensing and maintaining ΔΨm.

Keywords:  Biochemistry; Cell biology; Functional aspects of cell biology

DOI:  https://doi.org/10.1016/j.isci.2024.109808
Mol Cell. 2024 May 16. pii: S1097-2765(24)00324-1. [Epub ahead of print]84(10): 1964-1979.e6

Unraveling ETC complex I function in ferroptosis reveals a potential ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.

Chao Mao, Guang Lei, Amber Horbath, Min Wang, Zhengze Lu, Yuelong Yan, Xiaoguang Liu, Lavanya Kondiparthi, Xiong Chen, Jun Cheng, Qidong Li, Zhihao Xu, Li Zhuang, Bingliang Fang, Joseph R Marszalek, Masha V Poyurovsky, Kellen Olszewski, Boyi Gan.

  The role of the mitochondrial electron transport chain (ETC) in regulating ferroptosis is not fully elucidated. Here, we reveal that pharmacological inhibition of the ETC complex I reduces ubiquinol levels while decreasing ATP levels and activating AMP-activated protein kinase (AMPK), the two effects known for their roles in promoting and suppressing ferroptosis, respectively. Consequently, the impact of complex I inhibitors on ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition is limited. The pharmacological inhibition of complex I in LKB1-AMPK-inactivated cells, or genetic ablation of complex I (which does not trigger apparent AMPK activation), abrogates the AMPK-mediated ferroptosis-suppressive effect and sensitizes cancer cells to GPX4-inactivation-induced ferroptosis. Furthermore, complex I inhibition synergizes with radiotherapy (RT) to selectively suppress the growth of LKB1-deficient tumors by inducing ferroptosis in mouse models. Our data demonstrate a multifaceted role of complex I in regulating ferroptosis and propose a ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.

Keywords:  AMPK; ETC complex I; LKB1; cancer therapy; ferroptosis; lipid peroxidation; mitochondria

DOI:  https://doi.org/10.1016/j.molcel.2024.04.009
Front Oncol. 2024 ;14 1362786

Residual OXPHOS is required to drive primary and metastatic lung tumours in an orthotopic breast cancer model.

Patries Herst, Georgia Carson, Danielle Lewthwaite, David Eccles, Alfonso Schmidt, Andrew Wilson, Carole Grasso, David O'Sullivan, Jiri Neuzil, Melanie McConnell, Michael Berridge.

  Background: Fast adaptation of glycolytic and mitochondrial energy pathways to changes in the tumour microenvironment is a hallmark of cancer. Purely glycolytic ρ0 tumour cells do not form primary tumours unless they acquire healthy mitochondria from their micro-environment. Here we explored the effects of severely compromised respiration on the metastatic capability of 4T1 mouse breast cancer cells.Methods: 4T1 cell lines with different levels of respiratory capacity were generated; the Seahorse extracellular flux analyser was used to evaluate oxygen consumption rates, fluorescent confocal microscopy to assess the number of SYBR gold-stained mitochondrial DNA nucleoids, and the presence of the ATP5B protein in the cytoplasm and fluorescent in situ nuclear hybridization was used to establish ploidy. MinION nanopore RNA sequence analysis was used to compare mitochondrial DNA transcription between cell lines. Orthotopic injection was used to determine the ability of cells to metastasize to the lungs of female Balb/c mice.
Results: OXPHOS-deficient ATP5B-KO3.1 cells did not generate primary tumours. Severely OXPHOS compromised ρ0D5 cells generated both primary tumours and lung metastases. Cells generated from lung metastasis of both OXPHOS-competent and OXPHOS-compromised cells formed primary tumours but no metastases when re-injected into mice. OXPHOS-compromised cells significantly increased their mtDNA content, but this did not result in increased OXPHOS capacity, which was not due to decreased mtDNA transcription. Gene set enrichment analysis suggests that certain cells derived from lung metastases downregulate their epithelial-to-mesenchymal related pathways.
Conclusion: In summary, OXPHOS is required for tumorigenesis in this orthotopic mouse breast cancer model but even very low levels of OXPHOS are sufficient to generate both primary tumours and lung metastases.

Keywords:  breast cancer; glycolysis; intercellular mitochondrial transport; metastasis; orthotopic mouse model; oxidative phosphorylation

DOI:  https://doi.org/10.3389/fonc.2024.1362786
Int J Mol Sci. 2024 Apr 25. pii: 4655. [Epub ahead of print]25(9):

Peptides Targeting the IF1-ATP Synthase Complex Modulate the Permeability Transition Pore in Cancer HeLa Cells.

Martina Grandi, Simone Fabbian, Giancarlo Solaini, Alessandra Baracca, Massimo Bellanda, Valentina Giorgio.

  The mitochondrial protein IF1 is upregulated in many tumors and acts as a pro-oncogenic protein through its interaction with the ATP synthase and the inhibition of apoptosis. We have recently characterized the molecular nature of the IF1-Oligomycin Sensitivity Conferring Protein (OSCP) subunit interaction; however, it remains to be determined whether this interaction could be targeted for novel anti-cancer therapeutic intervention. We generated mitochondria-targeting peptides to displace IF1 from the OSCP interaction. The use of one selective peptide led to displacement of the inhibitor IF1 from ATP synthase, as shown by immunoprecipitation. NMR spectroscopy analysis, aimed at clarifying whether these peptides were able to directly bind to the OSCP protein, identified a second peptide which showed affinity for the N-terminal region of this subunit overlapping the IF1 binding region. In situ treatment with the membrane-permeable derivatives of these peptides in HeLa cells, that are silenced for the IF1 inhibitor protein, showed significant inhibition in mitochondrial permeability transition and no effects on mitochondrial respiration. These peptides mimic the effects of the IF1 inhibitor protein in cancer HeLa cells and confirm that the IF1-OSCP interaction inhibits apoptosis. A third peptide was identified which counteracts the anti-apoptotic role of IF1, showing that OSCP is a promising target for anti-cancer therapies.

Keywords:  ATP synthase; cancer; inhibitor protein IF1; mitochondria; permeability transition pore; therapy

DOI:  https://doi.org/10.3390/ijms25094655
ACS Chem Biol. 2024 May 13.

Ophiobolin A Covalently Targets Mitochondrial Complex IV Leading to Metabolic Collapse in Cancer Cells.

Flor A Gowans, Danny Q Thach, Zhouyang Zhu, Yangzhi Wang, Belen E Altamirano Poblano, Dustin Dovala, John A Tallarico, Jeffrey M McKenna, Markus Schirle, Thomas J Maimone, Daniel K Nomura.

Ophiobolin A (OPA) is a sesterterpenoid fungal natural product with broad anticancer activity. While OPA possesses multiple electrophilic moieties that can covalently react with nucleophilic amino acids on proteins, the proteome-wide targets and mechanism of OPA remain poorly understood in many contexts. In this study, we used covalent chemoproteomic platforms to map the proteome-wide reactivity of the OPA in a highly sensitive lung cancer cell line. Among several proteins that OPA engaged, we focused on two targets: lysine-72 of cytochrome c oxidase subunit 5A (COX5A) and cysteine-53 of mitochondrial hypoxia induced gene 1 domain family member 2A (HIGD2A). These two subunit proteins are part of complex IV (cytochrome C oxidase) within the electron transport chain and contributed significantly to the antiproliferative activity of OPA. OPA activated mitochondrial respiration in a COX5A- and HIGD2A-dependent manner, leading to an initial spike in mitochondrial ATP and heightened mitochondrial oxidative stress. OPA compromised mitochondrial membrane potential, ultimately leading to ATP depletion. We have used chemoproteomic strategies to discover a unique anticancer mechanism of OPA through activation of complex IV leading to compromised mitochondrial energetics and rapid cell death.

DOI: https://doi.org/10.1021/acschembio.4c00064
bioRxiv. 2024 May 05. pii: 2024.05.04.592520. [Epub ahead of print]

HIF2α-dependent inhibition of mitochondrial clustering of glutaminase suppresses clear cell renal cell carcinoma.

Boa Kim, Wencao Zhao, Nathan J Coffey, Caitlyn E Bowman, Michael Noji, Cholsoon Jang, M Celeste Simon, Zoltan Arany.

Clear cell renal cell carcinomas (ccRCC) are largely driven by HIF2α and are avid consumers of glutamine. However, inhibitors of glutaminase1 (GLS1), the first step in glutaminolysis, have not shown benefit in phase III trials, and HIF2α inhibition, recently FDA-approved for treatment of ccRCC, shows great but incomplete benefits, underscoring the need to better understand the roles of glutamine and HIF2α in ccRCC. Here, we report that glutamine deprivation rapidly redistributes GLS1 into isolated clusters within mitochondria across diverse cell types, excluding ccRCC. GLS1 clustering is rapid (1-3 hours) and reversible, is specifically driven by the level of intracellular glutamate, and is mediated by mitochondrial fission. Clustered GLS1 has markedly enhanced glutaminase activity and promotes cell death under glutamine-deprived conditions. We further show that HIF2α prevents GLS1 clustering, independently of its transcriptional activity, thereby protecting ccRCC cells from cell death induced by glutamine deprivation. Reversing this protection, by genetic expression of GLS1 mutants that constitutively cluster, enhances ccRCC cell death in culture and suppresses ccRCC growth in vivo . These finding provide multiple insights into cellular glutamine handling, including a novel metabolic pathway by which HIF2α promotes ccRCC, and reveals a potential therapeutic avenue to synergize with HIF2α inhibition in the treatment of ccRCC.

DOI: https://doi.org/10.1101/2024.05.04.592520
Nat Commun. 2024 May 14. 15(1): 4083

mTORC1 regulates cell survival under glucose starvation through 4EBP1/2-mediated translational reprogramming of fatty acid metabolism.

Tal Levy, Kai Voeltzke, Laura Hruby, Khawla Alasad, Zuelal Bas, Marteinn Snaebjörnsson, Ran Marciano, Katerina Scharov, Mélanie Planque, Kim Vriens, Stefan Christen, Cornelius M Funk, Christina Hassiepen, Alisa Kahler, Beate Heider, Daniel Picard, Jonathan K M Lim, Anja Stefanski, Katja Bendrin, Andres Vargas-Toscano, Ulf D Kahlert, Kai Stühler, Marc Remke, Moshe Elkabets, Thomas G P Grünewald, Andreas S Reichert, Sarah-Maria Fendt, Almut Schulze, Guido Reifenberger, Barak Rotblat, Gabriel Leprivier.

Energetic stress compels cells to evolve adaptive mechanisms to adjust their metabolism. Inhibition of mTOR kinase complex 1 (mTORC1) is essential for cell survival during glucose starvation. How mTORC1 controls cell viability during glucose starvation is not well understood. Here we show that the mTORC1 effectors eukaryotic initiation factor 4E binding proteins 1/2 (4EBP1/2) confer protection to mammalian cells and budding yeast under glucose starvation. Mechanistically, 4EBP1/2 promote NADPH homeostasis by preventing NADPH-consuming fatty acid synthesis via translational repression of Acetyl-CoA Carboxylase 1 (ACC1), thereby mitigating oxidative stress. This has important relevance for cancer, as oncogene-transformed cells and glioma cells exploit the 4EBP1/2 regulation of ACC1 expression and redox balance to combat energetic stress, thereby supporting transformation and tumorigenicity in vitro and in vivo. Clinically, high EIF4EBP1 expression is associated with poor outcomes in several cancer types. Our data reveal that the mTORC1-4EBP1/2 axis provokes a metabolic switch essential for survival during glucose starvation which is exploited by transformed and tumor cells.

DOI: https://doi.org/10.1038/s41467-024-48386-y
Front Oncol. 2024 ;14 1355559

The clinical significance of mitochondrial calcium uniporter in gastric cancer patients and its preliminary exploration of the impact on mitochondrial function and metabolism.

Zipeng Xu, Xia Chen, Haicun Zhou, Luming Sun, Ruobing Bai, Wenwen Yu, Junhao Yang, Hongbin Liu.

  Objective: The objective of this study is to elucidate the influence of MCU on the clinical pathological features of GC patients, to investigate the function and mechanism of the mitochondrial calcium uptake transporter MCU in the initiation and progression of GC, and to explore its impact on the metabolic pathways and biosynthesis of mitochondria. The ultimate goal is to identify novel targets and strategies for the clinical management of GC patients.Methods: Tumor and adjacent tissue specimens were obtained from 205 patients with gastric cancer, and immunohistochemical tests were performed to assess the expression of MCU and its correlation with clinical pathological characteristics and prognosis. Data from TCGA, GTEx and GEO databases were retrieved for gastric cancer patients, and bioinformatics analysis was utilized to investigate the association between MCU expression and clinical pathological features. Furthermore, we conducted an in-depth analysis of the role of MCU in GC patients. We investigated the correlation between MCU expression in GC and its impact on mitochondrial function, metabolism, biosynthesis, and immune cells. Additionally, we studied the proteins or molecules that interact with MCU.
Results: Our research revealed high expression of MCU in the GC tissues. This high expression was associated with poorer T and N staging, and indicated a worse disease-free survival period. MCU expression was positively correlated with mitochondrial function, mitochondrial metabolism, nucleotide, amino acid, and fatty acid synthesis metabolism, and negatively correlated with nicotinate and nicotinamide metabolism. Furthermore, the MCU also regulates the function of the mitochondrial oxidative respiratory chain. The MCU influences the immune cells of GC patients and regulates ROS generation, cell proliferation, apoptosis, and resistance to platinum-based drugs in gastric cancer cells.
Conclusion: High expression of MCU in GC indicates poorer clinical outcomes. The expression of the MCU are affected through impacts the function of mitochondria, energy metabolism, and cellular biosynthesis in gastric cancer cells, thereby influencing the growth and metastasis of gastric cancer cells. Therefore, the mitochondrial changes regulated by MCU could be a new focus for research and treatment of GC.

Keywords:  biosynthesis; gastric cancer; metabolism; mitochondrial; mitochondrial calcium uniporter

DOI:  https://doi.org/10.3389/fonc.2024.1355559