bims-mibica 2024-10-27 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2024–10–27
seventeen papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Lipid availability influences ferroptosis sensitivity in cancer cells by regulating polyunsaturated fatty acid trafficking.
Dissected antiporter modules establish minimal proton-conduction elements of the respiratory complex I.
PINK1-Mediated Mitochondrial Activity Confers Olaparib Resistance in Prostate Cancer Cells.
Mitochondrial DNA damage, repair, and replacement in cancer.
Cyclophilin D plays a critical role in the survival of senescent cells.
Mitoception, or transfer of normal cell mitochondria to cancer cells, reverses remodeling of store-operated Ca2+ entry in tumor cells.
Mitochondrial fatty acid oxidation drives senescence.
Mitochondrial mechanotransduction through MIEF1 coordinates the nuclear response to forces.
A phase 1 study of the amino acid modulator pegcrisantaspase and venetoclax for relapsed/refractory acute myeloid leukemia.
Potential role of heteroplasmic mitochondrial DNA mutations in modulating the subtype-specific adaptation of oral squamous cell carcinoma to cisplatin therapy.
Glutamine sensing licenses cholesterol synthesis.
Sphingosine-1-Phosphate Signalling Inhibition Suppresses Th1-Like Treg Generation by Reversing Mitochondrial Uncoupling.
Bioengineered Extracellular Vesicles Delivering siMDM2 Sensitize Oxaliplatin Therapy Efficacy in Colorectal Cancer.
Adipocyte-derived glutathione promotes obesity-related breast cancer by regulating the SCARB2-ARF1-mTORC1 complex.
SLC7A9 suppression increases chemosensitivity by inducing ferroptosis via the inhibition of cystine transport in gastric cancer.
Bicarbonate-mediated proton transfer requires cations.
Cell specific mitochondria targeted metabolic alteration for precision medicine.

Cell Chem Biol. 2024 Oct 14. pii: S2451-9456(24)00404-5. [Epub ahead of print]

Lipid availability influences ferroptosis sensitivity in cancer cells by regulating polyunsaturated fatty acid trafficking.

Kelly H Sokol, Cameron J Lee, Thomas J Rogers, Althea Waldhart, Abigail E Ellis, Sahithi Madireddy, Samuel R Daniels, Rachel Rae J House, Xinyu Ye, Mary Olesnavich, Amy Johnson, Benjamin R Furness, Ryan D Sheldon, Evan C Lien.

  Ferroptosis is a form of cell death caused by lipid peroxidation that is emerging as a target for cancer therapy, highlighting the need to identify factors that govern ferroptosis susceptibility. Lipid peroxidation occurs primarily on phospholipids containing polyunsaturated fatty acids (PUFAs). Here, we show that even though extracellular lipid limitation reduces cellular PUFA levels, lipid-starved cancer cells are paradoxically more sensitive to ferroptosis. Using mass spectrometry-based lipidomics with stable isotope fatty acid labeling, we show that lipid limitation induces a fatty acid trafficking pathway in which PUFAs are liberated from triglycerides to synthesize highly unsaturated PUFAs such as arachidonic and adrenic acid. These PUFAs then accumulate in phospholipids, including ether phospholipids, to promote ferroptosis sensitivity. Therefore, PUFA levels within cancer cells do not necessarily correlate with ferroptosis susceptibility. Rather, how cancer cells respond to extracellular lipid levels by trafficking PUFAs into proper phospholipid pools contributes to their sensitivity to ferroptosis.

Keywords:  cancer; ferroptosis; lipid metabolism; phospholipids; polyunsaturated fatty acids; triglycerides

DOI:  https://doi.org/10.1016/j.chembiol.2024.09.008
Nat Commun. 2024 Oct 22. 15(1): 9098

Dissected antiporter modules establish minimal proton-conduction elements of the respiratory complex I.

Adel Beghiah, Patricia Saura, Sofia Badolato, Hyunho Kim, Johanna Zipf, Dirk Auman, Ana P Gamiz-Hernandez, Johan Berg, Grant Kemp, Ville R I Kaila.

The respiratory Complex I is a highly intricate redox-driven proton pump that powers oxidative phosphorylation across all domains of life. Yet, despite major efforts in recent decades, its long-range energy transduction principles remain highly debated. We create here minimal proton-conducting membrane modules by engineering and dissecting the key elements of the bacterial Complex I. By combining biophysical, biochemical, and computational experiments, we show that the isolated antiporter-like modules of Complex I comprise all functional elements required for conducting protons across proteoliposome membranes. We find that the rate of proton conduction is controlled by conformational changes of buried ion-pairs that modulate the reaction barriers by electric field effects. The proton conduction is also modulated by bulky residues along the proton channels that are key for establishing a tightly coupled proton pumping machinery in Complex I. Our findings provide direct experimental evidence that the individual antiporter modules are responsible for the proton transport activity of Complex I. On a general level, our findings highlight electrostatic and conformational coupling mechanisms in the modular energy-transduction machinery of Complex I with distinct similarities to other enzymes.

DOI: https://doi.org/10.1038/s41467-024-53194-5
Cancer Res Commun. 2024 Oct 23.

PINK1-Mediated Mitochondrial Activity Confers Olaparib Resistance in Prostate Cancer Cells.

Zachary A Schaaf, Shu Ning, Amy R Leslie, Masuda Sharifi, Richard Y Gao, James P Maine, Wei Lou, Alan P Lombard, Chengfei Liu, Ai-Ming Yu, Nicholas Mitsiades, Allen C Gao.

Olaparib, a PARP inhibitor, is a targeted therapy used in treating various cancers including castration-resistant prostate cancer (CRPC). Despite its efficacy, resistance to Olaparib remains a significant challenge. Understanding the molecular mechanisms underpinning this resistance is crucial for developing more effective treatment strategies. This study focuses on elucidating the role of mitochondrial alterations and the PINK1 gene in conferring Olaparib resistance in CRPC cells. We investigated the transcriptomic and functional differences in mitochondrial activity between Olaparib-resistant (2B-OlapR, LN-OlapR) and treatment naïve prostate cancer (PCa) cells (C4-2B, LNCaP) in both castration sentitive and resistant settings. Through RNA sequencing and Gene Set Enrichment Analysis (GSEA), we identified significant enrichment of mitochondrial and oxidative phosphorylation-related gene sets in Olaparib Resistant derived cell lines. Resistant lines exhibited enhanced mitochondrial functionality including increased basal and maximal respiration rates, as well as elevated ATP production and spare respiratory capacity compared to parental cells. Subsequent investigations revealed a substantial increase in mitochondrial mass and electron transport chain complex I activity in Olaparib-resistant cells. Furthermore, overexpression of the PINK1 gene was observed in resistant cells, which was correlated with resistance to Olaparib and poor clinical outcomes in prostate cancer patients. Inhibition of PINK1 expression significantly reduced mitochondrial function and mass, impaired cell growth, and decreased resistance to Olaparib. These findings suggest that PINK1 plays a crucial role in modulating mitochondrial dynamics that confer therapeutic resistance, highlighting its potential as a therapeutic target for overcoming Olaparib resistance in PCa.

DOI: https://doi.org/10.1158/2767-9764.CRC-24-0339
Trends Cancer. 2024 Oct 21. pii: S2405-8033(24)00212-7. [Epub ahead of print]

Mitochondrial DNA damage, repair, and replacement in cancer.

Pavel Vodicka, Sona Vodenkova, Natalie Danesova, Ludmila Vodickova, Renata Zobalova, Kristyna Tomasova, Stepana Boukalova, Michael V Berridge, Jiri Neuzil.

  Mitochondria are vital organelles with their own DNA (mtDNA). mtDNA is circular and composed of heavy and light chains that are structurally more accessible than nuclear DNA (nDNA). While nDNA is typically diploid, the number of mtDNA copies per cell is higher and varies considerably during development and between tissues. Compared with nDNA, mtDNA is more prone to damage that is positively linked to many diseases, including cancer. Similar to nDNA, mtDNA undergoes repair processes, although these mechanisms are less well understood. In this review, we discuss the various forms of mtDNA damage and repair and their association with cancer initiation and progression. We also propose horizontal mitochondrial transfer as a novel mechanism for replacing damaged mtDNA.

Keywords:  DNA stability; base excision repair; cancer; horizontal mitochondrial transfer; mitochondrial DNA; mitochondrial DNA damage repair; nuclear DNA

DOI:  https://doi.org/10.1016/j.trecan.2024.09.010
EMBO J. 2024 Oct 24.

Cyclophilin D plays a critical role in the survival of senescent cells.

Margherita Protasoni, Vanessa López-Polo, Camille Stephan-Otto Attolini, Julian Brandariz, Nicolas Herranz, Joaquin Mateo, Sergio Ruiz, Oscar Fernandez-Capetillo, Marta Kovatcheva, Manuel Serrano.

  Senescent cells play a causative role in many diseases, and their elimination is a promising therapeutic strategy. Here, through a genome-wide CRISPR/Cas9 screen, we identify the gene PPIF, encoding the mitochondrial protein cyclophilin D (CypD), as a novel senolytic target. Cyclophilin D promotes the transient opening of the mitochondrial permeability transition pore (mPTP), which serves as a failsafe mechanism for calcium efflux. We show that senescent cells exhibit a high frequency of transient CypD/mPTP opening events, known as 'flickering'. Inhibition of CypD using genetic or pharmacologic tools, including cyclosporin A, leads to the toxic accumulation of mitochondrial Ca2+ and the death of senescent cells. Genetic or pharmacological inhibition of NCLX, another mitochondrial calcium efflux channel, also leads to senolysis, while inhibition of the main Ca2+ influx channel, MCU, prevents senolysis induced by CypD inhibition. We conclude that senescent cells are highly vulnerable to elevated mitochondrial Ca2+ ions, and that transient CypD/mPTP opening is a critical adaptation mechanism for the survival of senescent cells.

Keywords:  Cellular Senescence; Cyclophilin D; Mitochondria; Senolytic Therapy; mPTP Flickering

DOI:  https://doi.org/10.1038/s44318-024-00259-2
Biochim Biophys Acta Mol Cell Res. 2024 Oct 20. pii: S0167-4889(24)00205-2. [Epub ahead of print]1872(1): 119862

Mitoception, or transfer of normal cell mitochondria to cancer cells, reverses remodeling of store-operated Ca2+ entry in tumor cells.

Verónica Feijóo, Sendoa Tajada, Alejandra Méndez-Mena, Lucía Núñez, Carlos Villalobos.

  Most cancer cells show the Warburg effect, the rewiring of aerobic metabolism to glycolysis due to defective mitochondrial ATP synthesis. As a consequence, tumor cells display enhanced mitochondrial potential (∆Ψ), the driving force for mitochondrial Ca2+ uptake. Mitochondria control the Ca2+-dependent inactivation of store-operated channels (SOCs), leading to enhanced and sustained store-operated Ca2+ entry (SOCE) involved in cancer hallmarks. We asked here whether the transfer of mitochondria (mitoception) from normal cells to tumor cells may reverse SOCE remodeling in cancer cells. For this end, we labeled mitochondria in normal NCM460 human colonic cells, isolated them and transferred them to tumor HT29 cells. We tested the viability and efficiency of mitoception using flow cytometry and confocal microscopy, as well as calcium imaging to investigate the effects of mitoception on SOCE. Our results show that mitoception of tumor HT29 cells with normal mitochondria restores a low ∆Ψ and SOCE. Conversely, self-mitoception of tumor HT29 cells with tumor cell mitochondria increases further ∆Ψ and SOCE, thus excluding the possibility that effects of mitoception are due to increased mitochondrial mass. Strikingly, mitoception of normal NCM460 cells with tumor cell mitochondria has no effects on either ∆Ψ or SOCE. These results are consistent with the previous proposal that transformed mitochondria may modulate SOC channels involved in SOCE. Further research is warranted to test whether mitoception of cancer cells with normal mitochondria may reverse Ca2+ remodeling associated to cancer.

Keywords:  Colon cancer; Mitoception; Mitochondria; Store-operated Ca(2+) entry

DOI:  https://doi.org/10.1016/j.bbamcr.2024.119862
Sci Adv. 2024 Oct 25. 10(43): eado5887

Mitochondrial fatty acid oxidation drives senescence.

Shota Yamauchi, Yuki Sugiura, Junji Yamaguchi, Xiangyu Zhou, Satoshi Takenaka, Takeru Odawara, Shunsuke Fukaya, Takao Fujisawa, Isao Naguro, Yasuo Uchiyama, Akiko Takahashi, Hidenori Ichijo.

Cellular senescence is a stress-induced irreversible cell cycle arrest involved in tumor suppression and aging. Many stresses, such as telomere shortening and oncogene activation, induce senescence by damaging nuclear DNA. However, the mechanisms linking DNA damage to senescence remain unclear. Here, we show that DNA damage response (DDR) signaling to mitochondria triggers senescence. A genome-wide small interfering RNA screen implicated the outer mitochondrial transmembrane protein BNIP3 in senescence induction. We found that BNIP3 is phosphorylated by the DDR kinase ataxia telangiectasia mutated (ATM) and contributes to an increase in the number of mitochondrial cristae. Stable isotope labeling metabolomics indicated that the increase in cristae enhances fatty acid oxidation (FAO) to acetyl-coenzyme A (acetyl-CoA). This promotes histone acetylation and expression of the cyclin-dependent kinase inhibitor p16INK4a. Notably, pharmacological activation of FAO alone induced senescence both in vitro and in vivo. Thus, mitochondrial energy metabolism plays a critical role in senescence induction and is a potential intervention target to control senescence.

DOI: https://doi.org/10.1126/sciadv.ado5887
Nat Cell Biol. 2024 Oct 21.

Mitochondrial mechanotransduction through MIEF1 coordinates the nuclear response to forces.

Patrizia Romani, Giada Benedetti, Martina Cusan, Mattia Arboit, Carmine Cirillo, Xi Wu, Georgia Rouni, Vassiliki Kostourou, Mariaceleste Aragona, Costanza Giampietro, Paolo Grumati, Graziano Martello, Sirio Dupont.

Tissue-scale architecture and mechanical properties instruct cell behaviour under physiological and diseased conditions, but our understanding of the underlying mechanisms remains fragmentary. Here we show that extracellular matrix stiffness, spatial confinements and applied forces, including stretching of mouse skin, regulate mitochondrial dynamics. Actomyosin tension promotes the phosphorylation of mitochondrial elongation factor 1 (MIEF1), limiting the recruitment of dynamin-related protein 1 (DRP1) at mitochondria, as well as peri-mitochondrial F-actin formation and mitochondrial fission. Strikingly, mitochondrial fission is also a general mechanotransduction mechanism. Indeed, we found that DRP1- and MIEF1/2-dependent fission is required and sufficient to regulate three transcription factors of broad relevance-YAP/TAZ, SREBP1/2 and NRF2-to control cell proliferation, lipogenesis, antioxidant metabolism, chemotherapy resistance and adipocyte differentiation in response to mechanical cues. This extends to the mouse liver, where DRP1 regulates hepatocyte proliferation and identity-hallmark YAP-dependent phenotypes. We propose that mitochondria fulfil a unifying signalling function by which the mechanical tissue microenvironment coordinates complementary cell functions.

DOI: https://doi.org/10.1038/s41556-024-01527-3
Blood. 2024 Oct 22. pii: blood.2024024837. [Epub ahead of print]

A phase 1 study of the amino acid modulator pegcrisantaspase and venetoclax for relapsed/refractory acute myeloid leukemia.

Yuchen Liu, Dominique R Bollino, Osman M Bah, Erin T Strovel, Tien Van Le, Jinoos Zarrabi, Sunita Philip, Rena G Lapidus, Maria R Baer, Sandrine Niyongere, Vu H Duong, Christine C Dougherty, Jan Hendrik Beumer, Katherine D Caprinolo, Farin Kamangar, Ashkan Emadi.

Glutamine dependency has been shown to be a metabolic vulnerability in acute myeloid leukemia (AML). Prior studies using several in vivo AML models showed that depletion of plasma glutamine induced by the long-acting crisantaspase (pegcrisantaspase or PegC) was synergistic with the BCL-2 inhibitor venetoclax (Ven), resulting in significantly reduced leukemia burden and enhanced survival. Here, we report a phase 1 study (NCT04666649) of Ven and PegC combination (VenPegC) for treating adult patients with relapsed or refractory AML, including patients who had previously received Ven. The primary endpoints were incidence of regimen limiting toxicities (RLT) and maximum tolerated dose (MTD). Twenty-five patients received at least one PegC dose with Ven and 18 efficacy-evaluable patients completed at least one VenPegC cycle; 12 (67%) had previously received Ven. Hyperbilirubinemia was the RLT and occurred in 60% of patients treated with VenPegC; 20% had Grade ≥3 bilirubin elevations. MTD was determined to be Ven 400 mg daily with biweekly PegC 750 IU/m2. The most common treatment-related adverse events of any Grade in 25 patients who received VenPegC included antithrombin III decrease (52%), elevated transaminases (36-48%), fatigue (28%), and hypofibrinogenemia (24%). No thromboembolic or hemorrhagic adverse events or clinical pancreatitis were observed. The overall complete remission rate in efficacy-evaluable patients was 33%. Response correlated with alterations in proteins involved in mRNA translation. In patients with RUNX1 mutations, the composite complete rate was 100%.

DOI: https://doi.org/10.1182/blood.2024024837
Discov Oncol. 2024 Oct 19. 15(1): 573

Potential role of heteroplasmic mitochondrial DNA mutations in modulating the subtype-specific adaptation of oral squamous cell carcinoma to cisplatin therapy.

Amnani Aminuddin, Pei Yuen Ng, Chee Onn Leong, Suzana Makpol, Eng Wee Chua.

  Cancer cells are constantly evolving to adapt to environmental changes, particularly during exposure to drug treatment. In this work, we aimed to characterize genetic and epigenetic changes in mitochondrial DNA (mtDNA) that may increase the resistance of oral squamous cell carcinoma (OSCC) to cisplatin. We first derived drug-resistant cells from two human OSCC cell lines, namely SAS and H103, by continual cisplatin treatments for about 4 months. To determine mtDNA changes induced by cisplatin, we performed nanopore sequencing and quantitative polymerase chain reaction analysis of mtDNA extracted from the cells pre- and post-treatment. We also assessed the mitochondrial functions of the cells and their capacity to generate intracellular reactive oxygen species (ROS). We found that in the cisplatin-resistant cells derived from SAS, there was a reduction in mtDNA content and significant enrichment of a m.3910G > C mutation in the MT-ND1 gene. However, such changes were not detected in cisplatin-resistant H103 cells. The cisplatin treatment also altered methylation patterns in both SAS and H103 cells and decreased their sensitivity to ROS-induced cytotoxicity. We suggest that the sequence alterations and epigenetic changes in mtDNA and the reduction in mtDNA content could be key drivers of cisplatin resistance in OSCC. These mtDNA alterations may participate in cellular adaptation that serves as a response to adverse changes in the environment, particularly exposure to cytotoxic agents. Importantly, the observed mtDNA changes may be influenced by the distinct genetic landscapes of various cancer subtypes. Overall, this study reveals significant insights into cisplatin resistance driven by complex mtDNA dynamics, particularly in OSCC. This underscores the need for targeted therapies tailored to the genetic profiles of individual OSCC patients to improve disease prognosis.

Keywords:  Cisplatin resistance; Mitochondrial DNA alterations; Oral squamous cell carcinoma; Oxford nanopore technology

DOI:  https://doi.org/10.1007/s12672-024-01445-8
EMBO J. 2024 Oct 21.

Glutamine sensing licenses cholesterol synthesis.

Bruna Martins Garcia, Philipp Melchinger, Tania Medeiros, Sebastian Hendrix, Kavan Prabhu, Mauro Corrado, Jenina Kingma, Andrej Gorbatenko, Soni Deshwal, Matteo Veronese, Luca Scorrano, Erika Pearce, Patrick Giavalisco, Noam Zelcer, Lena Pernas.

  The mevalonate pathway produces essential lipid metabolites such as cholesterol. Although this pathway is negatively regulated by metabolic intermediates, little is known of the metabolites that positively regulate its activity. We found that the amino acid glutamine is required to activate the mevalonate pathway. Glutamine starvation inhibited cholesterol synthesis and blocked transcription of the mevalonate pathway-even in the presence of glutamine derivatives such as ammonia and α-ketoglutarate. We pinpointed this glutamine-dependent effect to a loss in the ER-to-Golgi trafficking of SCAP that licenses the activation of SREBP2, the major transcriptional regulator of cholesterol synthesis. Both enforced Golgi-to-ER retro-translocation and the expression of a nuclear SREBP2 rescued mevalonate pathway activity during glutamine starvation. In a cell model of impaired mitochondrial respiration in which glutamine uptake is enhanced, SREBP2 activation and cellular cholesterol were increased. Thus, the mevalonate pathway senses and is activated by glutamine at a previously uncharacterized step, and the modulation of glutamine synthesis may be a strategy to regulate cholesterol levels in pathophysiological conditions.

Keywords:  Cholesterol; HMGCR; MFN2; Nutrient Sensing; SREBP2

DOI:  https://doi.org/10.1038/s44318-024-00269-0
Immunology. 2024 Oct 24.

Sphingosine-1-Phosphate Signalling Inhibition Suppresses Th1-Like Treg Generation by Reversing Mitochondrial Uncoupling.

Rachel Coulombeau, Claudia Selck, Nicolas Giang, Abdulrahman Al-Mohammad, Natalie Ng, Allison K Maher, Rafael Argüello, Antonio Scalfari, James Varley, Richard Nicholas, Margarita Dominguez-Villar.

  Inflammatory environments induce the generation of dysfunctional IFNγ+T-bet+FOXP3+ Th1-like Tregs, which show defective function and are found in autoimmune conditions including multiple sclerosis (MS). The pathways that control the generation of Th1-like Tregs are not well understood. Sphingosine-1-phosphate (S1P) signalling molecules are upregulated in Th1-like Tregs, and in vivo S1P inhibition with Fingolimod (FTY720) inhibits the expression of genes responsible for Treg plasticity in MS patients. However, the underlying mechanisms are unknown. Here we show that S1P signalling inhibition by FTY720 inhibits the generation of Th1-like Tregs and rescues their suppressive function. These effects are mediated by a decrease in mTORC1 signalling and reversal of the mitochondrial uncoupling that Tregs undergo during their reprogramming into Th1-like Tregs in vitro. Finally, these results are validated in in vivo-generated Th1-like Tregs, as Tregs from MS patients treated with FTY720 display decreased Th1-like Treg frequency, increased suppressive function and mitochondrial metabolism rebalance. These results highlight the involvement of mitochondrial uncoupling in Treg reprogramming and identify S1P signalling inhibition as a target to suppress the generation of dysfunctional Th1-like Tregs.

Keywords:  EAE/MS; Treg; autoimmunity

DOI:  https://doi.org/10.1111/imm.13870
Adv Healthc Mater. 2024 Oct 23. e2403531

Bioengineered Extracellular Vesicles Delivering siMDM2 Sensitize Oxaliplatin Therapy Efficacy in Colorectal Cancer.

Yunlong Li, Zhiyuan Liu, Ping Wang, Xuerong Gu, Fei Ling, Jiayuan Zhong, Dong Yin, Rui Liu, Xueqing Yao, Chengzhi Huang.

  Oxaliplatin (OXA) is the first-line drug for the treatment of colorectal cancer (CRC), and susceptibility to drug resistance affects patient prognosis. However, the exact underlying mechanisms remain unclear. Platinum-acquired resistance in CRC is a continuous transition process; though, current research has mainly focused on the end state of drug resistance, and the early events of drug resistance have been ignored. In this study, single-cell transcriptome sequencing is combined with a dynamic network biomarker (DNB), and found that the functional inhibition of the mitochondrial electron transport chain complex I occur early in the development of attained resistance to OXA in CRC cells, as evidenced by a decrease in the levels of subunit proteins, primarily NDUFB8. Specifically, the mouse double minute 2 homologue (MDM2) mediates the ubiquitination and degradation of NDUFB8, reducing intracellular reactive oxygen species (ROS) generation under chemotherapeutic stress, consequently contributing to drug resistance. Based on this, the study constructs engineered extracellular vesicles carrying siMDM2 by electroporation and validates the application of EV-siMDM2 to improve the efficacy of OXA-based chemotherapy by inhibiting the MDM2/NDUFB8/ROS signaling axis in patient-derived xenograft (PDX) and hepatic and pulmonary metastasis mouse models, thus providing new ideas and an experimental basis for the platinum-resistant treatment of CRC.

Keywords:  chemoresistance; colorectal cancer; engineered extracellular vesicles; murine two‐microsomal homolog gene 2; ubiquitination

DOI:  https://doi.org/10.1002/adhm.202403531
Cell Metab. 2024 Oct 18. pii: S1550-4131(24)00395-4. [Epub ahead of print]

Adipocyte-derived glutathione promotes obesity-related breast cancer by regulating the SCARB2-ARF1-mTORC1 complex.

Chenxi Zhao, Tingting Zhang, Si-Tu Xue, Peitao Zhang, Feng Wang, Yunxuan Li, Ying Liu, Luyao Zhao, Jie Wu, Yechao Yan, Xiaoyun Mao, Yuping Chen, Jian Yuan, Zhuorong Li, Ke Li.

  Obesity is a major risk factor for poor breast cancer outcomes, but the impact of obesity-induced tumor microenvironment (TME) metabolites on breast cancer growth and metastasis remains unclear. Here, we performed TME metabolomic analysis in high-fat diet (HFD) mouse models and found that glutathione (GSH) levels were elevated in the TME of obesity-accelerated breast cancer. The deletion of glutamate-cysteine ligase catalytic subunit (GCLC), the rate-limiting enzyme in GSH biosynthesis, in adipocytes but not tumor cells reduced obesity-related tumor progression. Mechanistically, we identified that GSH entered tumor cells and directly bound to lysosomal integral membrane protein-2 (scavenger receptor class B, member 2 [SCARB2]), interfering with the interaction between its N and C termini. This, in turn, recruited mTORC1 to lysosomes through ARF1, leading to the activation of mTOR signaling. Overall, we demonstrated that GSH links obesity and breast cancer progression by acting as an activator of mTOR signaling. Targeting the GSH/SCARB2/mTOR axis could benefit breast cancer patients with obesity.

Keywords:  ARF1; GSH; SCARB2; adipocyte; breast cancer; glutathione; lysosomal integral membrane protein-2; mTORC1; mammalian target of rapamycin complex 1; obesity

DOI:  https://doi.org/10.1016/j.cmet.2024.09.013
EBioMedicine. 2024 Oct 21. pii: S2352-3964(24)00411-0. [Epub ahead of print]109 105375

SLC7A9 suppression increases chemosensitivity by inducing ferroptosis via the inhibition of cystine transport in gastric cancer.

Haoran Feng, Junxian Yu, Zhuoqing Xu, Qingqing Sang, Fangyuan Li, Mengdi Chen, Yunqin Chen, Beiqin Yu, Nan Zhu, Jiazeng Xia, Changyu He, Junyi Hou, Xiongyan Wu, Chao Yan, Zhenggang Zhu, Liping Su, Jianfang Li, Wentao Dai, Yuan-Yuan Li, Bingya Liu.

   BACKGROUND: SLC7A9 is responsible for the exchange of dibasic amino acids and cystine (influx) for neutral amino acids (efflux). Cystine/cysteine transport is related to ferroptosis.
METHODS: Sanger sequencing detected TP53 status of cancer cells. Transcriptomic sequencing and untargeted metabolome profiling were used to identify differentially expressed genes and metabolites, respectively, upon SLC7A9 overexpression. CCK8, cell clonality, and EdU assays were used to observe cell proliferation. Cystine probes, glutathione (GSH) probes, and lipid ROS probes were used to examine cystine, GSH, and lipid ROS levels. 13C metabolic flow assays were used to monitor cellular cystine and GSH metabolism. Patient-derived organoids (PDO), immunocompetent MFC mice allograft models and patient-derived xenograft (PDX) models were used to evaluate SLC7A9 impact on chemotherapeutic response and to observe therapeutic effect of SLC7A9 knockdown.
FINDINGS: Elevated SLC7A9 expression levels in gastric cancer cells were attributed to p53 loss. SLC7A9 knockdown suppressed the proliferation and increased the chemotherapy sensitivity of the cells. Chemotherapy was more effective in PDX and immunocompetent mice models upon SLC7A9 knockdown. Differentially expressed genes and metabolites between the SLC7A9 overexpression and control groups were associated with ferroptosis and GSH metabolism. SLC7A9 knockdown reduced cystine transport into cells, hampered intracellular cystine and GSH metabolic flow, decreased GSH synthesis, and increased lipid ROS levels in gastric cancer cells. Erastin was more effective at inducing ferroptosis in PDO and PDX models upon SLC7A9 knockdown.
INTERPRETATION: SLC7A9 promotes gastric cancer progression by acting as a suppressor of ferroptosis, independent of SLC7A11, which is negatively regulated by p53.
FUNDING: This work was supported by National Natural Science Foundation of China, Innovation Promotion Program of NHC and Shanghai Key Labs SIBPT, and Shanghai Academy of Science & Technology.

Keywords:  Ferroptosis; GPX4; Gastric cancer; Glutathione metabolism; SLC7A9

DOI:  https://doi.org/10.1016/j.ebiom.2024.105375
Nat Commun. 2024 Oct 23. 15(1): 9145

Bicarbonate-mediated proton transfer requires cations.

Qianbao Wu, Na Yang, Mengjun Xiao, Wei Wang, Chunhua Cui.

Near-neutral HCO3- aqueous solution plays an essential role in respiratory, mineralization and catalysis, yet the interconversion between hydrated CO2, HCO3- and CO32- and the associated proton transfer under such proton-deficient conditions remain uncovered. Here we reveal that cation enables HCO3- to self-dissociate into OH- and CO2 through a pH-independent process, where CO2 hydration and subsequent proton transfer in acid-base reactions lead to the overall exchange of oxygen isotopes between HCO3- and H2O tracked by oxygen isotope-labeled Raman spectroscopy. Isolating HCO3- from cations with crown ether impedes HCO3- dissociation and the following reactions. Further molecular dynamics simulations demonstrate that the interplay between HCO3- and hydrated cations drives HCO3- dissociation. This study suggests a natural proton channel upon coupling HCO3- with cations.

DOI: https://doi.org/10.1038/s41467-024-53526-5
Nanoscale. 2024 Oct 23.

Cell specific mitochondria targeted metabolic alteration for precision medicine.

Akash Ashokan, Michael Birnhak, Bapurao Surnar, Felix Nguyen, Uttara Basu, Subham Guin, Shanta Dhar.

Mitochondria play important roles in the maintenance of cellular health. In cancer, these dynamic organelles undergo significant changes in terms of membrane hyperpolarization, altered metabolic functions, fusion-fission balance, and several other parameters. These alterations promote cancer growth, proliferation and spread, and the eventual development of metastatic disease and therapeutic resistance. Thus, routing therapeutics to the mitochondrial compartments can be one of the most promising methodologies for tackling such changes to achieve cancer control. Over the last decade, targeted cancer medicine has experienced tremendous growth, enabling the targeting of mitochondria for greater therapeutic specificity. Here, we demonstrate a feasibility method to specifically target the mitochondria of prostate cancer cells. We achieve such dual targeting by utilizing two functionalized polymers and constructing a single blended nanoparticle (NP). Such a targeting strategy was developed utilizing a polymeric platform that differed in terms of the length of the amphiphilic portions, the linker between the hydrophobic portions, and the attached targeting moieties. In doing this, we demonstrate prostate cancer specific mitochondrial delivery of a chemotherapeutic prodrug to create repair-resistant adducts within mitochondrial DNA promoting cellular death. This article documents the synthetic strategy, optimization of blended NPs for cell specific mitochondria targeting, and the utility of the proof-of-concept design was demonstrated using a combination of analytical and in vitro studies.

DOI: https://doi.org/10.1039/d4nr01450b