bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2022–09–25
25 papers selected by
Kelsey Fisher-Wellman, East Carolina University
  1. YY1 promotes pancreatic cancer cell proliferation by enhancing mitochondrial respiration.
  2. Mitochondrial Protein Cox7b Is a Metabolic Sensor Driving Brain-Specific Metastasis of Human Breast Cancer Cells.
  3. Functional expression of mitochondrial KCa3.1 channels in non-small cell lung cancer cells.
  4. Binding of Natural Inhibitors to Respiratory Complex I.
  5. Primary and metastatic tumors exhibit systems-level differences in dependence on mitochondrial respiratory function.
  6. EPR Investigations to Study the Impact of Mito-Metformin on the Mitochondrial Function of Prostate Cancer Cells.
  7. Ketogenic Diets and Mitochondrial Function: Benefits for Aging but not for Athletes.
  8. Chimeric nanoparticles for targeting mitochondria in cancer cells.
  9. ORP5/8 and MIB/MICOS link ER-mitochondria and intra-mitochondrial contacts for non-vesicular transport of phosphatidylserine.
  10. Cell-free DNA topology is unique to its sub-cellular and cellular origins in cancer.
  11. Targeting STAT5 signaling overcomes resistance to IDH inhibitors in acute myeloid leukemia through suppression of stemness.
  12. A mitochondria-specific mutational signature of aging: increased rate of A > G substitutions on the heavy strand.
  13. Valproic acid regulates MIEF1 through MST2-HIPPO to suppress breast cancer growth.
  14. COA3 overexpression promotes non-small cell lung cancer metastasis by reprogramming glucose metabolism.
  15. Reaction-based fluorogenic probes for detecting protein cysteine oxidation in living cells.
  16. Metabolic collateral lethal target identification reveals MTHFD2 paralogue dependency in ovarian cancer.
  17. Flow pattern-dependent mitochondrial dynamics regulates the metabolic profile and inflammatory state of endothelial cells.
  18. Sensitisation of cancer cells to radiotherapy by serine and glycine starvation.
  19. HPV E6 regulates therapy responses in oropharyngeal cancer by repressing the PGC-1α/ERRα axis.
  20. The requirement for mitochondrial respiration in cancer varies with disease stage.
  21. A cellular hierarchy in melanoma uncouples growth and metastasis.
  22. Increased Efficiency of Mitochondrial Coupling with a Reduction in Other Mitochondrial Respiratory Parameters in Peripheral Blood Mononuclear Cells is Observed in Older Adults.
  23. Targeting oxidative phosphorylation as an approach for the treatment of ovarian cancer.
  24. Knockdown of NDUFC1 inhibits cell proliferation, migration, and invasion of hepatocellular carcinoma.
  25. Concomitant Inhibition of FASN and SREBP Provides a Promising Therapy for CTCL.
  1. Cancer Cell Int. 2022 Sep 19. 22(1): 287
    YY1 promotes pancreatic cancer cell proliferation by enhancing mitochondrial respiration.
    Bin Li, Junyi Wang, Jing Liao, Minghui Wu, Xiangshu Yuan, Hezhi Fang, Lijun Shen, Minghua Jiang.
      KRAS-driven metabolic reprogramming is a known peculiarity features of pancreatic ductal adenocarcinoma (PDAC) cells. However, the metabolic roles of other oncogenic genes, such as YY1, in PDAC development are still unclear. In this study, we observed significantly elevated expression of YY1 in human PDAC tissues, which positively correlated with a poor disease progression. Furthermore, in vitro studies confirmed that YY1 deletion inhibited PDAC cell proliferation and tumorigenicity. Moreover, YY1 deletion led to impaired mitochondrial RNA expression, which further inhibited mitochondrial oxidative phosphorylation (OXPHOS) complex assembly and altered cellular nucleotide homeostasis. Mechanistically, the impairment of mitochondrial OXPHOS function reduced the generation of aspartate, an output of the tricarboxylic acid cycle (TCA), and resulted in the inhibition of cell proliferation owing to unavailability of aspartate-associated nucleotides. Conversely, exogenous supplementation with aspartate fully restored PDAC cell proliferation. Our findings suggest that YY1 promotes PDAC cell proliferation by enhancing mitochondrial respiration and the TCA, which favors aspartate-associated nucleotide synthesis. Thus, targeting nucleotide biosynthesis is a promising strategy for PDAC treatment.
    Keywords:  Aspartate; Nucleotide metabolism; OXPHOS; PDAC; YY1
    DOI:  https://doi.org/10.1186/s12935-022-02712-w
  2. Cancers (Basel). 2022 Sep 08. pii: 4371. [Epub ahead of print]14(18):
    Mitochondrial Protein Cox7b Is a Metabolic Sensor Driving Brain-Specific Metastasis of Human Breast Cancer Cells.
    Marine C N M Blackman, Tania Capeloa, Justin D Rondeau, Luca X Zampieri, Zohra Benyahia, Justine A Van de Velde, Maude Fransolet, Evangelos P Daskalopoulos, Carine Michiels, Christophe Beauloye, Pierre Sonveaux.
      Distant metastases are detrimental for cancer patients, but the increasingly early detection of tumors offers a chance for metastasis prevention. Importantly, cancers do not metastasize randomly: depending on the type of cancer, metastatic progenitor cells have a predilection for well-defined organs. This has been theorized by Stephen Paget, who proposed the "seed-and-soil hypothesis", according to which metastatic colonization occurs only when the needs of a given metastatic progenitor cell (the seed) match with the resources provided by a given organ (the soil). Here, we propose to explore the seed-and-soil hypothesis in the context of cancer metabolism, thus hypothesizing that metastatic progenitor cells must be capable of detecting the availability of metabolic resources in order to home in a secondary organ. If true, it would imply the existence of metabolic sensors. Using human triple-negative MDA-MB-231 breast cancer cells and two independent brain-seeking variants as models, we report that cyclooxygenase 7b (Cox7b), a structural component of Complex IV of the mitochondrial electron transport chain, belongs to a probably larger family of proteins responsible for breast cancer brain tropism in mice. For metastasis prevention therapy, this proof-of-principle study opens a quest for the identification of therapeutically targetable metabolic sensors that drive cancer organotropism.
    Keywords:  brain metastasis; breast cancer; cancer metabolism; cyclooxygenase 7b (Cox7b); mitochondria; organotropism; oxidative phosphorylation (OXPHOS); tissue-specific metastasis
    DOI:  https://doi.org/10.3390/cancers14184371
  3. Pflugers Arch. 2022 Sep 24.
    Functional expression of mitochondrial KCa3.1 channels in non-small cell lung cancer cells.
    Etmar Bulk, Luca Matteo Todesca, Magdalena Bachmann, Ildiko Szabo, Marius Rieke, Albrecht Schwab.
      Lung cancer is one of the leading causes of cancer-related deaths worldwide. The Ca2+-activated K+ channel KCa3.1 contributes to the progression of non-small cell lung cancer (NSCLC). Recently, KCa3.1 channels were found in the inner membrane of mitochondria in different cancer cells. Mitochondria are the main sources for the generation of reactive oxygen species (ROS) that affect the progression of cancer cells. Here, we combined Western blotting, immunofluorescence, and fluorescent live-cell imaging to investigate the expression and function of KCa3.1 channels in the mitochondria of NSCLC cells. Western blotting revealed KCa3.1 expression in mitochondrial lysates from different NSCLC cells. Using immunofluorescence, we demonstrate a co-localization of KCa3.1 channels with mitochondria of NSCLC cells. Measurements of the mitochondrial membrane potential with TMRM reveal a hyperpolarization following the inhibition of KCa3.1 channels with the cell-permeable blocker senicapoc. This is not the case when cells are treated with the cell-impermeable peptidic toxin maurotoxin. The hyperpolarization of the mitochondrial membrane potential is accompanied by an increased generation of ROS in NSCLC cells. Collectively, our results provide firm evidence for the functional expression of KCa3.1 channels in the inner membrane of mitochondria of NSCLC cells.
    Keywords:  KCa3.1; Mitochondria; NSCLC; ROS
    DOI:  https://doi.org/10.1007/s00424-022-02748-x
  4. Pharmaceuticals (Basel). 2022 Aug 31. pii: 1088. [Epub ahead of print]15(9):
    Binding of Natural Inhibitors to Respiratory Complex I.
    Jonathan Schiller, Volker Zickermann.
      NADH:ubiquinone oxidoreductase (respiratory complex I) is a redox-driven proton pump with a central role in mitochondrial oxidative phosphorylation. The ubiquinone reduction site of complex I is located in the matrix arm of this large protein complex and connected to the membrane via a tunnel. A variety of chemically diverse compounds are known to inhibit ubiquinone reduction by complex I. Rotenone, piericidin A, and annonaceous acetogenins are representatives of complex I inhibitors from biological sources. The structure of complex I is determined at high resolution, and inhibitor binding sites are described in detail. In this review, we summarize the state of knowledge of how natural inhibitors bind in the Q reduction site and the Q access pathway and how their inhibitory mechanisms compare with that of a synthetic anti-cancer agent.
    Keywords:  NADH dehydrogenase; Parkinson’s disease; acetogenin; mitochondria; piericidin; respiratory chain; rotenone
    DOI:  https://doi.org/10.3390/ph15091088
  5. PLoS Biol. 2022 Sep;20(9): e3001753
    Primary and metastatic tumors exhibit systems-level differences in dependence on mitochondrial respiratory function.
    Neal K Bennett, Hiroki J Nakaoka, Danny Laurent, Ross A Okimoto, Yoshitaka Sei, Andrew E Horvai, Trever G Bivona, Johanna Ten Hoeve, Thomas G Graeber, Ken Nakamura, Jean L Nakamura.
      The Warburg effect, aerobic glycolysis, is a hallmark feature of cancer cells grown in culture. However, the relative roles of glycolysis and respiratory metabolism in supporting in vivo tumor growth and processes such as tumor dissemination and metastatic growth remain poorly understood, particularly on a systems level. Using a CRISPRi mini-library enriched for mitochondrial ribosomal protein and respiratory chain genes in multiple human lung cancer cell lines, we analyzed in vivo metabolic requirements in xenograft tumors grown in distinct anatomic contexts. While knockdown of mitochondrial ribosomal protein and respiratory chain genes (mito-respiratory genes) has little impact on growth in vitro, tumor cells depend heavily on these genes when grown in vivo as either flank or primary orthotopic lung tumor xenografts. In contrast, respiratory function is comparatively dispensable for metastatic tumor growth. RNA-Seq and metabolomics analysis of tumor cells expressing individual sgRNAs against mito-respiratory genes indicate overexpression of glycolytic genes and increased sensitivity of glycolytic inhibition compared to control when grown in vitro, but when grown in vivo as primary tumors these cells down-regulate glycolytic mechanisms. These studies demonstrate that discrete perturbations of mitochondrial respiratory chain function impact in vivo tumor growth in a context-specific manner with differential impacts on primary and metastatic tumors.
    DOI:  https://doi.org/10.1371/journal.pbio.3001753
  6. Molecules. 2022 Sep 10. pii: 5872. [Epub ahead of print]27(18):
    EPR Investigations to Study the Impact of Mito-Metformin on the Mitochondrial Function of Prostate Cancer Cells.
    Donatienne d'Hose, Barbara Mathieu, Lionel Mignion, Micael Hardy, Olivier Ouari, Bénédicte F Jordan, Pierre Sonveaux, Bernard Gallez.
       BACKGROUND: Mito-metformin10 (MM10), synthesized by attaching a triphenylphosphonium cationic moiety via a 10-carbon aliphatic side chain to metformin, is a mitochondria-targeted analog of metformin that was recently demonstrated to alter mitochondrial function and proliferation in pancreatic ductal adenocarcinoma. Here, we hypothesized that this compound may decrease the oxygen consumption rate (OCR) in prostate cancer cells, increase the level of mitochondrial ROS, alleviate tumor hypoxia, and radiosensitize tumors.
    METHODS: OCR and mitochondrial superoxide production were assessed by EPR (9 GHz) in vitro in PC-3 and DU-145 prostate cancer cells. Reduced and oxidized glutathione were assessed before and after MM10 exposure. Tumor oxygenation was measured in vivo using 1 GHz EPR oximetry in PC-3 tumor model. Tumors were irradiated at the time of maximal reoxygenation.
    RESULTS: 24-hours exposure to MM10 significantly decreased the OCR of PC-3 and DU-145 cancer cells. An increase in mitochondrial superoxide levels was observed in PC-3 but not in DU-145 cancer cells, an observation consistent with the differences observed in glutathione levels in both cancer cell lines. In vivo, the tumor oxygenation significantly increased in the PC-3 model (daily injection of 2 mg/kg MM10) 48 and 72 h after initiation of the treatment. Despite the significant effect on tumor hypoxia, MM10 combined to irradiation did not increase the tumor growth delay compared to the irradiation alone.
    CONCLUSIONS: MM10 altered the OCR in prostate cancer cells. The effect of MM10 on the superoxide level was dependent on the antioxidant capacity of cell line. In vivo, MM10 alleviated tumor hypoxia, yet without consequence in terms of response to irradiation.
    Keywords:  EPR; ESR; cancer; irradiation; mitochondrial ROS; oximetry; oxygen consumption; tumor hypoxia; tumor oxygenation
    DOI:  https://doi.org/10.3390/molecules27185872
  7. Exerc Sport Sci Rev. 2022 Sep 16.
    Ketogenic Diets and Mitochondrial Function: Benefits for Aging but not for Athletes.
    Suraj J Pathak, Keith Baar.
       ABSTRACT: As humans age, we lose skeletal muscle mass, even in the absence of disease (sarcopenia), increasing the risk of death. Low mitochondrial mass and activity contributes to sarcopenia. It is our hypothesis that, a ketogenic diet improves skeletal muscle mitochondrial mass and function when they have declined due to aging or disease, but not in athletes where mitochondrial quality is high.
    DOI:  https://doi.org/10.1249/JES.0000000000000307
  8. Nanoscale Adv. 2022 Feb 15. 4(4): 1112-1118
    Chimeric nanoparticles for targeting mitochondria in cancer cells.
    Aman Bajpai, Nakshi Nayan Desai, Shalini Pandey, Chinmayee Shukla, Bhaskar Datta, Sudipta Basu.
      Mitochondrial dysfunction is implicated in myriad diseases, including cancer. Subsequently, targeting mitochondrial DNA (mt-DNA) in cancer cells has emerged as an unorthodox strategy for anti-cancer therapy. However, approaches targeting only one component of the mitochondrial "central dogma" can be evaded by cancer cells through various mechanisms. To address this, herein, we have engineered mitochondria-targeting cholesterol-based chimeric nanoparticles (mt-CNPs) consisting of cisplatin, camptothecin, and tigecycline, which can simultaneously impair mt-DNA, mitochondrial topoisomerase I (mt-Top1), and mitochondrial ribosomes. mt-CNPs were characterized as being positively charged, spherical in shape, and 187 nm in diameter. Confocal microscopy confirmed that mt-CNPs efficiently localized into the mitochondria of A549 lung cancer cells within 6 h, followed by mitochondrial morphology damage and the subsequent generation of reactive oxygen species (ROS). mt-CNPs showed remarkable cancer-cell killing abilities compared to free-drug combinations in A549 (lung), HeLa (cervical), and MCF7 (breast) cancer cells. These mitochondria-targeting lipidic chimeric nanoparticles could be explored further to impair multiple targets in mitochondria, helping researchers to gain an understanding of mitochondrial translational and transcriptional machinery and to develop new strategies for cancer therapy.
    DOI:  https://doi.org/10.1039/d1na00644d
  9. Cell Rep. 2022 Sep 20. pii: S2211-1247(22)01196-2. [Epub ahead of print]40(12): 111364
    ORP5/8 and MIB/MICOS link ER-mitochondria and intra-mitochondrial contacts for non-vesicular transport of phosphatidylserine.
    Vera F Monteiro-Cardoso, Leila Rochin, Amita Arora, Audrey Houcine, Eeva Jääskeläinen, Annukka M Kivelä, Cécile Sauvanet, Romain Le Bars, Eyra Marien, Jonas Dehairs, Julie Neveu, Naima El Khallouki, Elena Santonico, Johannes V Swinnen, David Tareste, Vesa M Olkkonen, Francesca Giordano.
      Mitochondria are dynamic organelles essential for cell survival whose structural and functional integrity rely on selective and regulated transport of lipids from/to the endoplasmic reticulum (ER) and across the mitochondrial intermembrane space. As they are not connected by vesicular transport, the exchange of lipids between ER and mitochondria occurs at membrane contact sites. However, the mechanisms and proteins involved in these processes are only beginning to emerge. Here, we show that the main physiological localization of the lipid transfer proteins ORP5 and ORP8 is at mitochondria-associated ER membrane (MAM) subdomains, physically linked to the mitochondrial intermembrane space bridging (MIB)/mitochondrial contact sites and cristae junction organizing system (MICOS) complexes that bridge the two mitochondrial membranes. We also show that ORP5/ORP8 mediate non-vesicular transport of phosphatidylserine (PS) lipids from the ER to mitochondria by cooperating with the MIB/MICOS complexes. Overall our study reveals a physical and functional link between ER-mitochondria contacts involved in lipid transfer and intra-mitochondrial membrane contacts maintained by the MIB/MICOS complexes.
    Keywords:  CP: Cell biology; MAM; MICOS; Mic60; ORP; SAM50; cristae junctions; membrane contact sites; mitochondria; phosphatidylserine
    DOI:  https://doi.org/10.1016/j.celrep.2022.111364
  10. JCI Insight. 2022 Sep 20. pii: e159590. [Epub ahead of print]
    Cell-free DNA topology is unique to its sub-cellular and cellular origins in cancer.
    Ethan Z Malkin, Steven De Michino, Meghan Lambie, Rita G Gill, Zhen Zhao, Ariana Rostami, Andrea Arruda, Mark D Minden, Scott V Bratman.
      Cancer cells release large quantities of cell-free DNA (cfDNA) into the surrounding tissue and circulation. As cfDNA is a common source of biomarkers for liquid biopsy and has been implicated as a functional mediator for intercellular communication, fundamental characterization of cfDNA topology has widespread biological and clinical ramifications. Whether the topology of cfDNA is such that it exists predominantly in membrane-bound extracellular vesicles (EVs) or in non-vesicular DNA-protein complexes remains poorly understood. Here, we employed a DNA-targeted approach to comprehensively assess total cfDNA topology in cancer. Using preclinical models and patient samples, we demonstrate that nuclear cfDNA is predominantly associated with nucleosomal particles and not EVs, while a substantial subset of mitochondrial cfDNA is membrane-protected and disproportionately derived from non-tumour cells. In addition, discrimination between membrane-protected and accessible mitochondrial cfDNA added diagnostic and prognostic value in a cohort of head and neck cancer patients. Our results support a revised model for cfDNA topology in cancer. Due to its abundance, nuclear cfDNA within nucleosomal particles is the most compelling liquid biopsy substrate, while EV-bound and accessible mitochondrial cfDNA represent distinct reservoirs of potential cancer biomarkers whose structural conformations may also influence their extracellular stability and propensity for uptake by recipient cells.
    Keywords:  Cancer; Cell Biology; Diagnostics; Mitochondria; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.159590
  11. Cancer Res. 2022 Sep 23. pii: CAN-22-1293. [Epub ahead of print]
    Targeting STAT5 signaling overcomes resistance to IDH inhibitors in acute myeloid leukemia through suppression of stemness.
    Alex C H Liu, Severine Cathelin, Yitong Yang, David L Dai, Dhanoop Manikoth Ayyathan, Mohsen Hosseini, Mark D Minden, Anne Tierens, Steven M Chan.
      Mutant isocitrate dehydrogenase 1 (IDH1) and IDH2 block the differentiation of acute myeloid leukemia (AML) cells through production of R-2-hydroxyglutarate (R-2-HG). IDH inhibitors can induce differentiation of AML cells by lowering R-2-HG but have limited clinical efficacy as single agents. Here, we performed a genome-wide CRISPR knockout screen in an Idh1-mutated hematopoietic progenitor cell line to identify genes that increased the differentiation response to ivosidenib, an IDH1 inhibitor. The screen identified C-type lectin member 5a (Clec5a), which encodes a spleen tyrosine kinase (SYK)-coupled surface receptor, as one of the top hits. Knockout of Clec5a and Syk rendered cells more sensitive to ivosidenib-induced differentiation through a reduction in signal transducer and activator of transcription 5 (STAT5)-dependent expression of stemness-related genes, including genes in the homeobox (HOX) family. Importantly, direct inhibition of STAT5 activity was sufficient to increase the differentiation response to IDH inhibitors in primary human IDH1 and IDH2-mutated AML cells, including those harboring mutations in receptor tyrosine kinase (RTK) and mitogen-activated protein kinase (MAPK) genes that have been linked to drug resistance. In patient-derived xenograft (PDX) models of IDH1-mutated AML, combination treatment with ivosidenib and the STAT5 inhibitor pimozide was superior to each agent alone in inducing differentiation in leukemic cells without compromising normal hematopoiesis. These findings demonstrate that STAT5 is a critical mediator of resistance to IDH inhibitors and provide the rationale for combining STAT5 and IDH inhibitors in the treatment of IDH-mutated AML.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-1293
  12. Nucleic Acids Res. 2022 Sep 21. pii: gkac779. [Epub ahead of print]
    A mitochondria-specific mutational signature of aging: increased rate of A > G substitutions on the heavy strand.
    Alina G Mikhailova, Alina A Mikhailova, Kristina Ushakova, Evgeny O Tretiakov, Dmitrii Iliushchenko, Victor Shamansky, Valeria Lobanova, Ivan Kozenkov, Bogdan Efimenko, Andrey A Yurchenko, Elena Kozenkova, Evgeny M Zdobnov, Vsevolod Makeev, Valerian Yurov, Masashi Tanaka, Irina Gostimskaya, Zoe Fleischmann, Sofia Annis, Melissa Franco, Kevin Wasko, Stepan Denisov, Wolfram S Kunz, Dmitry Knorre, Ilya Mazunin, Sergey Nikolaev, Jacques Fellay, Alexandre Reymond, Konstantin Khrapko, Konstantin Gunbin, Konstantin Popadin.
      The mutational spectrum of the mitochondrial DNA (mtDNA) does not resemble any of the known mutational signatures of the nuclear genome and variation in mtDNA mutational spectra between different organisms is still incomprehensible. Since mitochondria are responsible for aerobic respiration, it is expected that mtDNA mutational spectrum is affected by oxidative damage. Assuming that oxidative damage increases with age, we analyse mtDNA mutagenesis of different species in regards to their generation length. Analysing, (i) dozens of thousands of somatic mtDNA mutations in samples of different ages (ii) 70053 polymorphic synonymous mtDNA substitutions reconstructed in 424 mammalian species with different generation lengths and (iii) synonymous nucleotide content of 650 complete mitochondrial genomes of mammalian species we observed that the frequency of AH > GH substitutions (H: heavy strand notation) is twice bigger in species with high versus low generation length making their mtDNA more AH poor and GH rich. Considering that AH > GH substitutions are also sensitive to the time spent single-stranded (TSSS) during asynchronous mtDNA replication we demonstrated that AH > GH substitution rate is a function of both species-specific generation length and position-specific TSSS. We propose that AH > GH is a mitochondria-specific signature of oxidative damage associated with both aging and TSSS.
    DOI:  https://doi.org/10.1093/nar/gkac779
  13. Life Sci. 2022 Sep 17. pii: S0024-3205(22)00676-2. [Epub ahead of print] 120976
    Valproic acid regulates MIEF1 through MST2-HIPPO to suppress breast cancer growth.
    Shuguang Du, Xuanyu Wang, Ye Hu, Shuxian Zhang, Dan Wang, Qinggao Zhang, Shuangping Liu.
       AIMS: To determine the effects of valproic acid (VPA) on anti-proliferative effects and mitochondrial function in breast cancer cells and the underlying mechanisms involved in the effects, with a focus on signal transduction.
    MAIN METHODS: The inhibitory effect of valproic acid on breast cancer in vivo and in vitro was evaluated by cellular and animal experiments. Mitochondria-related proteins as well as hippo pathway were monitored by western blotting. The effects of VPA on mitochondrial membrane potential, reactive oxygen species, and apoptosis were confirmed by flow cytometry. In addition, the involvement of hippo pathway in the regulation of mitochondrial function by VPA was verified by XMU-MP-1 (MST2 inhibitor).
    KEY FINDINGS: In this study, we highlight that VPA significantly attenuates mitochondrial function, leading to inhibited cell proliferation and reduced colony formation in MCF-7 and MDA-MB-231 breast cancer cells. Mechanistically, VPA-induced suppression of mitochondrial aerobic respiration was mediated by decreased expression of mitochondrial elongation factor 1 through activation of the hippo pathway, resulting in impaired breast cancer growth. In summary, we uncover a novel mechanism of VPA in regulating mitochondrial aerobic respiration, which is essential for developing an effective approach in breast cancer therapy.
    SIGNIFICANCE: Mitochondrial aerobic respiration and its products are the main sources of energy for tumors; therefore, studying the role of mitochondrial function in tumor cells is significant. VPA has been used as a therapeutic agent for cancer. However, the detail mechanism underlying the effects of VPA on mitochondrial function in breast cancer remains unclear.
    Keywords:  Breast cancer; Hippo pathway; MIEF1; Mitochondria; Valproic acid
    DOI:  https://doi.org/10.1016/j.lfs.2022.120976
  14. Am J Cancer Res. 2022 ;12(8): 3662-3678
    COA3 overexpression promotes non-small cell lung cancer metastasis by reprogramming glucose metabolism.
    Hongwei Lin, Yanjun Gao, Kang Sun, Qian Zhang, Yujuan Li, Min Chen, Faguang Jin.
      Recent advances in cancer research have revealed a close relationship between mitochondrial dysfunction and cancer development. Human COX assembly factor 3 (COA3), also known as CCDC56, is a mitochondrial transmembrane protein responsible for cytochrome c oxidase (COX) protein complex assembly. However, the clinical implication and biological functions of COA3 remain unexplored in human cancers, including non-small cell lung cancer (NSCLC). Here, we found that COA3 is overexpressed at both mRNA and protein levels in human NSCLC cells, mainly as a result of decreased miR-338-3p level. The protein expression level of COA3 is positively associated with lymph node metastasis and predicts poor survival in patients with NSCLC. Silencing of COA3 significantly attenuated, while forced COA3 expression enhanced the migration and invasiveness of NSCLC cells. Mechanistically, we found that aerobic glycolysis, induced at least in part by dynamic-related protein 1 (DRP1) phosphorylation-mediated mitochondrial fragmentation, contributed to COA3-promoted NSCLC metastasis. Together, our study illustrates that COA3 plays a crucial role in NSCLC carcinogenesis, implying COA3 as a prognostic marker and treatment target in NSCLC.
    Keywords:  COA3; NSCLC; glycolysis; metastasis; mitochondrial fragmentation
  15. Nat Commun. 2022 Sep 21. 13(1): 5522
    Reaction-based fluorogenic probes for detecting protein cysteine oxidation in living cells.
    Renan B Ferreira, Ling Fu, Youngeun Jung, Jing Yang, Kate S Carroll.
      'Turn-on' fluorescence probes for detecting H2O2 in cells are established, but equivalent tools to monitor the products of its reaction with protein cysteines have not been reported. Here we describe fluorogenic probes for detecting sulfenic acid, a redox modification inextricably linked to H2O2 signaling and oxidative stress. The reagents exhibit excellent cell permeability, rapid reactivity, and high selectivity with minimal cytotoxicity. We develop a high-throughput assay for measuring S-sulfenation in cells and use it to screen a curated kinase inhibitor library. We reveal a positive association between S-sulfenation and inhibition of TK, AGC, and CMGC kinase group members including GSK3, a promising target for neurological disorders. Proteomic mapping of GSK3 inhibitor-treated cells shows that S-sulfenation sites localize to the regulatory cysteines of antioxidant enzymes. Our studies highlight the ability of kinase inhibitors to modulate the cysteine sulfenome and should find broad application in the rapidly growing field of redox medicine.
    DOI:  https://doi.org/10.1038/s41467-022-33124-z
  16. Nat Metab. 2022 Sep;4(9): 1119-1137
    Metabolic collateral lethal target identification reveals MTHFD2 paralogue dependency in ovarian cancer.
    Abhinav Achreja, Tao Yu, Anjali Mittal, Srinadh Choppara, Olamide Animasahun, Minal Nenwani, Fulei Wuchu, Noah Meurs, Aradhana Mohan, Jin Heon Jeon, Itisam Sarangi, Anusha Jayaraman, Sarah Owen, Reva Kulkarni, Michele Cusato, Frank Weinberg, Hye Kyong Kweon, Chitra Subramanian, Max S Wicha, Sofia D Merajver, Sunitha Nagrath, Kathleen R Cho, Analisa DiFeo, Xiongbin Lu, Deepak Nagrath.
      Recurrent loss-of-function deletions cause frequent inactivation of tumour suppressor genes but often also involve the collateral deletion of essential genes in chromosomal proximity, engendering dependence on paralogues that maintain similar function. Although these paralogues are attractive anticancer targets, no methodology exists to uncover such collateral lethal genes. Here we report a framework for collateral lethal gene identification via metabolic fluxes, CLIM, and use it to reveal MTHFD2 as a collateral lethal gene in UQCR11-deleted ovarian tumours. We show that MTHFD2 has a non-canonical oxidative function to provide mitochondrial NAD+, and demonstrate the regulation of systemic metabolic activity by the paralogue metabolic pathway maintaining metabolic flux compensation. This UQCR11-MTHFD2 collateral lethality is confirmed in vivo, with MTHFD2 inhibition leading to complete remission of UQCR11-deleted ovarian tumours. Using CLIM's machine learning and genome-scale metabolic flux analysis, we elucidate the broad efficacy of targeting MTHFD2 despite distinct cancer genetic profiles co-occurring with UQCR11 deletion and irrespective of stromal compositions of tumours.
    DOI:  https://doi.org/10.1038/s42255-022-00636-3
  17. JCI Insight. 2022 Sep 22. pii: e159286. [Epub ahead of print]7(18):
    Flow pattern-dependent mitochondrial dynamics regulates the metabolic profile and inflammatory state of endothelial cells.
    Soon-Gook Hong, Junchul Shin, Soo Young Choi, Jeffery C Powers, Benjamin M Meister, Jacqueline Sayoc, Jun Seok Son, Ryan Tierney, Fabio A Recchia, Michael D Brown, Xiaofeng Yang, Joon-Young Park.
      Endothelial mitochondria play a pivotal role in maintaining endothelial cell (EC) homeostasis through constantly altering their size, shape, and intracellular localization. Studies show that the disruption of the basal mitochondrial network in EC, forming excess fragmented mitochondria, implicates cardiovascular disease. However, cellular consequences underlying the morphological changes in the endothelial mitochondria under distinctively different, but physiologically occurring, flow patterns (i.e., unidirectional flow [UF] versus disturbed flow [DF]) are largely unknown. The purpose of this study was to investigate the effect of different flow patterns on mitochondrial morphology and its implications in EC phenotypes. We show that mitochondrial fragmentation is increased at DF-exposed vessel regions, where elongated mitochondria are predominant in the endothelium of UF-exposed regions. DF increased dynamin-related protein 1 (Drp1), mitochondrial reactive oxygen species (mtROS), hypoxia-inducible factor 1, glycolysis, and EC activation. Inhibition of Drp1 significantly attenuated these phenotypes. Carotid artery ligation and microfluidics experiments further validate that the significant induction of mitochondrial fragmentation was associated with EC activation in a Drp1-dependent manner. Contrarily, UF in vitro or voluntary exercise in vivo significantly decreased mitochondrial fragmentation and enhanced fatty acid uptake and OXPHOS. Our data suggest that flow patterns profoundly change mitochondrial fusion/fission events, and this change contributes to the determination of proinflammatory and metabolic states of ECs.
    Keywords:  Atherosclerosis; Endothelial cells; Mitochondria; Vascular Biology
    DOI:  https://doi.org/10.1172/jci.insight.159286
  18. Br J Cancer. 2022 Sep 17.
    Sensitisation of cancer cells to radiotherapy by serine and glycine starvation.
    Mattia Falcone, Alejandro Huerta Uribe, Vasileios Papalazarou, Alice C Newman, Dimitris Athineos, Katrina Stevenson, Charles-Etienne Gabriel Sauvé, Yajing Gao, Jin K Kim, Michael Del Latto, Maria Kierstead, Chao Wu, J Joshua Smith, Paul B Romesser, Anthony J Chalmers, Karen Blyth, Oliver D K Maddocks.
       BACKGROUND: Cellular metabolism is an integral component of cellular adaptation to stress, playing a pivotal role in the resistance of cancer cells to various treatment modalities, including radiotherapy. In response to radiotherapy, cancer cells engage antioxidant and DNA repair mechanisms which mitigate and remove DNA damage, facilitating cancer cell survival. Given the reliance of these resistance mechanisms on amino acid metabolism, we hypothesised that controlling the exogenous availability of the non-essential amino acids serine and glycine would radiosensitise cancer cells.
    METHODS: We exposed colorectal, breast and pancreatic cancer cell lines/organoids to radiation in vitro and in vivo in the presence and absence of exogenous serine and glycine. We performed phenotypic assays for DNA damage, cell cycle, ROS levels and cell death, combined with a high-resolution untargeted LCMS metabolomics and RNA-Seq.
    RESULTS: Serine and glycine restriction sensitised a range of cancer cell lines, patient-derived organoids and syngeneic mouse tumour models to radiotherapy. Comprehensive metabolomic and transcriptomic analysis of central carbon metabolism revealed that amino acid restriction impacted not only antioxidant response and nucleotide synthesis but had a marked inhibitory effect on the TCA cycle.
    CONCLUSION: Dietary restriction of serine and glycine is a viable radio-sensitisation strategy in cancer.
    DOI:  https://doi.org/10.1038/s41416-022-01965-6
  19. JCI Insight. 2022 Sep 22. pii: e159600. [Epub ahead of print]7(18):
    HPV E6 regulates therapy responses in oropharyngeal cancer by repressing the PGC-1α/ERRα axis.
    Malay K Sannigrahi, Pavithra Rajagopalan, Ling Lai, Xinyi Liu, Varun Sahu, Hiroshi Nakagawa, Jalal B Jalaly, Robert M Brody, Iain M Morgan, Bradford E Windle, Xiaowei Wang, Phyllis A Gimotty, Daniel P Kelly, Elizabeth A White, Devraj Basu.
      Therapy with radiation plus cisplatin kills HPV+ oropharyngeal squamous cell carcinomas (OPSCCs) by increasing reactive oxygen species beyond cellular antioxidant capacity. To explore why these standard treatments fail for some patients, we evaluated whether the variation in HPV oncoprotein levels among HPV+ OPSCCs affects mitochondrial metabolism, a source of antioxidant capacity. In cell line and patient-derived xenograft models, levels of HPV full-length E6 (fl-E6) inversely correlated with oxidative phosphorylation, antioxidant capacity, and therapy resistance, and fl-E6 was the only HPV oncoprotein to display such correlations. Ectopically expressing fl-E6 in models with low baseline levels reduced mitochondrial mass, depleted antioxidant capacity, and sensitized to therapy. In this setting, fl-E6 repressed the peroxisome proliferator-activated receptor gamma co-activator 1α/estrogen-related receptor α (PGC-1α/ERRα) pathway for mitochondrial biogenesis by reducing p53-dependent PGC-1α transcription. Concordant observations were made in 3 clinical cohorts, where expression of mitochondrial components was higher in tumors of patients with reduced survival. These tumors contained the lowest fl-E6 levels, the highest p53 target gene expression, and an activated PGC-1α/ERRα pathway. Our findings demonstrate that E6 can potentiate treatment responses by depleting mitochondrial antioxidant capacity and provide evidence for low E6 negatively affecting patient survival. E6's interaction with the PGC-1α/ERRα axis has implications for predicting and targeting treatment resistance in OPSCC.
    Keywords:  Head and neck cancer; Oncology; Therapeutics
    DOI:  https://doi.org/10.1172/jci.insight.159600
  20. PLoS Biol. 2022 Sep;20(9): e3001800
    The requirement for mitochondrial respiration in cancer varies with disease stage.
    Colin Sheehan, Alexander Muir.
      The roles for glycolytic and respiratory metabolism in supporting in vivo tumor growth in different contexts are not well understood. In this issue of PLOS Biology, a new study reveals that primary and metastatic tumors demonstrate divergent metabolic requirements.
    DOI:  https://doi.org/10.1371/journal.pbio.3001800
  21. Nature. 2022 Sep 21.
    A cellular hierarchy in melanoma uncouples growth and metastasis.
    Panagiotis Karras, Ignacio Bordeu, Joanna Pozniak, Ada Nowosad, Cecilia Pazzi, Nina Van Raemdonck, Ewout Landeloos, Yannick Van Herck, Dennis Pedri, Greet Bervoets, Samira Makhzami, Jia Hui Khoo, Benjamin Pavie, Jochen Lamote, Oskar Marin-Bejar, Michael Dewaele, Han Liang, Xingju Zhang, Yichao Hua, Jasper Wouters, Robin Browaeys, Gabriele Bergers, Yvan Saeys, Francesca Bosisio, Joost van den Oord, Diether Lambrechts, Anil K Rustgi, Oliver Bechter, Cedric Blanpain, Benjamin D Simons, Florian Rambow, Jean-Christophe Marine.
      Although melanoma is notorious for its high degree of heterogeneity and plasticity1,2, the origin and magnitude of cell-state diversity remains poorly understood. Equally, it is unclear whether growth and metastatic dissemination are supported by overlapping or distinct melanoma subpopulations. Here, by combining mouse genetics, single-cell and spatial transcriptomics, lineage tracing and quantitative modelling, we provide evidence of a hierarchical model of tumour growth that mirrors the cellular and molecular logic underlying the cell-fate specification and differentiation of the embryonic neural crest. We show that tumorigenic competence is associated with a spatially localized perivascular niche, a phenotype acquired through an intercellular communication pathway established by endothelial cells. Consistent with a model in which only a fraction of cells are fated to fuel growth, temporal single-cell tracing of a population of melanoma cells with a mesenchymal-like state revealed that these cells do not contribute to primary tumour growth but, instead, constitute a pool of metastatic initiating cells that switch cell identity while disseminating to secondary organs. Our data provide a spatially and temporally resolved map of the diversity and trajectories of melanoma cell states and suggest that the ability to support growth and metastasis are limited to distinct pools of cells. The observation that these phenotypic competencies can be dynamically acquired after exposure to specific niche signals warrant the development of therapeutic strategies that interfere with the cancer cell reprogramming activity of such microenvironmental cues.
    DOI:  https://doi.org/10.1038/s41586-022-05242-7
  22. J Gerontol A Biol Sci Med Sci. 2022 Sep 23. pii: glac201. [Epub ahead of print]
    Increased Efficiency of Mitochondrial Coupling with a Reduction in Other Mitochondrial Respiratory Parameters in Peripheral Blood Mononuclear Cells is Observed in Older Adults.
    Sirawit Sriwichaiin, Nattayaporn Apaijai, Arintaya Phrommintikul, Thidarat Jaiwongkam, Sasiwan Kerdphoo, Wasana Pratchayasakul, Nisakron Thongmung, Usanee Mahantassanapong, Prin Vathesatogkit, Chagriya Kitiyakara, Piyamitr Sritara, Nipon Chattipakorn, Siriporn C Chattipakorn.
      Mitochondrial dysfunction is a factor potentially contributing to the aging process. However, evidence surrounding changes in mitochondrial function and aging is still limited, therefore this study aimed to investigate further the association between them. Possible confounding factors were included in the statistical analysis to explore the possibility of any independent associations. One thousand seven hundred and sixty-nine participants (619 middle-aged adults (age<65) and 1,150 older adults (age≥65)) from the Electricity Generating Authority of Thailand were enrolled onto the study. The clinical characteristics and medical history were collected. Peripheral blood mononuclear cells (PBMCs) were isolated from venous blood and used for analysis of mitochondrial function. Several parameters pertinent to mitochondrial respiration including non-mitochondrial respiration, basal respiration, maximal respiration, proton leak, and spare respiratory capacity were found to be two to three times lower in the mitochondria isolated from the cells of older adults. Interestingly, the mitochondrial ATP production was only slightly reduced, and the percentage of coupling efficiency of PBMC mitochondria was significantly higher in the older adult group. The mitochondrial mass and oxidative stress were significantly reduced in older adult participants, however, the ratio of oxidative stress to mass was significantly increased. The association of these parameters with age were still shown to be the same from the outcome of the multivariate analyses. The mitochondrial functions and mitochondrial mass in PBMCs were shown to decline in association with age. However, the upregulation of mitochondrial oxidative stress production and mitochondrial coupling efficiency might indicate a compensatory response in mitochondria during aging.
    Keywords:  ATP; PBMCs; mitochondria; oxidative stress
    DOI:  https://doi.org/10.1093/gerona/glac201
  23. Front Oncol. 2022 ;12 971479
    Targeting oxidative phosphorylation as an approach for the treatment of ovarian cancer.
    Yinjie Wu, Xuewei Zhang, Ziyi Wang, Wanzhen Zheng, Huimin Cao, Wenjing Shen.
      Ovarian cancer is an aggressive tumor that remains to be the most lethal gynecological malignancy in women. Metabolic adaptation is an emerging hallmark of tumors. It is important to exploit metabolic vulnerabilities of tumors as promising strategies to develop more effective anti-tumor regimens. Tumor cells reprogram the metabolic pathways to meet the bioenergetic, biosynthetic, and mitigate oxidative stress required for tumor cell proliferation and survival. Oxidative phosphorylation has been found to be altered in ovarian cancer, and oxidative phosphorylation is proposed as a therapeutic target for management of ovarian cancer. Herein, we initially introduced the overview of oxidative phosphorylation in cancer. Furthermore, we discussed the role of oxidative phosphorylation and chemotherapeutic resistance of ovarian cancer. The role of oxidative phosphorylation in other components of tumor microenvironment of ovarian cancer has also been discussed.
    Keywords:  metabolic reprograming; mitochondria; ovarian cancer; oxidative phoshorylation; resistance
    DOI:  https://doi.org/10.3389/fonc.2022.971479
  24. Front Oncol. 2022 ;12 860084
    Knockdown of NDUFC1 inhibits cell proliferation, migration, and invasion of hepatocellular carcinoma.
    Fang Han, Junwei Liu, Hongwu Chu, Dan Cao, Jia Wu, Hong Fu, Anyang Guo, Weiqin Chen, Yingping Xu, Xiangdong Cheng, Yuhua Zhang.
       Background: NADH: ubiquinone oxidoreductase subunit C1(NDUFC1) encodes a subunit of the Complex I, which may support the structural stability of Complex I and assist in its biogenesis. The expression and functional roles of NDUFC1 in hepatocellular carcinoma (HCC) remain unknown.
    Result: We knocked down the expression of NDUFC1 in HCC cell lines to explore the effects of NDUFC1 downregulation on HCC in vitro. MTT assay determined that downregulation of NDUFC1 significantly inhibited cell proliferation. Flow cytometry with (propidium iodide) PI staining indicated silencing of NDUFC1 arrested cell cycle of BEL-7404 cells at G2 phase and SK-HEP-1 cells at S/G2 phase. Annexin V-PI double staining and flow cytometric analysis showed that the downregulation of NDUFC1 significantly increased the population of apoptotic cells. Wound-healing assay and transwell assay indicated that the downregulation of NDUFC1 suppressed the migration and invasion of HCC cells. According to the detection of complex1 activity, we found that the activity of NDUFC1 silenced group decreased, whereas the content of ROS increased. Furthermore, combined with bioinformatics analysis of senescence-related genes, we found that the silence of NDUFC1 in HCC could induce senescence and inhibit autophagy. In addition, NDUFC1 could correlate positively with cancer-related pathways, among which the p53 pathways and the PI3K/Akt/mTOR pathways. Finally, NDUFC1 is high expression in HCC specimens. High NDUFC1 expression was associated with poor prognosis and was an independent risk factor for reduced overall survival (OS).
    Conclusions: Our study indicated, for the first time, that NDUFC1 is an independent risk factor for the poor prognosis of HCC patients. NDUFC1 may promote tumor progression by inhibiting mitochondrial Complex I and up-regulating ROS through multiple cancer-related and senescence-related pathways of HCC, including p53 pathways and PI3K/Akt/mTOR pathways. We suppose that NDUFC1 might be a potential target for the mitochondrial metabolism therapy of HCC.
    Keywords:  HCC; NADH: ubiquinone oxidoreductase complexes I; NDUFC1; prognosis; senescence
    DOI:  https://doi.org/10.3389/fonc.2022.860084
  25. Cancers (Basel). 2022 Sep 16. pii: 4491. [Epub ahead of print]14(18):
    Concomitant Inhibition of FASN and SREBP Provides a Promising Therapy for CTCL.
    Cheng Chi, Lisa Harth, Marina Ramírez Galera, Marina Passos Torrealba, Chella Krishna Vadivel, Carsten Geisler, Charlotte Menné Bonefeld, Pia Rude Nielsen, Michael Bzorek, Jürgen C Becker, Lise Mette Rahbek Gjerdrum, Niels Ødum, Anders Woetmann.
      Cutaneous T cell lymphoma (CTCL) is a group of non-Hodgkin's primary cutaneous T cell lymphomas, with Mycosis Fungoides and Sézary syndrome (SS) being the two most common subtypes. Fatty acid synthase (FASN) is a crucial enzyme that catalyses the biosynthesis of fatty acids, which has been reported to play an oncogenic role in various malignancies but not in CTCL so far. Herein, we show that FASN is highly expressed in CTCL cell lines and in peripheral blood mononuclear cells (PBMCs) from CTCL patients, while it is not in PBMCs from healthy individuals. The inhibition of FASN in CTCL cell lines impairs cell viability, survival, and proliferation, but, interestingly, it also increases FASN expression. However, inhibiting sterol regulatory element binding protein (SREBP), a transcription factor that promotes the expression of FASN, partially reversed the upregulation of FASN induced by FASN inhibitors. Thus, the combination of FASN and SREBP inhibitors enhanced the effects on both CTCL cell lines and PBMCs from SS patients, where a valid inhibition on cell proliferation could be verified. Importantly, compared to non-malignant cells, primary malignant cells are more sensitive to the inhibition of FASN and SREBP, making the combination of FASN and SREBP inhibitors a promising novel therapeutic strategy in CTCL.
    Keywords:  CTCL; FASN; SREBP; cancer therapy
    DOI:  https://doi.org/10.3390/cancers14184491
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