bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2022‒05‒22
34 papers selected by
Kelsey Fisher-Wellman
East Carolina University
  1. Targeting Mitochondrial Oxidative Phosphorylation Eradicates Acute Myeloid Leukemic Stem Cells.
  2. Cryo-EM structures define ubiquinone-10 binding to mitochondrial complex I and conformational transitions accompanying Q-site occupancy.
  3. Mitochondrial TrxR2 regulates metabolism and protects from metabolic disease through enhanced TCA and ETC function.
  4. Mutational profiling of mtDNA control region reveals tumor-specific evolutionary selection involved in mitochondrial dysfunction.
  5. Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia.
  6. Inducing respiratory complex I impairment elicits an increase in PGC1α in ovarian cancer.
  7. Mitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment.
  8. Metabolic flux analysis of 3D spheroids reveals significant differences in glucose metabolism from matched 2D cultures of colorectal cancer and pancreatic ductal adenocarcinoma cell lines.
  9. PHGDH heterogeneity potentiates cancer cell dissemination and metastasis.
  10. Mitochondria preserve an autarkic one-carbon cycle to confer growth-independent cancer cell migration and metastasis.
  11. Tumor suppressor p53 restrains cancer cell dissemination by modulating mitochondrial dynamics.
  12. Upregulation of mitochondrial ATPase inhibitory factor 1 (ATPIF1) mediates increased glycolysis in mouse hearts.
  13. Pyruvate kinase M1 suppresses development and progression of prostate adenocarcinoma.
  14. KAT2A affects tumor metabolic reprogramming in colon cancer progression through epigenetic activation of E2F1.
  15. Apoptotic priming is defined by the dynamic exchange of Bcl-2 proteins between mitochondria and cytosol.
  16. Purine nucleotide depletion prompts cell migration by stimulating the serine synthesis pathway.
  17. Lipid droplet degradation by autophagy connects mitochondria metabolism to Prox1-driven expression of lymphatic genes and lymphangiogenesis.
  18. A mitochondria-targeted rhodol fluorescent probe for imaging of hydrogen peroxide in living cells.
  19. Beyond being an energy supplier, ATP synthase is a sculptor of mitochondrial cristae.
  20. SQSTM1 and its MAP1LC3B-binding domain induce forced mitophagy to degrade mitochondrial carryover during mitochondrial replacement therapy.
  21. Suppression of nuclear GSK3 signaling promotes serine/one-carbon metabolism and confers metabolic vulnerability in lung cancer cells.
  22. HuR-dependent SOD2 protein synthesis is an early adaptation to anchorage-independence.
  23. A bioinformatics pipeline for estimating mitochondrial DNA copy number and heteroplasmy levels from whole genome sequencing data.
  24. UCP2 - Taking the heat out of P-glycoprotein?
  25. Mitochondrial transfer/transplantation: an emerging therapeutic approach for multiple diseases.
  26. Low expression of PGC-1β and other mitochondrial biogenesis modulators in melanoma is associated with growth arrest and the induction of an immunosuppressive gene expression program dependent on MEK and IRF-1.
  27. Mitochondrial complex complexification.
  28. Mitochondrial 1555 G>A variant as a potential risk factor for childhood glioblastoma.
  29. Metabolic diversity drives cancer cell invasion.
  30. Ketotherapy: Cutting carbs to treat cancer.
  31. DDR1 promotes LoVo cell proliferation by regulating energy metabolism.
  32. AK2 is an AMP-sensing negative regulator of BRAF in tumorigenesis.
  33. The Glutaminase Inhibitor Compound 968 Exhibits Potent in vitro and in vivo Anti-tumor Effects in Endometrial Cancer.
  34. SIRT5 is involved in the proliferation and metastasis of breast cancer by promoting aerobic glycolysis.
  1. Front Oncol. 2022 ;12 899502
    Targeting Mitochondrial Oxidative Phosphorylation Eradicates Acute Myeloid Leukemic Stem Cells.
    Meixi Peng, Yongxiu Huang, Ling Zhang, Xueya Zhao, Yu Hou.
      Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by multiple cytogenetic and molecular abnormalities, with a very poor prognosis. Current treatments for AML often fail to eliminate leukemic stem cells (LSCs), which perpetuate the disease. LSCs exhibit a unique metabolic profile, especially dependent on oxidative phosphorylation (OXPHOS) for energy production. Whereas, normal hematopoietic stem cells (HSCs) and leukemic blasts rely on glycolysis for adenosine triphosphate (ATP) production. Thus, understanding the regulation of OXPHOS in LSCs may offer effective targets for developing clinical therapies in AML. This review summarizes these studies with a focus on the regulation of the electron transport chain (ETC) and tricarboxylic acid (TCA) cycle in OXPHOS and discusses potential therapies for eliminating LSCs.
    Keywords:  electron transport chain; leukemic stem cells (LSCs); mitochondria; oxidative phosphorylation (OXPHOS); tricarboxylic acid cycle (TCA cycle)
    DOI:  https://doi.org/10.3389/fonc.2022.899502
  2. Nat Commun. 2022 May 19. 13(1): 2758
    Cryo-EM structures define ubiquinone-10 binding to mitochondrial complex I and conformational transitions accompanying Q-site occupancy.
    Injae Chung, John J Wright, Hannah R Bridges, Bozhidar S Ivanov, Olivier Biner, Caroline S Pereira, Guilherme M Arantes, Judy Hirst.
      Mitochondrial complex I is a central metabolic enzyme that uses the reducing potential of NADH to reduce ubiquinone-10 (Q10) and drive four protons across the inner mitochondrial membrane, powering oxidative phosphorylation. Although many complex I structures are now available, the mechanisms of Q10 reduction and energy transduction remain controversial. Here, we reconstitute mammalian complex I into phospholipid nanodiscs with exogenous Q10. Using cryo-EM, we reveal a Q10 molecule occupying the full length of the Q-binding site in the 'active' (ready-to-go) resting state together with a matching substrate-free structure, and apply molecular dynamics simulations to propose how the charge states of key residues influence the Q10 binding pose. By comparing ligand-bound and ligand-free forms of the 'deactive' resting state (that require reactivating to catalyse), we begin to define how substrate binding restructures the deactive Q-binding site, providing insights into its physiological and mechanistic relevance.
    DOI:  https://doi.org/10.1038/s41467-022-30506-1
  3. Commun Biol. 2022 May 16. 5(1): 467
    Mitochondrial TrxR2 regulates metabolism and protects from metabolic disease through enhanced TCA and ETC function.
    E Sandra Chocron, Kennedy Mdaki, Nisi Jiang, Jodie Cropper, Andrew M Pickering.
      Mitochondrial dysfunction is a key driver of diabetes and other metabolic diseases. Mitochondrial redox state is highly impactful to metabolic function but the mechanism driving this is unclear. We generated a transgenic mouse which overexpressed the redox enzyme Thioredoxin Reductase 2 (TrxR2), the rate limiting enzyme in the mitochondrial thioredoxin system. We found augmentation of TrxR2 to enhance metabolism in mice under a normal diet and to increase resistance to high-fat diet induced metabolic dysfunction by both increasing glucose tolerance and decreasing fat deposition. We show this to be caused by increased mitochondrial function which is driven at least in part by enhancements to the tricarboxylic acid cycle and electron transport chain function. Our findings demonstrate a role for TrxR2 and mitochondrial thioredoxin as metabolic regulators and show a critical role for redox enzymes in controlling functionality of key mitochondrial metabolic systems.
    DOI:  https://doi.org/10.1038/s42003-022-03405-w
  4. EBioMedicine. 2022 May 17. pii: S2352-3964(22)00239-0. [Epub ahead of print]80 104058
    Mutational profiling of mtDNA control region reveals tumor-specific evolutionary selection involved in mitochondrial dysfunction.
    Xiaoying Ji, Wenjie Guo, Xiwen Gu, Shanshan Guo, Kaixiang Zhou, Liping Su, Qing Yuan, Yang Liu, Xu Guo, Qichao Huang, Jinliang Xing.
      BACKGROUND: Mitochondrial DNA (mtDNA) mutations alter mitochondrial function in oxidative metabolism and play an important role in tumorigenesis. A series of studies have demonstrated that the mtDNA control region (mtCTR), which is essential for mtDNA replication and transcription, represents a mutational hotspot in human tumors. However, a comprehensive pan-cancer evolutionary pattern analysis of mtCTR mutations is urgently needed.METHODS: We generated a comprehensive combined dataset containing 10026 mtDNA somatic mutations from 4664 patients, covering 20 tumor types based on public and private next-generation sequencing data.
    FINDINGS: Our results demonstrated a significantly higher and much more variable mutation rate in mtCTR than in the coding region across different tumor types. Moreover, our data showed a remarkable distributional bias of tumor somatic mutations between the hypervariable segment (HVS) and non-HVS, with a significantly higher mutation density and average mutation sites in HVS. Importantly, the tumor-specific mutational pattern between mtCTR HVS and non-HVS was identified, which was classified into three evolutionary selection types (relaxed, moderate, and strict constraint types). Analysis of substitution patterns revealed that the prevalence of CH > TH in non-HVS greatly contributed to the mutational selection pattern of mtCTR across different tumor types. Furthermore, we found that the mutational pattern of mtCTR in the four tumor types was clearly associated with mitochondrial biogenesis, mitochondrial oxidative metabolism, and the overall survival of patients.
    INTERPRETATION: Our results suggest that somatic mutations in mtCTR may be shaped by tumor-specific selective pressure and are involved in tumorigenesis.
    FUNDINGS: National Natural Science Foundation of China [grants 82020108023, 81830070, 81872302], and Autonomous Project of State Key Laboratory of Cancer Biology, China [grants CBSKL2019ZZ06, CBSKL2019ZZ27].
    Keywords:  Control region; Evolutionary selection; Hypervariable segment; Mitochondrial DNA; Somatic mutation
    DOI:  https://doi.org/10.1016/j.ebiom.2022.104058
  5. Nat Commun. 2022 May 19. 13(1): 2801
    Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia.
    Natalia Baran, Alessia Lodi, Yogesh Dhungana, Shelley Herbrich, Meghan Collins, Shannon Sweeney, Renu Pandey, Anna Skwarska, Shraddha Patel, Mathieu Tremblay, Vinitha Mary Kuruvilla, Antonio Cavazos, Mecit Kaplan, Marc O Warmoes, Diogo Troggian Veiga, Ken Furudate, Shanti Rojas-Sutterin, Andre Haman, Yves Gareau, Anne Marinier, Helen Ma, Karine Harutyunyan, May Daher, Luciana Melo Garcia, Gheath Al-Atrash, Sujan Piya, Vivian Ruvolo, Wentao Yang, Sriram Saravanan Shanmugavelandy, Ningping Feng, Jason Gay, Di Du, Jun J Yang, Fieke W Hoff, Marcin Kaminski, Katarzyna Tomczak, R Eric Davis, Daniel Herranz, Adolfo Ferrando, Elias J Jabbour, M Emilia Di Francesco, David T Teachey, Terzah M Horton, Steven Kornblau, Katayoun Rezvani, Guy Sauvageau, Mihai Gagea, Michael Andreeff, Koichi Takahashi, Joseph R Marszalek, Philip L Lorenzi, Jiyang Yu, Stefano Tiziani, Trang Hoang, Marina Konopleva.
      T-cell acute lymphoblastic leukemia (T-ALL) is commonly driven by activating mutations in NOTCH1 that facilitate glutamine oxidation. Here we identify oxidative phosphorylation (OxPhos) as a critical pathway for leukemia cell survival and demonstrate a direct relationship between NOTCH1, elevated OxPhos gene expression, and acquired chemoresistance in pre-leukemic and leukemic models. Disrupting OxPhos with IACS-010759, an inhibitor of mitochondrial complex I, causes potent growth inhibition through induction of metabolic shut-down and redox imbalance in NOTCH1-mutated and less so in NOTCH1-wt T-ALL cells. Mechanistically, inhibition of OxPhos induces a metabolic reprogramming into glutaminolysis. We show that pharmacological blockade of OxPhos combined with inducible knock-down of glutaminase, the key glutamine enzyme, confers synthetic lethality in mice harboring NOTCH1-mutated T-ALL. We leverage on this synthetic lethal interaction to demonstrate that IACS-010759 in combination with chemotherapy containing L-asparaginase, an enzyme that uncovers the glutamine dependency of leukemic cells, causes reduced glutaminolysis and profound tumor reduction in pre-clinical models of human T-ALL. In summary, this metabolic dependency of T-ALL on OxPhos provides a rational therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-022-30396-3
  6. Sci Rep. 2022 May 16. 12(1): 8020
    Inducing respiratory complex I impairment elicits an increase in PGC1α in ovarian cancer.
    Monica De Luise, Manuela Sollazzo, Eleonora Lama, Camelia Alexandra Coadă, Licia Bressi, Maria Iorio, Beatrice Cavina, Luigi D'Angelo, Sara Milioni, Lorena Marchio, Stefano Miglietta, Sara Coluccelli, Greta Tedesco, Anna Ghelli, Silvia Lemma, Anna Myriam Perrone, Ivana Kurelac, Luisa Iommarini, Anna Maria Porcelli, Giuseppe Gasparre.
      Anticancer strategies aimed at inhibiting Complex I of the mitochondrial respiratory chain are increasingly being attempted in solid tumors, as functional oxidative phosphorylation is vital for cancer cells. Using ovarian cancer as a model, we show that a compensatory response to an energy crisis induced by Complex I genetic ablation or pharmacological inhibition is an increase in the mitochondrial biogenesis master regulator PGC1α, a pleiotropic coactivator of transcription regulating diverse biological processes within the cell. We associate this compensatory response to the increase in PGC1α target gene expression, setting the basis for the comprehension of the molecular pathways triggered by Complex I inhibition that may need attention as drawbacks before these approaches are implemented in ovarian cancer care.
    DOI:  https://doi.org/10.1038/s41598-022-11620-y
  7. Nat Commun. 2022 May 19. 13(1): 2769
    Mitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment.
    Enrique Balderas, David R Eberhardt, Sandra Lee, John M Pleinis, Salah Sommakia, Anthony M Balynas, Xue Yin, Mitchell C Parker, Colin T Maguire, Scott Cho, Marta W Szulik, Anna Bakhtina, Ryan D Bia, Marisa W Friederich, Timothy M Locke, Johan L K Van Hove, Stavros G Drakos, Yasemin Sancak, Martin Tristani-Firouzi, Sarah Franklin, Aylin R Rodan, Dipayan Chaudhuri.
      Calcium entering mitochondria potently stimulates ATP synthesis. Increases in calcium preserve energy synthesis in cardiomyopathies caused by mitochondrial dysfunction, and occur due to enhanced activity of the mitochondrial calcium uniporter channel. The signaling mechanism that mediates this compensatory increase remains unknown. Here, we find that increases in the uniporter are due to impairment in Complex I of the electron transport chain. In normal physiology, Complex I promotes uniporter degradation via an interaction with the uniporter pore-forming subunit, a process we term Complex I-induced protein turnover. When Complex I dysfunction ensues, contact with the uniporter is inhibited, preventing degradation, and leading to a build-up in functional channels. Preventing uniporter activity leads to early demise in Complex I-deficient animals. Conversely, enhancing uniporter stability rescues survival and function in Complex I deficiency. Taken together, our data identify a fundamental pathway producing compensatory increases in calcium influx during Complex I impairment.
    DOI:  https://doi.org/10.1038/s41467-022-30236-4
  8. Cancer Metab. 2022 May 16. 10(1): 9
    Metabolic flux analysis of 3D spheroids reveals significant differences in glucose metabolism from matched 2D cultures of colorectal cancer and pancreatic ductal adenocarcinoma cell lines.
    Tia R Tidwell, Gro V Røsland, Karl Johan Tronstad, Kjetil Søreide, Hanne R Hagland.
      BACKGROUND: Most in vitro cancer cell experiments have been performed using 2D models. However, 3D spheroid cultures are increasingly favored for being more representative of in vivo tumor conditions. To overcome the translational challenges with 2D cell cultures, 3D systems better model more complex cell-to-cell contact and nutrient levels present in a tumor, improving our understanding of cancer complexity. Despite this need, there are few reports on how 3D cultures differ metabolically from 2D cultures.METHODS: Well-described cell lines from colorectal cancer (HCT116 and SW948) and pancreatic ductal adenocarcinoma (Panc-1 and MIA-Pa-Ca-2) were used to investigate metabolism in 3D spheroid models. The metabolic variation under normal glucose conditions were investigated comparing 2D and 3D cultures by metabolic flux analysis and expression of key metabolic proteins.
    RESULTS: We find significant differences in glucose metabolism of 3D cultures compared to 2D cultures, both related to glycolysis and oxidative phosphorylation. Spheroids have higher ATP-linked respiration in standard nutrient conditions and higher non-aerobic ATP production in the absence of supplemented glucose. In addition, ATP-linked respiration is significantly inversely correlated with OCR/ECAR (p = 0.0096). Mitochondrial transport protein, TOMM20, expression decreases in all spheroid models compared to 2D, and monocarboxylate transporter (MCT) expression increases in 3 of the 4 spheroid models.
    CONCLUSIONS: In this study of CRC and PDAC cell lines, we demonstrate that glucose metabolism in 3D spheroids differs significantly from 2D cultures, both in terms of glycolytic and oxidative phosphorylation metrics. The metabolic phenotype shift from 2D to 3D culture in one cell line is greater than the phenotypic differences between each cell line and tumor source. The results herein emphasize the need to use 3D cell models for investigating nutrient utilization and metabolic flux for a better understanding of tumor metabolism and potential metabolic therapeutic targets.
    Keywords:  2D cell culture; 3D cell culture; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1186/s40170-022-00285-w
  9. Nature. 2022 May 18.
    PHGDH heterogeneity potentiates cancer cell dissemination and metastasis.
    Matteo Rossi, Patricia Altea-Manzano, Margherita Demicco, Ginevra Doglioni, Laura Bornes, Marina Fukano, Anke Vandekeere, Alejandro M Cuadros, Juan Fernández-García, Carla Riera-Domingo, Cristina Jauset, Mélanie Planque, H Furkan Alkan, David Nittner, Dongmei Zuo, Lindsay A Broadfield, Sweta Parik, Antonino Alejandro Pane, Francesca Rizzollo, Gianmarco Rinaldi, Tao Zhang, Shao Thing Teoh, Arin B Aurora, Panagiotis Karras, Ines Vermeire, Dorien Broekaert, Joke Van Elsen, Maximilian M L Knott, Martin F Orth, Sofie Demeyer, Guy Eelen, Lacey E Dobrolecki, Ayse Bassez, Thomas Van Brussel, Karl Sotlar, Michael T Lewis, Harald Bartsch, Manfred Wuhrer, Peter van Veelen, Peter Carmeliet, Jan Cools, Sean J Morrison, Jean-Christophe Marine, Diether Lambrechts, Massimiliano Mazzone, Gregory J Hannon, Sophia Y Lunt, Thomas G P Grünewald, Morag Park, Jacco van Rheenen, Sarah-Maria Fendt.
      Cancer metastasis requires the transient activation of cellular programs enabling dissemination and seeding in distant organs1. Genetic, transcriptional and translational heterogeneity contributes to this dynamic process2,3. Metabolic heterogeneity has also been observed4, yet its role in cancer progression is less explored. Here we find that the loss of phosphoglycerate dehydrogenase (PHGDH) potentiates metastatic dissemination. Specifically, we find that heterogeneous or low PHGDH expression in primary tumours of patients with breast cancer is associated with decreased metastasis-free survival time. In mice, circulating tumour cells and early metastatic lesions are enriched with Phgdhlow cancer cells, and silencing Phgdh in primary tumours increases metastasis formation. Mechanistically, Phgdh interacts with the glycolytic enzyme phosphofructokinase, and the loss of this interaction activates the hexosamine-sialic acid pathway, which provides precursors for protein glycosylation. As a consequence, aberrant protein glycosylation occurs, including increased sialylation of integrin αvβ3, which potentiates cell migration and invasion. Inhibition of sialylation counteracts the metastatic ability of Phgdhlow cancer cells. In conclusion, although the catalytic activity of PHGDH supports cancer cell proliferation, low PHGDH protein expression non-catalytically potentiates cancer dissemination and metastasis formation. Thus, the presence of PHDGH heterogeneity in primary tumours could be considered a sign of tumour aggressiveness.
    DOI:  https://doi.org/10.1038/s41586-022-04758-2
  10. Nat Commun. 2022 May 16. 13(1): 2699
    Mitochondria preserve an autarkic one-carbon cycle to confer growth-independent cancer cell migration and metastasis.
    Nicole Kiweler, Catherine Delbrouck, Vitaly I Pozdeev, Laura Neises, Leticia Soriano-Baguet, Kim Eiden, Feng Xian, Mohaned Benzarti, Lara Haase, Eric Koncina, Maryse Schmoetten, Christian Jaeger, Muhammad Zaeem Noman, Alexei Vazquez, Bassam Janji, Gunnar Dittmar, Dirk Brenner, Elisabeth Letellier, Johannes Meiser.
      Metastasis is the most common cause of death in cancer patients. Canonical drugs target mainly the proliferative capacity of cancer cells, which leaves slow-proliferating, persistent cancer cells unaffected. Metabolic determinants that contribute to growth-independent functions are still poorly understood. Here we show that antifolate treatment results in an uncoupled and autarkic mitochondrial one-carbon (1C) metabolism during cytosolic 1C metabolism impairment. Interestingly, antifolate dependent growth-arrest does not correlate with decreased migration capacity. Therefore, using methotrexate as a tool compound allows us to disentangle proliferation and migration to profile the metabolic phenotype of migrating cells. We observe that increased serine de novo synthesis (SSP) supports mitochondrial serine catabolism and inhibition of SSP using the competitive PHGDH-inhibitor BI-4916 reduces cancer cell migration. Furthermore, we show that sole inhibition of mitochondrial serine catabolism does not affect primary breast tumor growth but strongly inhibits pulmonary metastasis. We conclude that mitochondrial 1C metabolism, despite being dispensable for proliferative capacities, confers an advantage to cancer cells by supporting their motility potential.
    DOI:  https://doi.org/10.1038/s41467-022-30363-y
  11. Oncogenesis. 2022 May 19. 11(1): 26
    Tumor suppressor p53 restrains cancer cell dissemination by modulating mitochondrial dynamics.
    Trinh T T Phan, Yu-Chun Lin, Yu-Ting Chou, Chien-Wei Wu, Lih-Yuan Lin.
      Tumor suppressor p53 plays a central role in preventing tumorigenesis. Here, we unravel how p53 modulates mitochondrial dynamics to restrain the metastatic properties of cancer cells. p53 inhibits the mammalian target of rapamycin complex 1 (mTORC1) signaling to attenuate the protein level of mitochondrial fission process 1 (MTFP1), which fosters the pro-fission dynamin-related protein 1 (Drp1) phosphorylation. This regulatory mechanism allows p53 to restrict cell migration and invasion governed by Drp1-mediated mitochondrial fission. Downregulating p53 expression or elevating the molecular signature of mitochondrial fission correlates with aggressive tumor phenotypes and poor prognosis in cancer patients. Upon p53 loss, exaggerated mitochondrial fragmentation stimulates the activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling resulting in epithelial-to-mesenchymal transition (EMT)-like changes in cell morphology, accompanied by accelerated matrix metalloproteinase 9 (MMP9) expression and invasive cell migration. Notably, blocking the activation of mTORC1/MTFP1/Drp1/ERK1/2 axis completely abolishes the p53 deficiency-driven cellular morphological switch, MMP9 expression, and cancer cell dissemination. Our findings unveil a hitherto unrecognized mitochondria-dependent molecular mechanism underlying the metastatic phenotypes of p53-compromised cancers.
    DOI:  https://doi.org/10.1038/s41389-022-00401-x
  12. J Clin Invest. 2022 May 16. pii: e155333. [Epub ahead of print]132(10):
    Upregulation of mitochondrial ATPase inhibitory factor 1 (ATPIF1) mediates increased glycolysis in mouse hearts.
    Bo Zhou, Arianne Caudal, Xiaoting Tang, Juan D Chavez, Timothy S McMillen, Andrew Keller, Outi Villet, Mingyue Zhao, Yaxin Liu, Julia Ritterhoff, Pei Wang, Stephen C Kolwicz, Wang Wang, James E Bruce, Rong Tian.
      In hypertrophied and failing hearts, fuel metabolism is reprogrammed to increase glucose metabolism, especially glycolysis. This metabolic shift favors biosynthetic function at the expense of ATP production. Mechanisms responsible for the switch are poorly understood. We found that inhibitory factor 1 of the mitochondrial FoF1-ATP synthase (ATPIF1), a protein known to inhibit ATP hydrolysis by the reverse function of ATP synthase during ischemia, was significantly upregulated in pathological cardiac hypertrophy induced by pressure overload, myocardial infarction, or α-adrenergic stimulation. Chemical cross-linking mass spectrometry analysis of hearts hypertrophied by pressure overload suggested that increased expression of ATPIF1 promoted the formation of FoF1-ATP synthase nonproductive tetramer. Using ATPIF1 gain- and loss-of-function cell models, we demonstrated that stalled electron flow due to impaired ATP synthase activity triggered mitochondrial ROS generation, which stabilized HIF1α, leading to transcriptional activation of glycolysis. Cardiac-specific deletion of ATPIF1 in mice prevented the metabolic switch and protected against the pathological remodeling during chronic stress. These results uncover a function of ATPIF1 in nonischemic hearts, which gives FoF1-ATP synthase a critical role in metabolic rewiring during the pathological remodeling of the heart.
    Keywords:  Cardiology; Heart failure; Metabolism; Mitochondria; Structural biology
    DOI:  https://doi.org/10.1172/JCI155333
  13. Cancer Res. 2022 May 18. pii: canres.CAN-21-2352-E.2021. [Epub ahead of print]
    Pyruvate kinase M1 suppresses development and progression of prostate adenocarcinoma.
    Shawn M Davdison, Daniel R Schmidt, Julia E Heyman, James P O'Brien, Amy C Liu, William J Israelsen, Talya L Dayton, Raghav Sehgal, Roderick T Bronson, Elizaveta Freinkman, Howard H Mak, Giuseppe Nicolo Fanelli, Scott Malstrom, Gary Bellinger, Arkaitz Carracedo, Pier Paolo Pandolfi, Kevin D Courtney, Abhishek Jha, Ronald A DePinho, James W Horner, Craig J Thomas, Lewis C Cantley, Massimo Loda, Matthew G Vander Heiden.
      Altered metabolisms helps sustain cancer cell proliferation and survival. Most cancers, including prostate cancers, express the M2 splice isoform of pyruvate kinase (Pkm2), which can support anabolic metabolism to support cell proliferation. However, Pkm2 expression is dispensable for the formation and growth of many cancers in vivo. Expression of pyruvate kinase isoform M1 (Pkm1) is restricted to relatively few tissues and has been reported to promote growth of select tumors, but the role of Pkm1 in cancer has been less studied than Pkm2. To test how differential expression of pyruvate kinase isoforms affects cancer initiation and progression, we generated mice harboring a conditional allele of Pkm1, and crossed these mice or those with a Pkm2 conditional allele with a Pten loss-driven prostate cancer model. Pkm1 loss led to increased Pkm2 expression and accelerated prostate cancer development, while Pkm2 deletion of led to increased Pkm1 expression and suppressed tumor progression. Metabolic profiling revealed altered nucleotide levels in tumors with high Pkm1 expression, and failure of these tumors to progress was associated with DNA replication stress and senescence. Consistent with these data, a small molecule pyruvate kinase activator that mimics a high activity Pkm1-like state suppressed progression of established prostate tumors. Analysis of human specimens showed PKM2 expression is retained in most human prostate cancers. Overall, this study uncovers a role for pyruvate kinase isoforms in prostate cancer initiation and progression, and argues that pharmacological pyruvate kinase activation may be beneficial for treating prostate cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-2352
  14. Hum Cell. 2022 May 18.
    KAT2A affects tumor metabolic reprogramming in colon cancer progression through epigenetic activation of E2F1.
    Xiaofeng Han, Jie Chen.
      Lysine acetyltransferase 2 A (KAT2A) has been implicated in tumorigenesis; nevertheless, the mechanism underlying its tumor-initiating effect remains elusive. In the present study, we aimed to identify the possible role of KAT2A in regulating metabolic reprogramming, a hallmark of cancer, in colon cancer (CC). KAT2A was found to be overexpressed in CC and correlated with metastases. KAT2A induced proliferation, migration, invasion, and epithelial-mesenchymal transition of CC cells, along with elevated cellular glycolytic capacity and mitochondrial stress. Functional enrichment analyses predicted and ChIP assays verified that KAT2A activated E2F transcription factor 1 (E2F1) by modifying the acetylation of H3K9. Rescue experiments revealed that E2F1 downregulation inhibited cellular activity, aerobic glycolysis and mitochondrial respiration in CC in the presence of KAT2A. Moreover, KAT2A/E2F1 promoted tumorigenic activity and lung metastases of CC cells in mice. Taken together, our findings demonstrate the substantial role of KAT2A in the modulation of post-translational modifications of E2F1 in CC, suggesting that knockdown of KAT2A may be a potential strategy for CC treatment.
    Keywords:  Colon cancer; E2F1; KAT2A; Metastases; The Warburg effect
    DOI:  https://doi.org/10.1007/s13577-022-00707-3
  15. Cell Death Differ. 2022 May 18.
    Apoptotic priming is defined by the dynamic exchange of Bcl-2 proteins between mitochondria and cytosol.
    Louise E King, Ricardo Rodriguez-Enriquez, Robert Pedley, Charlotte E L Mellor, Pengbo Wang, Egor Zindy, Michael R H White, Keith Brennan, Andrew P Gilmore.
      Apoptosis is regulated by interactions between the BH3-only and multi-domain Bcl-2 family proteins. These interactions are integrated on the outer mitochondrial membrane (OMM) where they set the threshold for apoptosis, known as mitochondrial priming. However, how mitochondrial priming is controlled at the level of single cells remains unclear. Retrotranslocation of Bcl-XL has been proposed as one mechanism, removing pro-apoptotic Bcl-2 proteins from the OMM, thus reducing priming. Contrary to this view, we now show that Bcl-XL retrotranslocation is inhibited by binding to its BH3-only partners, resulting in accumulation of these protein complexes on mitochondria. We find that Bcl-XL retrotranslocation dynamics are tightly coupled to mitochondrial priming. Quantifying these dynamics indicates the heterogeneity in priming between cells within a population and predicts how they subsequently respond to a pro-apoptotic signal.
    DOI:  https://doi.org/10.1038/s41418-022-01013-z
  16. Nat Commun. 2022 May 16. 13(1): 2698
    Purine nucleotide depletion prompts cell migration by stimulating the serine synthesis pathway.
    Mona Hoseini Soflaee, Rushendhiran Kesavan, Umakant Sahu, Alpaslan Tasdogan, Elodie Villa, Zied Djabari, Feng Cai, Diem H Tran, Hieu S Vu, Eunus S Ali, Halie Rion, Brendan P O'Hara, Sherwin Kelekar, James Hughes Hallett, Misty Martin, Thomas P Mathews, Peng Gao, John M Asara, Brendan D Manning, Issam Ben-Sahra, Gerta Hoxhaj.
      Purine nucleotides are necessary for various biological processes related to cell proliferation. Despite their importance in DNA and RNA synthesis, cellular signaling, and energy-dependent reactions, the impact of changes in cellular purine levels on cell physiology remains poorly understood. Here, we find that purine depletion stimulates cell migration, despite effective reduction in cell proliferation. Blocking purine synthesis triggers a shunt of glycolytic carbon into the serine synthesis pathway, which is required for the induction of cell migration upon purine depletion. The stimulation of cell migration upon a reduction in intracellular purines required one-carbon metabolism downstream of de novo serine synthesis. Decreased purine abundance and the subsequent increase in serine synthesis triggers an epithelial-mesenchymal transition (EMT) and, in cancer models, promotes metastatic colonization. Thus, reducing the available pool of intracellular purines re-routes metabolic flux from glycolysis into de novo serine synthesis, a metabolic change that stimulates a program of cell migration.
    DOI:  https://doi.org/10.1038/s41467-022-30362-z
  17. Nat Commun. 2022 May 19. 13(1): 2760
    Lipid droplet degradation by autophagy connects mitochondria metabolism to Prox1-driven expression of lymphatic genes and lymphangiogenesis.
    Odeta Meçe, Diede Houbaert, Maria-Livia Sassano, Tania Durré, Hannelore Maes, Marco Schaaf, Sanket More, Maarten Ganne, Melissa García-Caballero, Mila Borri, Jelle Verhoeven, Madhur Agrawal, Kathryn Jacobs, Gabriele Bergers, Silvia Blacher, Bart Ghesquière, Mieke Dewerchin, Johan V Swinnen, Stefan Vinckier, María S Soengas, Peter Carmeliet, Agnès Noël, Patrizia Agostinis.
      Autophagy has vasculoprotective roles, but whether and how it regulates lymphatic endothelial cells (LEC) homeostasis and lymphangiogenesis is unknown. Here, we show that genetic deficiency of autophagy in LEC impairs responses to VEGF-C and injury-driven corneal lymphangiogenesis. Autophagy loss in LEC compromises the expression of main effectors of LEC identity, like VEGFR3, affects mitochondrial dynamics and causes an accumulation of lipid droplets (LDs) in vitro and in vivo. When lipophagy is impaired, mitochondrial ATP production, fatty acid oxidation, acetyl-CoA/CoA ratio and expression of lymphangiogenic PROX1 target genes are dwindled. Enforcing mitochondria fusion by silencing dynamin-related-protein 1 (DRP1) in autophagy-deficient LEC fails to restore LDs turnover and lymphatic gene expression, whereas supplementing the fatty acid precursor acetate rescues VEGFR3 levels and signaling, and lymphangiogenesis in LEC-Atg5-/- mice. Our findings reveal that lipophagy in LEC by supporting FAO, preserves a mitochondrial-PROX1 gene expression circuit that safeguards LEC responsiveness to lymphangiogenic mediators and lymphangiogenesis.
    DOI:  https://doi.org/10.1038/s41467-022-30490-6
  18. Anal Methods. 2022 May 18.
    A mitochondria-targeted rhodol fluorescent probe for imaging of hydrogen peroxide in living cells.
    Linlin Lv, Weiwei Luo, Quanping Diao.
      Hydrogen peroxide (H2O2) is a main member of reactive oxygen species (ROS) in cells that has a significant impact on various physiological and pathological processes of organisms. Here, we designed and synthesized a new type of fluorescent probe Rhodol-OAc for the specific detection of H2O2. The probe had good water solubility, high selectivity and sensitivity to H2O2, low cytotoxicity, excellent mitochondrial targeting ability, etc. It was successfully applied in the imaging of exogenous and endogenous H2O2 in living cells. In addition, theoretical calculations were carried out to clarify the luminescence mechanism of the probe. More importantly, we successfully applied the probe to indirectly detect xanthine and glucose, the metabolism of which generates H2O2, and achieved satisfactory results.
    DOI:  https://doi.org/10.1039/d2ay00522k
  19. Biochim Biophys Acta Bioenerg. 2022 May 14. pii: S0005-2728(22)00038-X. [Epub ahead of print]1863(6): 148569
    Beyond being an energy supplier, ATP synthase is a sculptor of mitochondrial cristae.
    Héctor Miranda-Astudillo, Marcos Ostolga-Chavarría, Pierre Cardol, Diego González-Halphen.
      Mitochondrial F1FO-ATP synthase plays a key role in cellular bioenergetics; this enzyme is present in all eukaryotic linages except in amitochondriate organisms. Despite its ancestral origin, traceable to the alpha proteobacterial endosymbiotic event, the actual structural diversity of these complexes, due to large differences in their polypeptide composition, reflects an important evolutionary divergence between eukaryotic lineages. We discuss the effect of these structural differences on the oligomerization of the complex and the shape of mitochondrial cristae.
    Keywords:  ATP synthase; F(1)-F(O) ATPase; Lineage-specific subunits; Mitochondrial ATPase
    DOI:  https://doi.org/10.1016/j.bbabio.2022.148569
  20. Autophagy. 2022 May 19. 1-2
    SQSTM1 and its MAP1LC3B-binding domain induce forced mitophagy to degrade mitochondrial carryover during mitochondrial replacement therapy.
    Xiao-Yan Fan, Shen Yin, Shi-Ming Luo.
      Mitophagy is a process that selectively degrades mitochondria in cells, and it involves a series of signaling events. Our recent paper shows that the ectopic expression of SQSTM1 and its MAP1LC3B-binding domain (Binding) at the mitochondrial outer membrane, can directly cause mitophagy. To distinguish this mitophagy from others, we called it forced mitophagy. Further results show that the forced mitophagy can degrade half of the mitochondria and their DNA in HeLa cells and mouse embryos. Meanwhile, there are no apparent effects on mitochondrial membrane potential (MMP), reactive oxygen species (ROS), mitosis and embryo development. Thus, the forced mitophagy was examined to selectively degrade mitochondrial carryover in the nuclear donor embryos' mitochondria by pre-labeling with Binding before mitochondrial replacement therapy (MRT). The results show that the forced mitophagy can reduce mitochondrial carryover from an average of 4% to 0.09% compared to the controls in mouse embryos and tissues. In addition, the offspring from MRT mice show negligible effects on growth, reproduction, exercise and behavior. Furthermore, results from human tri-pronuclear embryos show that the forced mitophagy results in undetectable mitochondrial carryover in 77% of embryos following MRT. Therefore, forced mitophagy is efficient and safe for degrading mitochondrial carryover in MRT.
    Keywords:  Forced mitophagy; NIX; SQSTM1; mitochondrial carryover; mitochondrial replacement therapy
    DOI:  https://doi.org/10.1080/15548627.2022.2077552
  21. Sci Adv. 2022 May 20. 8(20): eabm8786
    Suppression of nuclear GSK3 signaling promotes serine/one-carbon metabolism and confers metabolic vulnerability in lung cancer cells.
    Long He, Jennifer Endress, Sungyun Cho, Zhongchi Li, Yuxiang Zheng, John M Asara, John Blenis.
      Serine/one-carbon metabolism provides critical resources for nucleotide biosynthesis and epigenetic maintenance and is thus necessary in cancer cell growth, although the detailed regulatory mechanisms remain unclear. We uncover a critical role of glycogen synthase kinase 3 (GSK3) in regulating the expression of serine/one-carbon metabolic enzymes. Nuclear enrichment of GSK3 significantly suppresses genes that mediate de novo serine synthesis, including PHGDH, PSAT1, PSPH, and one-carbon metabolism, including SHMT2 and MTHFD2. FRAT1 promotes nuclear exclusion of GSK3, enhances serine/one-carbon metabolism, and, as a result, confers cell vulnerability to inhibitors that target this metabolic process such as SHIN1, a specific SHMT1/2 inhibitor. Furthermore, pharmacological or genetic suppression of GSK3 promotes serine/one-carbon metabolism and exhibits a significant synergistic effect in combination with SHIN1 in suppressing cancer cell proliferation in cultured cells and in vivo. Our observations indicate that inhibition of nuclear GSK3 signaling creates a vulnerability, which results in enhanced efficacy of serine/one-carbon metabolism inhibitors for the treatment of cancer.
    DOI:  https://doi.org/10.1126/sciadv.abm8786
  22. Redox Biol. 2022 May 13. pii: S2213-2317(22)00101-X. [Epub ahead of print]53 102329
    HuR-dependent SOD2 protein synthesis is an early adaptation to anchorage-independence.
    Yeon Soo Kim, Priscilla W Tang, Jaclyn E Welles, Weihua Pan, Zaineb Javed, Amal Taher Elhaw, Karthikeyan Mythreye, Scot R Kimball, Nadine Hempel.
      During metastasis cancer cells must adapt to survive loss of anchorage and evade anoikis. An important pro-survival adaptation is the ability of metastatic tumor cells to increase their antioxidant capacity and restore cellular redox balance. Although much is known about the transcriptional regulation of antioxidant enzymes in response to stress, how cells acutely adapt to alter antioxidant enzyme levels is less well understood. Using ovarian cancer cells as a model, we demonstrate that an increase in mitochondrial superoxide dismutase SOD2 protein expression is a very early event initiated in response to detachment, an important step during metastasis that has been associated with increased oxidative stress. SOD2 protein synthesis is rapidly induced within 0.5-2 h of matrix detachment, and polyribosome profiling demonstrates an increase in the number of ribosomes bound to SOD2 mRNA, indicating an increase in SOD2 mRNA translation in response to anchorage-independence. Mechanistically, we find that anchorage-independence induces cytosolic accumulation of the RNA binding protein HuR/ELAVL1 and promotes HuR binding to SOD2 mRNA. Using HuR siRNA-mediated knockdown, we show that the presence of HuR is necessary for the increase in SOD2 mRNA association with the heavy polyribosome fraction and consequent nascent SOD2 protein synthesis in anchorage-independence. Cellular detachment also activates the stress-response mitogen-activated kinase p38, which is necessary for HuR-SOD2 mRNA interactions and induction of SOD2 protein output. These findings illustrate a novel translational regulatory mechanism of SOD2 by which ovarian cancer cells rapidly increase their mitochondrial antioxidant capacity as an acute stress response to anchorage-independence.
    DOI:  https://doi.org/10.1016/j.redox.2022.102329
  23. NAR Genom Bioinform. 2022 Jun;4(2): lqac034
    A bioinformatics pipeline for estimating mitochondrial DNA copy number and heteroplasmy levels from whole genome sequencing data.
    TOPMed mtDNA Working Group
      Mitochondrial diseases are a heterogeneous group of disorders that can be caused by mutations in the nuclear or mitochondrial genome. Mitochondrial DNA (mtDNA) variants may exist in a state of heteroplasmy, where a percentage of DNA molecules harbor a variant, or homoplasmy, where all DNA molecules have the same variant. The relative quantity of mtDNA in a cell, or copy number (mtDNA-CN), is associated with mitochondrial function, human disease, and mortality. To facilitate accurate identification of heteroplasmy and quantify mtDNA-CN, we built a bioinformatics pipeline that takes whole genome sequencing data and outputs mitochondrial variants, and mtDNA-CN. We incorporate variant annotations to facilitate determination of variant significance. Our pipeline yields uniform coverage by remapping to a circularized chrM and by recovering reads falsely mapped to nuclear-encoded mitochondrial sequences. Notably, we construct a consensus chrM sequence for each sample and recall heteroplasmy against the sample's unique mitochondrial genome. We observe an approximately 3-fold increased association with age for heteroplasmic variants in non-homopolymer regions and, are better able to capture genetic variation in the D-loop of chrM compared to existing software. Our bioinformatics pipeline more accurately captures features of mitochondrial genetics than existing pipelines that are important in understanding how mitochondrial dysfunction contributes to disease.
    DOI:  https://doi.org/10.1093/nargab/lqac034
  24. Cancer Drug Resist. 2021 ;4(2): 503-511
    UCP2 - Taking the heat out of P-glycoprotein?
    Richard Callaghan, Mary Board.
      Cancer cells are highly proliferative, invasive, metastatic and initiate angiogenesis. These activities demand plentiful energy and bountiful stores of anabolic precursors, a situation that puts significant strain on metabolic pathways and necessitates juggling of finite resources. However, the location and erratic structural organisation of tumours means they reside in a nutrient-poor environment. The glycolytic phenotype has evolved in cancer cells to provide a suitable balance between bioenergetic and biosynthetic pathways. Does this adopted strategy also support the overexpression of an ATP-dependent transporter (P-glycoprotein) to maintain resistance against chemotherapy? This article highlights the metabolic adaptations used by cancer cells to maintain both a glycolytic phenotype and sustain the activity of P-glycoprotein. We argue that these cells negotiate an energy precipice to achieve these adaptations. Finally, we advocate the use of compounds that place resistant cells expressing P-glycoprotein under further metabolic strain and how uncoupling protein-2 may provide an ideal target for them.
    Keywords:  P-glycoprotein; chemotherapy; collateral sensitivity; glycolytic phenotype; mitochondria; multidrug resistance; uncoupling protein
    DOI:  https://doi.org/10.20517/cdr.2020.105
  25. Cell Biosci. 2022 May 19. 12(1): 66
    Mitochondrial transfer/transplantation: an emerging therapeutic approach for multiple diseases.
    Zonghan Liu, Yi Sun, Zhengtang Qi, Lu Cao, Shuzhe Ding.
      Mitochondria play a pivotal role in energy generation and cellular physiological processes. These organelles are highly dynamic, constantly changing their morphology, cellular location, and distribution in response to cellular stress. In recent years, the phenomenon of mitochondrial transfer has attracted significant attention and interest from biologists and medical investigators. Intercellular mitochondrial transfer occurs in different ways, including tunnelling nanotubes (TNTs), extracellular vesicles (EVs), and gap junction channels (GJCs). According to research on intercellular mitochondrial transfer in physiological and pathological environments, mitochondrial transfer hold great potential for maintaining body homeostasis and regulating pathological processes. Multiple research groups have developed artificial mitochondrial transfer/transplantation (AMT/T) methods that transfer healthy mitochondria into damaged cells and recover cellular function. This paper reviews intercellular spontaneous mitochondrial transfer modes, mechanisms, and the latest methods of AMT/T. Furthermore, potential application value and mechanism of AMT/T in disease treatment are also discussed.
    Keywords:  Ageing; Cancer therapy; Energy metabolism; Mitochondrial transfer; Mitochondrial transplantation; Stem cell; Tissue injury; mtDNA mutations and deletions
    DOI:  https://doi.org/10.1186/s13578-022-00805-7
  26. Cancer Lett. 2022 May 17. pii: S0304-3835(22)00222-1. [Epub ahead of print] 215738
    Low expression of PGC-1β and other mitochondrial biogenesis modulators in melanoma is associated with growth arrest and the induction of an immunosuppressive gene expression program dependent on MEK and IRF-1.
    Karl M Laurin, Katherine Coutu-Beaudry, Alejandro Salazar, Nour Méribout, Étienne Audet-Walsh, Simon-Pierre Gravel.
      Mitochondria are specialized metabolic and immune organelles that have important roles in tumor progression, metastasis, and response to chemotherapy and immunotherapy. Mitochondrial biogenesis and function are under the control of the peroxisome-proliferator activated receptor-gamma (PGC-1) transcriptional coactivators. Recent research unveiled the role of PGC-1α in bolstering mitochondrial oxidative functions and in the suppression of metastasis in melanoma, but the role of PGC-1s in tumor immunology remains elusive. Herein, we show that low PGC-1s expression in human melanoma tumors is associated with increased expression of a repertoire of immunosuppressive (CD73, PD-L2, Galectin-9) and pro-inflammatory (IL-8, TNF, IL-1β) transcripts, and that experimental depletion of PGC-1β recapitulates this signature in human melanoma cell lines. The depletion of PGC-1β reduces the expression of HSPA9, impairs mitochondrial activity, and leads to cell cycle arrest. Using pharmacological and gene silencing approaches, we further show that MEK1/2 and IRF-1 mediate the observed immune transcriptional response. Overall, this research suggests that mitochondrial biogenesis modulators can modulate tumor progression, immune evasion, and response to therapeutics through transcriptional control of immune pathways.
    Keywords:  Immunosuppression; Inflammation; Melanoma; Mitochondria; Transcription
    DOI:  https://doi.org/10.1016/j.canlet.2022.215738
  27. Science. 2022 May 20. 376(6595): 794-795
    Mitochondrial complex complexification.
    Martijn A Huynen, Dei M Elurbe.
      Variation in complex composition provides clues about the function of individual subunits.
    DOI:  https://doi.org/10.1126/science.abq0368
  28. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac045
    Mitochondrial 1555 G>A variant as a potential risk factor for childhood glioblastoma.
    Shaobo Li, Xiaowu Gai, Swe Swe Myint, Katti Arroyo, Libby Morimoto, Catherine Metayer, Adam J de Smith, Kyle M Walsh, Joseph L Wiemels.
      Background: Childhood glioblastoma multiforme (GBM) is a highly aggressive disease with low survival, and its etiology, especially concerning germline genetic risk, is poorly understood. Mitochondria play a key role in putative tumorigenic processes relating to cellular oxidative metabolism, and mitochondrial DNA variants were not previously assessed for association with pediatric brain tumor risk.Methods: We conducted an analysis of 675 mitochondrial DNA variants in 90 childhood GBM cases and 2789 controls to identify enrichment of mitochondrial variant associated with GBM risk. We also performed this analysis for other glioma subtypes including pilocytic astrocytoma. Nuclear-encoded mitochondrial gene variants were also analyzed.
    Results: We identified m1555 A>G was significantly associated with GBM risk (adjusted OR 29.30, 95% CI 5.25-163.4, P-value 9.5 X 10-4). No association was detected for other subtypes. Haplotype analysis further supported the independent risk contributed by m1555 G>A, instead of a haplogroup joint effect. Nuclear-encoded mitochondrial gene variants identified significant associations in European (rs62036057 in WWOX, adjusted OR = 2.99, 95% CI 1.88-4.75, P-value = 3.42 X 10-6) and Hispanic (rs111709726 in EFHD1, adjusted OR = 3.57, 95% CI 1.99-6.40, P-value = 1.41 X 10-6) populations in ethnicity-stratified analyses.
    Conclusion: We report for the first time a potential role played by a functional mitochondrial ribosomal RNA variant in childhood GBM risk, and a potential role for both mitochondrial and nuclear-mitochondrial DNA polymorphisms in GBM tumorigenesis. These data implicate cellular oxidative metabolic capacity as a contributor to the etiology of pediatric glioblastoma.
    Keywords:  mitochondrial genome; pediatric glioblastoma; risk factor; variant
    DOI:  https://doi.org/10.1093/noajnl/vdac045
  29. Nature. 2022 May 18.
    Metabolic diversity drives cancer cell invasion.
    Sanjeethan C Baksh, Lydia W S Finley.
      
    Keywords:  Cancer; Medical research; Metabolism
    DOI:  https://doi.org/10.1038/d41586-022-01301-1
  30. Med (N Y). 2022 Feb 11. pii: S2666-6340(22)00040-X. [Epub ahead of print]3(2): 87-89
    Ketotherapy: Cutting carbs to treat cancer.
    Megan D Radyk, Samuel A Kerk, Costas A Lyssiotis.
      Dietary interventions hold promise in cancer treatments. However, clinical application has been limited by a lack of mechanistic understanding of the metabolic effects. In this issue, Yang et al. use mouse models and isotope tracing to demonstrate that the ketogenic diet induces reductive stress and primes pancreatic tumors for chemotherapy.1.
    DOI:  https://doi.org/10.1016/j.medj.2022.01.005
  31. Acta Biochim Biophys Sin (Shanghai). 2022 Mar 25.
    DDR1 promotes LoVo cell proliferation by regulating energy metabolism.
    Bin Xiong, Zehui Xie, Feixue Song, Huiling Chen, Xiaojuan Wang, Zhengxu Jin, Tiyun Han, Yi Li, Dekui Zhang.
      Cellular energy metabolism dysregulation is associated with colorectal cancer (CRC) development and progression. Discoidin domain receptor1a (DDR1a), one of the five DDR1 isoforms, is closely related to cell proliferation, invasion, and apoptosis in various tumors. Whether it participates in cellular metabolic reprogramming and regulates CRC initiation and progression remains unclear. In this study, we compared the expression of DDR1 in CRC tissues and adjacent tissues from 126 postoperative CRC samples. Moreover, lentivirus-mediated DDR1a overexpression and knockdown were performed in LoVo cells, and cell viability and proliferation were determined by CCK-8 and BrdU assays, respectively. Oxygen consumption rate, extracellular acidification rate, and lactate production were used to determine the effect of DDR1a on metabolic reprogramming. Clinically, CRC patients with high DDR1 expression had poor differentiation and were at an advanced TNM stage. DDR1a promoted LoVo cell proliferation, mitochondrial function, and extracellular acidification. Moreover, DDR1a knockdown inhibited intracellular lactic acid production in LoVo cells, while a pyruvate kinase inhibitor (diamide, significantly reversed this progression. Taken together, our results reveal that DDR1 plays a crucial role in maintaining intracellular environment homeostasis through metabolic reprogramming.
    Keywords:  DDR1a; Warburg effect; colorectal cancer; lactic acid; proliferation
    DOI:  https://doi.org/10.3724/abbs.2022038
  32. Cell Death Dis. 2022 May 18. 13(5): 469
    AK2 is an AMP-sensing negative regulator of BRAF in tumorigenesis.
    Hyunjoo Kim, Muhah Jeong, Do-Hyeong Na, Shin-Hyeon Ryu, Eun Il Jeong, Kwangmin Jung, Jaemin Kang, Ho-June Lee, Taebo Sim, Dae-Yeul Yu, Hee Chul Yu, Baik-Hwan Cho, Yong-Keun Jung.
      The RAS-BRAF signaling is a major pathway of cell proliferation and their mutations are frequently found in human cancers. Adenylate kinase 2 (AK2), which modulates balance of adenine nucleotide pool, has been implicated in cell death and cell proliferation independently of its enzyme activity. Recently, the role of AK2 in tumorigenesis was in part elucidated in some cancer types including lung adenocarcinoma and breast cancer, but the underlying mechanism is not clear. Here, we show that AK2 is a BRAF-suppressor. In in vitro assays and cell model, AK2 interacted with BRAF and inhibited BRAF activity and downstream ERK phosphorylation. Energy-deprived conditions in cell model and the addition of AMP to cell lysates strengthened the AK2-BRAF interaction, suggesting that AK2 is involved in the regulation of BRAF activity in response to cell metabolic state. AMP facilitated the AK2-BRAF complex formation through binding to AK2. In a panel of HCC cell lines, AK2 expression was inversely correlated with ERK/MAPK activation, and AK2-knockdown or -knockout increased BRAF activity and promoted cell proliferation. Tumors from HCC patients showed low-AK2 protein expression and increased ERK activation compared to non-tumor tissues and the downregulation of AK2 was also verified by two microarray datasets (TCGA-LIHC and GSE14520). Moreover, AK2/BRAF interaction was abrogated by RAS activation in in vitro assay and cell model and in a mouse model of HRASG12V-driven HCC, and AK2 ablation promoted tumor growth and BRAF activity. AK2 also bound to BRAF inhibitor-insensitive BRAF mutants and attenuated their activities. These findings indicate that AK2 monitoring cellular AMP levels is indeed a negative regulator of BRAF, linking the metabolic status to tumor growth.
    DOI:  https://doi.org/10.1038/s41419-022-04921-7
  33. Anticancer Agents Med Chem. 2022 May 13.
    The Glutaminase Inhibitor Compound 968 Exhibits Potent in vitro and in vivo Anti-tumor Effects in Endometrial Cancer.
    Hui Guo, Wanhu Li, Guoyou Pan, Cong Wang, Dapeng Li, Naifu Liu, Xiugui Sheng, Lingqin Yuan.
      BACKGROUND: Glutamine is one of the primary nutrients utilized by cancer cells for energy production and biosynthesis. Hence, interfering with glutamine metabolism may impose anti-tumor effects.OBJECTIVE: In this study, we assessed the anti-tumorigenic effects of glutaminase-1 enzyme (GLS1) inhibition in endometrial cancer in vitro and in vivo.
    METHODS: The human endometrial cancer cell lines Ishikawa and HEC-1B were used. The effects of compound 968 on cell proliferation, cell cycle, apoptosis, cellular stress, and AKT/mTOR pathway inhibition were assessed. The synergistic effects of compound 968 and paclitaxel was also analyzed. The in vivo effect of compound 968 was evaluated using tumor xenografts.
    RESULTS: We found that the GLS1-targeting compound 968 was able to reduce cancer cell proliferation in a dose- and time-dependent manner. Compound 968 combined with low concentration of paclitaxel showed stronger inhibitory effects. Further analyses indicated that compound 968 induced cell cycle arrest at the G1 phase, as well as increased the production of cellular reactive oxygen species (ROS) and promoted cellular stress and cancer cell apoptosis. Additionally, the treatment of endometrial cancer with compound 968 downregulated the expression of GLS1 and cyclin D1, and upregulated the expression of P21 and E-cadherin. Moreover, the treatment of endometrial cancer cells with compound 968 significantly reduced levels of phospho-S6 ribosomal protein and phospho-AKT (Ser473), indicative of AKT/mTOR/S6 signaling pathway inhibition. In xenograft mouse models of endometrial cancer, compound 968 significantly suppressed tumor growth. In addition, western blotting analysis indicated that GLS1 expression was upregulated in human endometrial cancer tissues.
    CONCLUSION: Compound 968 may be a promising approach for the management of human endometrial cancer.
    Keywords:  Compound 968; Endometrial cancer; Glutaminase-1 enzyme (GLS1); Glutamine; Inhibitor; phospho-S6
    DOI:  https://doi.org/10.2174/1871520622666220513163341
  34. Pathol Res Pract. 2022 May 11. pii: S0344-0338(22)00187-X. [Epub ahead of print]235 153943
    SIRT5 is involved in the proliferation and metastasis of breast cancer by promoting aerobic glycolysis.
    Shuai He, Qingge Jia, Lei Zhou, Zhe Wang, Mingyang Li.
      OBJECTIVE: Breast cancer (BC) is the most commonly diagnosed cancer among females and has a poor prognosis, breast invasive ductal carcinoma is the most common histological type. The occurrence and development of BC is closely related to aberrant glucose metabolism. In the hyperglycemic environment caused by abnormal glucose metabolism, hypoxia-inducible factor-1 alpha (HIF-1α) enables tumor cells to absorb large amounts of glucose and enhance glycolysis by inducing the expression of glucose transporter type1 (GLUT1) and glycolysis genes, thus promoting tumor cell proliferation and metastasis. Mitochondrial Sirtuin5 (SIRT5) plays a role in the rewiring of glucose metabolism during the progression of cancers. Thus, we aimed to elucidate whether SIRT5 promotes BC proliferation and metastasis by facilitating aerobic glycolysis in BC.METHODS: The expression of SIRT5 in breast carcinoma tissue and cells was evaluated using immunohistochemical staining, western blot and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis to confirm the biological role of SIRT5 in breast carcinoma. We established a stable cell line with SIRT5 knockdown using lentiviral transduction in T47D cells to reduce SIRT5 expression and then evaluated the effect of SIRT5 on cells cultured in the presence of high glucose (4500 mg/L) and normal glucose (2000 mg/L) concentrations. Cell proliferation was detected using the CCK-8 assay, the cell cycle and cell apoptosis were measured using flow cytometry and Annexin V staining, and cell migration was tested by performing Celigo scratch and Transwell assays. The expression of PKM2, HK2, mTOR and HIF-1α, which play roles in aerobic glycolysis, was investigated using western blot.
    RESULTS: SIRT5 was overexpressed in BC tissues compared with paired normal tissues. Prognostic and OS analyses showed that the SIRT5 expression level was an individual prognostic factor for patients with BC. SIRT5 knockdown inhibited proliferation and metastasis and slightly increased apoptosis in T47D cells under high-glucose conditions. Furthermore, the downregulation of HK2 and HIF-1α caused by SIRT5 knockdown was a high glucose-dependent process, while the downregulation of PKM2 was mediated by a high glucose-independent process.
    CONCLUSIONS: SIRT5 is an independent prognostic factor for BC and contributes to cell proliferation and metastasis in a high glucose-dependent manner to some degree, which might be mediated by promoting aerobic glycolysis.
    Keywords:  Aerobic glycolysis; BC; HK2; PKM2; SIRT5
    DOI:  https://doi.org/10.1016/j.prp.2022.153943
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