bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2022‒04‒03
23 papers selected by
Kelsey Fisher-Wellman
East Carolina University
  1. Partial inhibition of mitochondrial-linked pyrimidine synthesis increases tumorigenic potential and lysosome accumulation.
  2. Mitochondrial ROS signalling requires uninterrupted electron flow and is lost during ageing in flies.
  3. Palmitoylation of MDH2 by ZDHHC18 activates mitochondrial respiration and accelerates ovarian cancer growth.
  4. PGC-1α induced mitochondrial biogenesis in stromal cells underpins mitochondrial transfer to melanoma.
  5. Targeting Mitochondrial Proteases for Therapy of Acute Myeloid Leukemia.
  6. Redox proteome analysis of auranofin exposed ovarian cancer cells (A2780).
  7. An In Vitro Approach to Study Mitochondrial Dysfunction: A Cybrid Model.
  8. Phase II trial of cytarabine and mitoxantrone with devimistat in acute myeloid leukemia.
  9. Inositol hexakisphosphate kinase-2 non-catalytically regulates mitophagy by attenuating PINK1 signaling.
  10. Docking and molecular simulations reveal a quinone binding site on the surface of respiratory complex I.
  11. Structures of Tetrahymena's respiratory chain reveal the diversity of eukaryotic core metabolism.
  12. Photocontrollable Probes for Mitochondrial Protein Profiling.
  13. Deacetylation of MTHFD2 by SIRT4 senses stress signal to inhibit cancer cell growth by remodeling folate metabolism.
  14. Time to Target Mitochondrial Reactive Oxygen Species Generation from Complex I.
  15. Rewiring mitochondrial metabolism to counteract exhaustion of CAR-T cells.
  16. A novel isoform of hydroxyacyl-CoA dehydrogenase inhibits cell proliferation.
  17. Simultaneous targeting of mitochondrial metabolism and immune checkpoints as a new strategy for renal cancer therapy.
  18. Context-specific effects of NOX4 inactivation in acute myeloid leukemia (AML).
  19. Exercise suppresses tumor growth independent of high fat food intake and associated immune dysfunction.
  20. Altered propionate metabolism contributes to tumour progression and aggressiveness.
  21. Bone Marrow Mononuclear Cells Restore Normal Mitochondrial Ca2+ Handling and Ca2+-Induced Depolarization of the Internal Mitochondrial Membrane by Inhibiting the Permeability Transition Pore After Ischemia/Reperfusion.
  22. Identification of a Mitochondria-Related Gene Signature to Predict the Prognosis in AML.
  23. IL-6 promotes chemoresistance via upregulating CD36 mediated fatty acids uptake in acute myeloid leukemia.
  1. Mitochondrion. 2022 Mar 25. pii: S1567-7249(22)00025-3. [Epub ahead of print]64 73-81
    Partial inhibition of mitochondrial-linked pyrimidine synthesis increases tumorigenic potential and lysosome accumulation.
    Claus Desler, Jon Ambæk Durhuus, Thomas Lau-Lindestrand Hansen, Sharath Anugula, Nadia Thaulov Zelander, Sisse Bøggild, Lene Juel Rasmussen.
      The correlation between mitochondrial function and oncogenesis is complex and is not fully understood. Here we determine the importance of mitochondrial-linked pyrimidine synthesis for the aggressiveness of cancer cells. The enzyme dihydroorotate dehydrogenase (DHODH) links oxidative phosphorylation to de novo synthesis of pyrimidines. We demonstrate that an inhibition of DHODH results in a respiration-independent significant increase of anchorage-independent growth but does not affect DNA repair ability. Instead, we show an autophagy-independent increase of lysosomes. The results of this study suggest that inhibition of mitochondrial-linked pyrimidine synthesis in cancer cells results in a more aggressive tumor phenotype.
    Keywords:  DNA repair; Lysosome increase; Mitochondria; Mitochondrial-linked pyrimidine synthesis; Tumorigenesis
    DOI:  https://doi.org/10.1016/j.mito.2022.03.005
  2. Geroscience. 2022 Mar 30.
    Mitochondrial ROS signalling requires uninterrupted electron flow and is lost during ageing in flies.
    Charlotte Graham, Rhoda Stefanatos, Angeline E H Yek, Ruth V Spriggs, Samantha H Y Loh, Alejandro Huerta Uribe, Tong Zhang, L Miguel Martins, Oliver D K Maddocks, Filippo Scialo, Alberto Sanz.
      Mitochondrial reactive oxygen species (mtROS) are cellular messengers essential for cellular homeostasis. In response to stress, reverse electron transport (RET) through respiratory complex I generates high levels of mtROS. Suppression of ROS production via RET (ROS-RET) reduces survival under stress, while activation of ROS-RET extends lifespan in basal conditions. Here, we demonstrate that ROS-RET signalling requires increased electron entry and uninterrupted electron flow through the electron transport chain (ETC). We find that in old fruit flies, ROS-RET is abolished when electron flux is decreased and that their mitochondria produce consistently high levels of mtROS. Finally, we demonstrate that in young flies, limiting electron exit, but not entry, from the ETC phenocopies mtROS generation observed in old individuals. Our results elucidate the mechanism by which ROS signalling is lost during ageing.
    Keywords:  Ageing; Complex I; Complex IV; Drosophila; Mitochondria; Reactive oxygen species; Reverse electron transport
    DOI:  https://doi.org/10.1007/s11357-022-00555-x
  3. Sci China Life Sci. 2022 Mar 25.
    Palmitoylation of MDH2 by ZDHHC18 activates mitochondrial respiration and accelerates ovarian cancer growth.
    Xuan Pei, Kai-Yue Li, Yuan Shen, Jin-Tao Li, Ming-Zhu Lei, Cai-Yun Fang, Hao-Jie Lu, Hui-Juan Yang, Wenyu Wen, Miao Yin, Jia Qu, Qun-Ying Lei.
      Epithelial ovarian cancer (EOC) exhibits strong dependency on the tricarboxylic acid (TCA) cycle and oxidative phosphorylation to fuel anabolic process. Here, we show that malate dehydrogenase 2 (MDH2), a key enzyme of the TCA cycle, is palmitoylated at cysteine 138 (C138) residue, resulting in increased activity of MDH2. We next identify that ZDHHC18 acts as a palmitoyltransferase of MDH2. Glutamine deprivation enhances MDH2 palmitoylation by increasing the binding between ZDHHC18 and MDH2. MDH2 silencing represses mitochondrial respiration as well as ovarian cancer cell proliferation both in vitro and in vivo. Intriguingly, re-expression of wild-type MDH2, but not its palmitoylation-deficient C138S mutant, sustains mitochondrial respiration and restores the growth as well as clonogenic capability of ovarian cancer cells. Notably, MDH2 palmitoylation level is elevated in clinical cancer samples from patients with high-grade serous ovarian cancer. These observations suggest that MDH2 palmitoylation catalyzed by ZDHHC18 sustains mitochondrial respiration and promotes the malignancy of ovarian cancer, yielding possibilities of targeting ZDHHC18-mediated MDH2 palmitoylation in the treatment of EOC.
    Keywords:  EOC; MDH2; ZDHHC18; cysteine palmitoylation; glutamine
    DOI:  https://doi.org/10.1007/s11427-021-2048-2
  4. Br J Cancer. 2022 Mar 26.
    PGC-1α induced mitochondrial biogenesis in stromal cells underpins mitochondrial transfer to melanoma.
    Prakrit R Kumar, Mona Saad, Charlotte Hellmich, Jayna J Mistry, Jamie A Moore, Shannon Conway, Christopher J Morris, Kristian M Bowles, Marc D Moncrieff, Stuart A Rushworth.
      INTRODUCTION: Progress in the knowledge of metabolic interactions between cancer and its microenvironment is ongoing and may lead to novel therapeutic approaches. Until recently, melanoma was considered a glycolytic tumour due to mutations in mitochondrial-DNA, however, these malignant cells can regain OXPHOS capacity via the transfer of mitochondrial-DNA, a process that supports their proliferation in-vitro and in-vivo. Here we study how melanoma cells acquire mitochondria and how this process is facilitated from the tumour microenvironment.METHODS: Primary melanoma cells, and MSCs derived from patients were obtained. Genes' expression and DNA quantification was analysed using Real-time PCR. MSC migration, melanoma proliferation and tumour volume, in a xenograft subcutaneous mouse model, were monitored through bioluminescent live animal imaging.
    RESULTS: Human melanoma cells attract bone marrow-derived stromal cells (MSCs) to the primary tumour site where they stimulate mitochondrial biogenesis in the MSCs through upregulation of PGC1a. Mitochondria are transferred to the melanoma cells via direct contact with the MSCs. Moreover, inhibition of MSC-derived PGC1a was able to prevent mitochondrial transfer and improve NSG melanoma mouse tumour burden.
    CONCLUSION: MSC mitochondrial biogenesis stimulated by melanoma cells is prerequisite for mitochondrial transfer and subsequent tumour growth, where targeting this pathway may provide an effective novel therapeutic approach in melanoma.
    DOI:  https://doi.org/10.1038/s41416-022-01783-w
  5. Br J Pharmacol. 2022 Mar 30.
    Targeting Mitochondrial Proteases for Therapy of Acute Myeloid Leukemia.
    Xinrong Xiang, Rui Bao, Yu Wu, Youfu Luo.
      Targeting cancer metabolism has emerged as an attractive approach to improve therapeutic regimens in acute myeloid leukemia (AML). Mitochondrial proteases are closely related to cancer metabolism, but their biological functions have not been well characterized in AML. According to different catogory, we comprehensively reviewed the role of mitochondrial proteases in AML. This review highlights some 'powerful' mitochondrial protease targets, including their biological function, chemical modulators, and applicative prospect in AML.
    Keywords:  acute myeloid leukemia; mitochondrial metabolism; mitochondrial proteases; oxidative phosphorylation
    DOI:  https://doi.org/10.1111/bph.15844
  6. Redox Biol. 2022 Mar 22. pii: S2213-2317(22)00066-0. [Epub ahead of print]52 102294
    Redox proteome analysis of auranofin exposed ovarian cancer cells (A2780).
    Giovanni Chiappetta, Tania Gamberi, Fiorella Faienza, Xhesika Limaj, Salvatore Rizza, Luigi Messori, Giuseppe Filomeni, Alessandra Modesti, Joelle Vinh.
      The effects of Auranofin (AF) on protein expression and protein oxidation in A2780 cancer cells were investigated through a strategy based on simultaneous expression proteomics and redox proteomics determinations. Bioinformatics analysis of the proteomics data supports the view that the most critical cellular changes elicited by AF treatment consist of thioredoxin reductase inhibition, alteration of the cell redox state, impairment of the mitochondrial functions, metabolic changes associated with conversion to a glycolytic phenotype, induction of ER stress. The occurrence of the above cellular changes was extensively validated by performing direct biochemical assays. Our data are consistent with the concept that AF produces its effects through a multitarget mechanism that mainly affects the redox metabolism and the mitochondrial functions and results into severe ER stress. Results are discussed in the context of the current mechanistic knowledge existing on AF.
    Keywords:  Auranofin; Cysteine; Gold drugs; Ovarian cancer; Redox proteomics
    DOI:  https://doi.org/10.1016/j.redox.2022.102294
  7. J Vis Exp. 2022 Mar 09.
    An In Vitro Approach to Study Mitochondrial Dysfunction: A Cybrid Model.
    Andrea Cavaliere, Silvia Marchet, Ivano Di Meo, Valeria Tiranti.
      Deficiency of the mitochondrial respiratory chain complexes that carry out oxidative phosphorylation (OXPHOS) is the biochemical marker of human mitochondrial disorders. From a genetic point of view, the OXPHOS represents a unique example because it results from the complementation of two distinct genetic systems: nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). Therefore, OXPHOS defects can be due to mutations affecting nuclear and mitochondrial encoded genes. The groundbreaking work by King and Attardi, published in 1989, showed that human cell lines depleted of mtDNA (named rho0) could be repopulated by exogenous mitochondria to obtain the so-called "transmitochondrial cybrids." Thanks to these cybrids containing mitochondria derived from patients with mitochondrial disorders (MDs) and nuclei from rho0 cells, it is possible to verify whether a defect is mtDNA- or nDNA-related. These cybrids are also a powerful tool to validate the pathogenicity of a mutation and study its impact at a biochemical level. This paper presents a detailed protocol describing cybrid generation, selection, and characterization.
    DOI:  https://doi.org/10.3791/63452
  8. Nat Commun. 2022 Mar 30. 13(1): 1673
    Phase II trial of cytarabine and mitoxantrone with devimistat in acute myeloid leukemia.
    Rebecca Anderson, Lance D Miller, Scott Isom, Jeff W Chou, Kristin M Pladna, Nathaniel J Schramm, Leslie R Ellis, Dianna S Howard, Rupali R Bhave, Megan Manuel, Sarah Dralle, Susan Lyerly, Bayard L Powell, Timothy S Pardee.
      Devimistat is a TCA cycle inhibitor. A previously completed phase I study of devimistat in combination with cytarabine and mitoxantrone in patients with relapsed or refractory AML showed promising response rates. Here we report the results of a single arm phase II study (NCT02484391). The primary outcome of feasibility of maintenance devimistat following induction and consolidation with devimistat in combination with high dose cytarabine and mitoxantrone was not met, as maintenance devimistat was only administered in 2 of 21 responders. The secondary outcomes of response (CR + CRi) and median survival were 44% (21/48) and 5.9 months respectively. There were no unexpected toxicities observed. An unplanned, post-hoc analysis of the phase I and II datasets suggests a trend of a dose response in older but not younger patients. RNA sequencing data from patient samples reveals an age-related decline in mitochondrial gene sets. Devimistat impairs ATP synthesis and we find a correlation between mitochondrial membrane potential and sensitivity to chemotherapy. Devimistat also induces mitochondrial reactive oxygen species and turnover consistent with mitophagy. We find that pharmacological or genetic inhibition of mitochondrial fission or autophagy sensitizes cells to devimistat. These findings suggest that an age related decline in mitochondrial quality and autophagy may be associated with response to devimistat however this needs to be confirmed in larger cohorts with proper trial design.
    DOI:  https://doi.org/10.1038/s41467-022-29039-4
  9. Proc Natl Acad Sci U S A. 2022 Apr 05. 119(14): e2121946119
    Inositol hexakisphosphate kinase-2 non-catalytically regulates mitophagy by attenuating PINK1 signaling.
    Latika Nagpal, Michael D Kornberg, Solomon H Snyder.
      SignificanceInositol pyrophosphates are versatile messenger molecules containing the energetic pyrophosphate bond. One of the principal enzymes generating the inositol pyrophosphate IP7 (5-diphosphoinositolpentakisphosphate) is inositol hexakisphosphate kinase 2 (IP6K2). Previous work has shown that IP6K2 is neuroprotective and maintains mitochondrial respiration. We now report that loss of IP6K2 leads to increased mitochondrial fission and mitophagy. Regulation of mitochondrial dynamics by IP6K2 depends on the protein PINK1 and, interestingly, is independent of IP6K2 enzymatic activity. These findings provide mechanistic insight into the regulation of mitochondrial function by IP6K2, which has implications for neuroprotection and mitochondrial physiology more generally.
    Keywords:  PINK1; inositol phosphate; mitochondrial biogenesis; mitophagy; neuroprotection
    DOI:  https://doi.org/10.1073/pnas.2121946119
  10. FEBS Lett. 2022 Apr 01.
    Docking and molecular simulations reveal a quinone binding site on the surface of respiratory complex I.
    Amina Djurabekova, Etienne Galemou Yoga, Aino Nyman, Antti Pirttikoski, Volker Zickermann, Outi Haapanen, Vivek Sharma.
      The first component of the mitochondrial electron transport chain is respiratory complex I. Several high-resolution structures of complex I from different species have been resolved. However, despite these significant achievements, the mechanism of redox-coupled proton pumping remains elusive. Here, we combined atomistic docking, molecular dynamics simulations and site-directed mutagenesis on respiratory complex I from Yarrowia lipolytica to identify a quinone (Q) binding site on its surface near the horizontal amphipathic helices of ND1 and NDUFS7 subunits. The surface-bound Q makes stable interactions with conserved charged and polar residues, including the highly conserved Arg72 from the NDUFS7 subunit. The binding and dynamics of a Q molecule at the surface-binding site raises interesting possibilities about the mechanism of complex I, which are discussed.
    DOI:  https://doi.org/10.1002/1873-3468.14346
  11. Science. 2022 Mar 31. eabn7747
    Structures of Tetrahymena's respiratory chain reveal the diversity of eukaryotic core metabolism.
    Long Zhou, María Maldonado, Abhilash Padavannil, Fei Guo, James A Letts.
      Respiration is a core biological energy-converting process whose last steps are carried out by a chain of multi-subunit complexes in the inner mitochondrial membrane. To probe the functional and structural diversity of eukaryotic respiration, we examined the respiratory chain of the ciliate Tetrahymena thermophila (Tt). Using cryo-electron microscopy on a mixed sample, we solved structures of a supercomplex between Tt-complex I (CI) and Tt-CIII2 (Tt-SC I+III2) and a structure of Tt-CIV2. Tt-SC I+III2 (~2.3 MDa) is a curved assembly with structural and functional symmetry breaking. Tt-CIV2 is a ~2.7 MDa dimer with over 52 subunits per protomer, including mitochondrial carriers and a TIM83-TIM133-like domain. Our structural and functional study of the T. thermophila respiratory chain reveals divergence in key components of eukaryotic respiration, expanding our understanding of core metabolism.
    DOI:  https://doi.org/10.1126/science.abn7747
  12. Chembiochem. 2022 Mar 28.
    Photocontrollable Probes for Mitochondrial Protein Profiling.
    Shuhong Guo, Chaonan Yuan, Wenjie Lang, Danqi Hong, Jian Liu, Jintao Huang, Jia Dong, Jingyan Ge.
      Mitochondrion is the core site of cell signaling, energy metabolism and biosynthesis. Here, taking advantage of activitybased probes, we synthesized two photocontrollable probes ( YGH-1 and YGH-2 ), composed of a mitochondrial localization moiety "triphenylphosphonium", a photo triggered group to achieve spatial and temporal controlled protein capture and an alkyne group to enrich the labeled protein. Proteomic validation was further carried out to facilitate identifications of mitochondrial proteomes in HeLa cells. The results showed that half of identified protein hits (~300) labeled by probes YGH-1 and YGH-2 belong to mitochondria, mostly localizing in mitochondrial matrix and inner mitochondrial membrane. Our research results provide a new tool for spatial and temporal analysis of subcellular proteome.
    Keywords:  mitochondrial proteome; photocontrollable; photocross linker; quinone methide
    DOI:  https://doi.org/10.1002/cbic.202200066
  13. J Mol Cell Biol. 2022 Mar 29. pii: mjac020. [Epub ahead of print]
    Deacetylation of MTHFD2 by SIRT4 senses stress signal to inhibit cancer cell growth by remodeling folate metabolism.
    Fan Zhang, Di Wang, Jintao Li, Ying Su, Suling Liu, Qun-Ying Lei, Miao Yin.
      Folate metabolism plays an essential role in tumor development. Various cancers display therapeutic response to reagents targeting key enzymes of folate cycle, but obtaining chemo-resistance later. Therefore, novel targets in folate metabolism are highly demanded. Methylenetetrahydrofolate dehydrogenase/methylenetetrahydrofolate cyclohydrolase 2 (MTHFD2) is one of the key enzymes in folate metabolism and its expression is highly increased in multiple human cancers. However, the underlying mechanism that regulates MTHFD2 expression remains unknown. Here, we elucidate that SIRT4 deacetylates the conserved lysine residue at 50 (K50) in MTHFD2. K50 de-acetylation destabilizes MTHFD2 by elevating Cullin 3 (CUL3) E3 ligase-mediated proteasomal degradation in response to stressful stimuli of folate deprivation, leading to suppression of nicotinamide adenine dinucleotide phosphate (NADPH) production in tumor cells and accumulation of intracellular reactive oxygen species (ROS), which in turn inhibits the growth of breast cancer cells. Collectively, our study reveals that SIRT4 senses folate availability to control MTHFD2 K50 acetylation and its protein stability, bridging nutrient/folate stress and cellular redox to act on cancer cell growth.
    Keywords:  CUL3; MTHFD2; SIRT4; acetylation; breast cancer; folate metabolism
    DOI:  https://doi.org/10.1093/jmcb/mjac020
  14. Function (Oxf). 2022 ;3(2): zqac010
    Time to Target Mitochondrial Reactive Oxygen Species Generation from Complex I.
    Qun Chen, Edward J Lesnefsky.
      
    DOI:  https://doi.org/10.1093/function/zqac010
  15. J Hematol Oncol. 2022 Mar 28. 15(1): 38
    Rewiring mitochondrial metabolism to counteract exhaustion of CAR-T cells.
    Yue Huang, Xiaohui Si, Mi Shao, Xinyi Teng, Gang Xiao, He Huang.
      Short persistence and early exhaustion of T cells are major limits to the efficacy and broad application of immunotherapy. Exhausted T and chimeric antigen receptor (CAR)-T cells upregulate expression of genes associated with terminated T cell differentiation, aerobic glycolysis and apoptosis. Among cell exhaustion characteristics, impaired mitochondrial function and dynamics are considered hallmarks. Here, we review the mitochondrial characteristics of exhausted T cells and particularly discuss different aspects of mitochondrial metabolism and plasticity. Furthermore, we propose a novel strategy of rewiring mitochondrial metabolism to emancipate T cells from exhaustion and of targeting mitochondrial plasticity to boost CAR-T cell therapy efficacy.
    Keywords:  CAR-T cell exhaustion; Metabolism; Mitochondria; Single-cell techniques
    DOI:  https://doi.org/10.1186/s13045-022-01255-x
  16. Biochem Biophys Res Commun. 2022 Mar 22. pii: S0006-291X(22)00441-7. [Epub ahead of print]606 75-79
    A novel isoform of hydroxyacyl-CoA dehydrogenase inhibits cell proliferation.
    Guiyu Xia, Yunyi Gao, Canlan Wu, Haitao Pan, Jingyu Hou, Jinfeng Su, Saisai Wei, Xiangwei Gao.
      Hydroxyacyl-CoA dehydrogenase (HADH) catalyzes the third reaction of mitochondrial β-oxidation cascade, while the regulation of its expression and function remains to be elucidated. Using the quantitative translation initiation sequencing (QTI-seq), we have identified that murine Hadh mRNA has two alternative translation start codons. We demonstrated that translation from upstream start codon encodes the mitochondrial isoform of HADH, while translation from downstream start codon produces a short isoform (HADH-S) with predominant nuclear localization. Moreover, overexpression of HADH-S inhibits the proliferation of mouse embryonic fibroblasts. Overall, our results identify a novel isoform of HADH participating in cell proliferation.
    Keywords:  Alternative translation initiation; Cell proliferation; HADH; Isoform
    DOI:  https://doi.org/10.1016/j.bbrc.2022.03.102
  17. Clin Transl Med. 2022 Mar;12(3): e645
    Simultaneous targeting of mitochondrial metabolism and immune checkpoints as a new strategy for renal cancer therapy.
    Sona Stemberkova-Hubackova, Renata Zobalova, Maria Dubisova, Jana Smigova, Sarka Dvorakova, Klara Korinkova, Zuzana Ezrova, Berwini Endaya, Kristyna Blazkova, Erik Vlcak, Petra Brisudova, Dan-Diem Thi Le, Stefan Juhas, Daniel Rosel, Cristina Daniela Kelemen, Dana Sovilj, Eliska Vacurova, Tomas Cajka, Vlada Filimonenko, Lanfeng Dong, Ladislav Andera, Pavel Hozak, Jan Brabek, Zuzana Bielcikova, Jan Stursa, Lukas Werner, Jiri Neuzil.
      
    DOI:  https://doi.org/10.1002/ctm2.645
  18. J Cancer Res Clin Oncol. 2022 Mar 29.
    Context-specific effects of NOX4 inactivation in acute myeloid leukemia (AML).
    Muhammed Burak Demircan, Tina M Schnoeder, Peter C Mgbecheta, Katrin Schröder, Frank-D Böhmer, Florian H Heidel.
      PURPOSE: Oxidative stress has been linked to initiation and progression of cancer and recent studies have indicated a potential translational role regarding modulation of ROS in various cancers, including acute myeloid leukemia (AML). Detailed understanding of the complex machinery regulating ROS including its producer elements in cancer is required to define potential translational therapeutic use. Based on previous studies in acute myeloid leukemia (AML) models, we considered NADPH oxidase (NOX) family members, specifically NOX4 as a potential target in AML.METHODS: Pharmacologic inhibition and genetic inactivation of NOX4 in murine and human models of AML were used to understand its functional role. For genetic inactivation, CRISPR-Cas9 technology was used in human AML cell lines in vitro and genetically engineered knockout mice for Nox4 were used for deletion of Nox4 in hematopoietic cells via Mx1-Cre recombinase activation.
    RESULTS: Pharmacologic NOX inhibitors and CRISPR-Cas9-mediated inactivation of NOX4 and p22-phox (an essential NOX component) decreased proliferative capacity and cell competition in FLT3-ITD-positive human AML cells. In contrast, conditional deletion of Nox4 enhanced the myeloproliferative phenotype of an FLT3-ITD induced knock-in mouse model. Finally, Nox4 inactivation in normal hematopoietic stem and progenitor cells (HSPCs) caused a minor reduction in HSC numbers and reconstitution capacity.
    CONCLUSION: The role of NOX4 in myeloid malignancies appears highly context-dependent and its inactivation results in either enhancing or inhibitory effects. Therefore, targeting NOX4 in FLT3-ITD positive myeloid malignancies requires additional pre-clinical assessment.
    Keywords:  Acute myeloid leukemia (AML); CRISPR-Cas9; FLT3-ITD; NADPH oxidases (NOX); Nox4; Oxidative stress; Reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1007/s00432-022-03986-3
  19. Sci Rep. 2022 Mar 31. 12(1): 5476
    Exercise suppresses tumor growth independent of high fat food intake and associated immune dysfunction.
    Pernille Hojman, Rikke Stagaard, Emi Adachi-Fernandez, Atul S Deshmukh, Andreas Mund, Caroline H Olsen, Lena Keller, Bente K Pedersen, Julie Gehl.
      Epidemiological data suggest that exercise training protects from cancer independent of BMI. Here, we aimed to elucidate mechanisms involved in voluntary wheel running-dependent control of tumor growth across chow and high-fat diets. Access to running wheels decreased tumor growth in B16F10 tumor-bearing on chow (- 50%) or high-fat diets (- 75%, p < 0.001), however, tumor growth was augmented in high-fat fed mice (+ 53%, p < 0.001). Tumor growth correlated with serum glucose (p < 0.01), leptin (p < 0.01), and ghrelin levels (p < 0.01), but not with serum insulin levels. Voluntary wheel running increased immune recognition of tumors as determined by microarray analysis and gene expression analysis of markers of macrophages, NK and T cells, but the induction of markers of macrophages and NK cells was attenuated with high-fat feeding. Moreover, we found that the regulator of innate immunity, ZBP1, was induced by wheel running, attenuated by high-fat feeding and associated with innate immune recognition in the B16F10 tumors. We observed no effects of ZBP1 on cell cycle arrest, or exercise-regulated necrosis in the tumors of running mice. Taken together, our data support epidemiological findings showing that exercise suppresses tumor growth independent of BMI, however, our data suggest that high-fat feeding attenuates exercise-mediated immune recognition of tumors.
    DOI:  https://doi.org/10.1038/s41598-022-08850-5
  20. Nat Metab. 2022 Mar 31.
    Altered propionate metabolism contributes to tumour progression and aggressiveness.
    Ana P Gomes, Didem Ilter, Vivien Low, Stanislav Drapela, Tanya Schild, Edouard Mullarky, Julie Han, Ilaria Elia, Dorien Broekaert, Adam Rosenzweig, Michal Nagiec, Joana B Nunes, Bethany E Schaffer, Anders P Mutvei, John M Asara, Lewis C Cantley, Sarah-Maria Fendt, John Blenis.
      The alteration of metabolic pathways is a critical strategy for cancer cells to attain the traits necessary for metastasis in disease progression. Here, we find that dysregulation of propionate metabolism produces a pro-aggressive signature in breast and lung cancer cells, increasing their metastatic potential. This occurs through the downregulation of methylmalonyl coenzyme A epimerase (MCEE), mediated by an extracellular signal-regulated kinase 2-driven transcription factor Sp1/early growth response protein 1 transcriptional switch driven by metastatic signalling at its promoter level. The loss of MCEE results in reduced propionate-driven anaplerotic flux and intracellular and intratumoral accumulation of methylmalonic acid, a by-product of propionate metabolism that promotes cancer cell invasiveness. Altogether, we present a previously uncharacterized dysregulation of propionate metabolism as an important contributor to cancer and a valuable potential target in the therapeutic treatment of metastatic carcinomas.
    DOI:  https://doi.org/10.1038/s42255-022-00553-5
  21. Cell Transplant. 2022 Jan-Dec;31:31 9636897221085883
    Bone Marrow Mononuclear Cells Restore Normal Mitochondrial Ca2+ Handling and Ca2+-Induced Depolarization of the Internal Mitochondrial Membrane by Inhibiting the Permeability Transition Pore After Ischemia/Reperfusion.
    Clara Rodrigues-Ferreira, Jarlene Alécia Lopes, Priscila Fonseca Carneiro, Cristiane Dos Santos Lessa, Antonio Galina, Adalberto Vieyra.
      Acute kidney injury due to ischemia followed by reperfusion (IR) is a severe clinical condition with high death rates. IR affects the proximal tubule segments due to their predominantly oxidative metabolism and profoundly altered mitochondrial functions. We previously described the impact of IR on oxygen consumption, the generation of membrane potential (ΔΨ), and formation of reactive oxygen species, together with inflammatory and structural alterations. We also demonstrated the benefits of bone marrow mononuclear cells (BMMC) administration in these alterations. The objective of the present study has been to investigate the effect of IR and the influence of BMMC on the mechanisms of Ca2+ handling in mitochondria of the proximal tubule cells. IR inhibited the rapid accumulation of Ca2+ (Ca2+ green fluorescence assays) and induced the opening of the cyclosporine A-sensitive permeability transition pore (PTP), alterations prevented by BMMC. IR accelerated Ca2+-induced decrease of ΔΨ (Safranin O fluorescence assays), as evidenced by decreased requirement for Ca2+ load and t1/2 for complete depolarization. Addition of BMMC and ADP recovered the normal depolarization profile, suggesting that stabilization of the adenine nucleotide translocase (ANT) in a conformation that inhibits PTP opening offers a partial defense mechanism against IR injury. Moreover, as ANT forms a complex with the voltage-dependent anion channel (VDAC) in the outer mitochondrial membrane, it is possible that this complex is also a target for IR injury-thus favoring Ca2+ release, as well as the supramolecular structure that BMMC protects. These beneficial effects are accompanied by a stimulus of the citric acid cycle-which feed the mitochondrial complexes with the electrons removed from different substrates-as the result of accentuated stimulus of citrate synthase activity by BMMC.
    Keywords:  bone marrow mononuclear cells; mitochondrial Ca2+ handling; mitochondrial membrane potential; permeability transition pore; renal ischemia/reperfusion
    DOI:  https://doi.org/10.1177/09636897221085883
  22. Front Oncol. 2022 ;12 823831
    Identification of a Mitochondria-Related Gene Signature to Predict the Prognosis in AML.
    Nan Jiang, Xinzhuo Zhang, Qi Chen, Fahsai Kantawong, Shengli Wan, Jian Liu, Hua Li, Jie Zhou, Bin Lu, Jianming Wu.
      Mitochondria-related metabolic reprogramming plays a major role in the occurrence, development, drug resistance, and recurrence of acute myeloid leukemia (AML). However, the roles of mitochondria-related genes (MRGs) in the prognosis and immune microenvironment for AML patients remain largely unknown. In this study, by least absolute shrinkage and selection operator (LASSO) Cox regression analysis, 4 MRGs' (HPDL, CPT1A, IDH3A, and ETFB) signature was established that demonstrated good robustness in TARGET AML datasets. The univariate and multivariate Cox regression analyses both demonstrated that the MRG signature was a robust independent prognostic factor in overall survival prediction with high accuracy for AML patients. Based on the risk score calculated by the signature, samples were divided into high- and low-risk groups. Gene set enrichment analysis (GSEA) suggested that the MRG signature is involved in the immune-related pathways. Via immune infiltration analysis and immunosuppressive genes analysis, we found that MRG risk of AML patients was strikingly positively correlated with an immune cell infiltration and expression of critical immune checkpoints, indicating that the poor prognosis might be caused by immunosuppressive tumor microenvironment (TME). In summary, the signature based on MRGs could act as an independent risk factor for predicting the clinical prognosis of AML and could also reflect an association with the immunosuppressive microenvironment, providing a novel method for AML metabolic and immune therapy based on the regulation of mitochondrial function.
    Keywords:  LASSOR; The Cancer Genome Atlas; Therapeutically Applicable Research to Generate Effective Treatments; acute myeloid leukemia; mitochondria-related genes; prognostic signature
    DOI:  https://doi.org/10.3389/fonc.2022.823831
  23. Exp Cell Res. 2022 Mar 25. pii: S0014-4827(22)00105-7. [Epub ahead of print]415(1): 113112
    IL-6 promotes chemoresistance via upregulating CD36 mediated fatty acids uptake in acute myeloid leukemia.
    Yanjie Zhang, Hezhou Guo, Zhaoli Zhang, Wei Lu, Jiang Zhu, Jun Shi.
      Chemoresistance contributes to poor survival and high relapse risk in acute myeloid leukemia (AML). As a pro-inflammatory cytokine, interleukin-6 (IL-6) plays a vital role in the chemoresistance of malignancies. However, the underlying mechanisms of chemoresistance in AML have not been widely studied. Lipid metabolism, which contributes to chemoresistance in AML, is enhanced by IL-6 in skeletal muscle cells. We hypothesized that IL-6 promotes the chemoresistance of AML by promoting lipid metabolism. Based on the positive correlation between IL-6 receptor expression and the cellular response to exogenous IL-6, we performed Gene Ontology analysis of a dataset consisting the information of 151 AML patients from The Cancer Genome Atlas. We found that lipid transport-associated genes were upregulated in the high IL-6 receptor expression group. Additionally, IL-6 promoted fatty acid (FA) uptake in both AML cell lines and primary AML cells. Inhibition of FA uptake by sulfo-N-succinimidyl oleate repressed IL-6-induced chemoresistance. Western blotting, quantitative polymerase chain reaction, and chromatin immunoprecipitation assays indicated that IL-6 promoted CD36 expression at both the mRNA and protein levels through stat3 signaling. Knockout of CD36 or stat3 repressed IL-6-induced FA uptake and chemoresistance. Furthermore, in five human AML samples, we validated that compared to CD36-cells, CD36+ primary AML cells were less sensitive to cytosine arabinoside (Ara-c) and that blockade of CD36 re-sensitized CD36+ AML cells to Ara-c. Mice injected with CD36 knockout cells followed by treatment with Ara-c showed markedly decreased leukemia burden and prolonged survival in vivo. Finally, treatment with the CD36 antibody in combination with Ara-c exhibited synergistic effects in vivo. In conclusion, IL-6 promotes chemoresistance in AML through the stat3/CD36-mediated FA uptake. Blockade of CD36 improved the effect of Ara-c, representing a promising strategy for AML therapy.
    Keywords:  Acute myeloid leukemia; CD36; Chemoresistance; Fatty acid uptake; Interleukin-6
    DOI:  https://doi.org/10.1016/j.yexcr.2022.113112
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