bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2021–06–27
43 papers selected by
Kelsey Fisher-Wellman, East Carolina University
  1. Hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells.
  2. Mitochondrial metabolism regulates macrophage biology.
  3. Anticancer gold(iii)-bisphosphine complex alters the mitochondrial electron transport chain to induce in vivo tumor inhibition.
  4. Monocarboxylate transporter antagonism reveals metabolic vulnerabilities of viral-driven lymphomas.
  5. Mitochondrial-derived vesicles compensate for loss of LC3-mediated mitophagy.
  6. Protein tyrosine phosphatome metabolic screen identifies TC-PTP as a positive regulator of cancer cell bioenergetics and mitochondrial dynamics.
  7. Quantitative analysis of mitochondrial ATP synthesis.
  8. Tumor chemical suffocation therapy by dual respiratory inhibitions.
  9. Mitochondrial transcription factor A plays opposite roles in the initiation and progression of colitis-associated cancer.
  10. Anoxia-reoxygenation alters H2O2 efflux and sensitivity of redox centers to copper in heart mitochondria.
  11. Fever supports CD8+ effector T cell responses by promoting mitochondrial translation.
  12. An update on methods and approaches for interrogating mitochondrial reactive oxygen species production.
  13. Water-soluble gold(III)-Metformin complex alters mitochondrial bioenergetics in breast cancer cells.
  14. Optical Control of CD8+ T Cell Metabolism and Effector Functions.
  15. Mitochondrial STAT5A promotes metabolic remodeling and the Warburg effect by inactivating the pyruvate dehydrogenase complex.
  16. Prostate cancer cells survive anti-androgen and mitochondrial metabolic inhibitors by modulating glycolysis and mitochondrial metabolic activities.
  17. Metformin induces Ferroptosis by inhibiting UFMylation of SLC7A11 in breast cancer.
  18. Differences in molecular phenotype in mouse and human hypertrophic cardiomyopathy.
  19. Light-inducible deformation of mitochondria in live cells.
  20. Suppression of oxidative phosphorylation and IDH2 sensitizes colorectal cancer to a naphthalimide derivative and mitoxantrone.
  21. KEAP1 deficiency drives glucose dependency and sensitizes lung cancer cells and tumors to GLUT inhibition.
  22. Compensatory expression of NRF2-dependent antioxidant genes is required to overcome the lethal effects of Kv11.1 activation in breast cancer cells and PDOs.
  23. Lupus susceptibility gene Esrrg modulates regulatory T cells through mitochondrial metabolism.
  24. Composition and stage dynamics of mitochondrial complexes in Plasmodium falciparum.
  25. Comparative proteomics reveals that lipid droplet-anchored mitochondria are more sensitive to cold in brown adipocytes.
  26. mTORC1 Activation is Not Sufficient to Suppress Hepatic PPARα Signaling or Ketogenesis.
  27. Impaired anaplerosis is a major contributor to glycolysis inhibitor toxicity in glioma.
  28. Coordinated pyruvate kinase activity is crucial for metabolic adaptation and cell survival during mitochondrial dysfunction.
  29. Mitochondrial NAD(P)+ transhydrogenase: from molecular features to physiology and disease.
  30. A guide to genetically encoded tools for the study of H2 O2.
  31. Mitochondrial function in development and disease.
  32. Combined epigenetic and metabolic treatments overcome differentiation blockade in acute myeloid leukemia.
  33. Single cell derived mRNA signals across human kidney tumors.
  34. Very-low-carbohydrate diet enhances human T-cell immunity through immunometabolic reprogramming.
  35. Mitochondrial Ca2+ oscillation induces mitophagy initiation through the PINK1-Parkin pathway.
  36. Systemic regulation of mitochondria by germline proteostasis prevents protein aggregation in the soma of C. elegans.
  37. Identification and functional validation of FDA-approved positive and negative modulators of the mitochondrial calcium uniporter.
  38. Blood Mitochondrial DNA Copy Number: What Are We Counting?
  39. PGC1α-Mediated Metabolic Reprogramming Drives the Stemness of Pancreatic Precursor Lesions.
  40. Intracellular H2S production is an autophagy-dependent adaptive response to DNA damage.
  41. Anti-Tumor Effects of BDH1 in Acute Myeloid Leukemia.
  42. LINC00842 inactivates transcription co-regulator PGC-1α to promote pancreatic cancer malignancy through metabolic remodelling.
  43. Fms-like tyrosine kinase 3-internal tandem duplications epigenetically activates checkpoint kinase 1 in acute myeloid leukemia cells.
  1. Nat Metab. 2021 Jun 21.
    Hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells.
    Andrew J Schwartz, Joshua W Goyert, Sumeet Solanki, Samuel A Kerk, Brandon Chen, Cristina Castillo, Peggy P Hsu, Brian T Do, Rashi Singhal, Michael K Dame, Ho-Joon Lee, Jason R Spence, Samira Lakhal-Littleton, Matthew G Vander Heiden, Costas A Lyssiotis, Xiang Xue, Yatrik M Shah.
      Colorectal cancer (CRC) requires massive iron stores, but the complete mechanisms by which CRC modulates local iron handling are poorly understood. Here, we demonstrate that hepcidin is activated ectopically in CRC. Mice deficient in hepcidin specifically in the colon tumour epithelium, compared with wild-type littermates, exhibit significantly diminished tumour number, burden and size in a sporadic model of CRC, whereas accumulation of intracellular iron by deletion of the iron exporter ferroportin exacerbates these tumour parameters. Metabolomic analysis of three-dimensional patient-derived CRC tumour enteroids indicates a prioritization of iron in CRC for the production of nucleotides, which is recapitulated in our hepcidin/ferroportin mouse CRC models. Mechanistically, our data suggest that iron chelation decreases mitochondrial function, thereby altering nucleotide synthesis, whereas exogenous supplementation of nucleosides or aspartate partially rescues tumour growth in patient-derived enteroids and CRC cell lines in the presence of an iron chelator. Collectively, these data suggest that ectopic hepcidin in the tumour epithelium establishes an axis to sequester iron in order to maintain the nucleotide pool and sustain proliferation in colorectal tumours.
    DOI:  https://doi.org/10.1038/s42255-021-00406-7
  2. J Biol Chem. 2021 Jun 19. pii: S0021-9258(21)00704-3. [Epub ahead of print] 100904
    Mitochondrial metabolism regulates macrophage biology.
    Yafang Wang, Na Li, Xin Zhang, Tiffany Horng.
      Mitochondria are critical for regulation of the activation, differentiation, and survival of macrophages and other immune cells. In response to various extracellular signals, such as microbial or viral infection, changes to mitochondrial metabolism and physiology could underlie the corresponding state of macrophage activation. These changes include alterations of oxidative metabolism, mitochondrial membrane potential, and tricarboxylic acid (TCA) cycling, as well as the release of mitochondrial reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA) and transformation of the mitochondrial ultrastructure. Here, we provide an updated review of how changes in mitochondrial metabolism and various metabolites such as fumarate, succinate, and itaconate coordinate to guide macrophage activation to distinct cellular states, thus clarifying the vital link between mitochondria metabolism and immunity. We also discuss how in disease settings, mitochondrial dysfunction and oxidative stress contribute to dysregulation of the inflammatory response. Therefore, mitochondria are a vital source of dynamic signals that regulate macrophage biology to fine-tune immune responses.
    Keywords:  macrophage activation; macrophage biology; mitochondrial dysfunction; mitochondrial metabolism; oxidative stress
    DOI:  https://doi.org/10.1016/j.jbc.2021.100904
  3. Chem Sci. 2021 Apr 29. 12(21): 7467-7479
    Anticancer gold(iii)-bisphosphine complex alters the mitochondrial electron transport chain to induce in vivo tumor inhibition.
    Jong Hyun Kim, Samuel Ofori, Sean Parkin, Hemendra Vekaria, Patrick G Sullivan, Samuel G Awuah.
      Expanding the chemical diversity of metal complexes provides a robust platform to generate functional bioactive reagents. To access an excellent repository of metal-based compounds for probe/drug discovery, we capitalized on the rich chemistry of gold to create organometallic gold(iii) compounds by ligand tuning. We obtained novel organogold(iii) compounds bearing a 1,2-bis(diphenylphosphino)benzene ligand, providing structural diversity with optimal physiological stability. Biological evaluation of the lead compound AuPhos-89 demonstrates mitochondrial complex I-mediated alteration of the mitochondrial electron transport chain (ETC) to drive respiration and diminish cellular energy in the form of adenosine triphosphate (ATP). Mechanism-of-action efforts, RNA-Seq, quantitative proteomics, and NCI-60 screening reveal a highly potent anticancer agent that modulates mitochondrial ETC. AuPhos-89 inhibits the tumor growth of metastatic triple negative breast cancer and represents a new strategy to study the modulation of mitochondrial respiration for the treatment of aggressive cancer and other disease states where mitochondria play a pivotal role in the pathobiology.
    DOI:  https://doi.org/10.1039/d1sc01418h
  4. Proc Natl Acad Sci U S A. 2021 Jun 22. pii: e2022495118. [Epub ahead of print]118(25):
    Monocarboxylate transporter antagonism reveals metabolic vulnerabilities of viral-driven lymphomas.
    Emmanuela N Bonglack, Joshua E Messinger, Jana M Cable, James Ch'ng, K Mark Parnell, Nicolás M Reinoso-Vizcaíno, Ashley P Barry, Veronica S Russell, Sandeep S Dave, Heather R Christofk, Micah A Luftig.
      Epstein-Barr virus (EBV) is a ubiquitous herpesvirus that typically causes asymptomatic infection but can promote B lymphoid tumors in the immune suppressed. In vitro, EBV infection of primary B cells stimulates glycolysis during immortalization into lymphoblastoid cell lines (LCLs). Lactate export during glycolysis is crucial for continued proliferation of many cancer cells-part of a phenomenon known as the "Warburg effect"- and is mediated by monocarboxylate transporters (MCTs). However, the role of MCTs has yet to be studied in EBV-associated malignancies, which display Warburg-like metabolism in vitro. Here, we show that EBV infection of B lymphocytes directly promotes temporal induction of MCT1 and MCT4 through the viral proteins EBNA2 and LMP1, respectively. Functionally, MCT1 was required for early B cell proliferation, and MCT4 up-regulation promoted acquired resistance to MCT1 antagonism in LCLs. However, dual MCT1/4 inhibition led to LCL growth arrest and lactate buildup. Metabolic profiling in LCLs revealed significantly reduced oxygen consumption rates (OCRs) and NAD+/NADH ratios, contrary to previous observations of increased OCR and unaltered NAD+/NADH ratios in MCT1/4-inhibited cancer cells. Furthermore, U-13C6-glucose labeling of MCT1/4-inhibited LCLs revealed depleted glutathione pools that correlated with elevated reactive oxygen species. Finally, we found that dual MCT1/4 inhibition also sensitized LCLs to killing by the electron transport chain complex I inhibitors phenformin and metformin. These findings were extended to viral lymphomas associated with EBV and the related gammaherpesvirus KSHV, pointing at a therapeutic approach for targeting both viral lymphomas.
    Keywords:  Epstein–Barr virus; cancer metabolism; lactate export; monocarboxylate transporter; viral lymphoma
    DOI:  https://doi.org/10.1073/pnas.2022495118
  5. Dev Cell. 2021 Jun 24. pii: S1534-5807(21)00481-0. [Epub ahead of print]
    Mitochondrial-derived vesicles compensate for loss of LC3-mediated mitophagy.
    Christina G Towers, Darya K Wodetzki, Jacqueline Thorburn, Katharine R Smith, M Cecilia Caino, Andrew Thorburn.
      Mitochondria are critical metabolic and signaling hubs, and dysregulated mitochondrial homeostasis is implicated in many diseases. Degradation of damaged mitochondria by selective GABARAP/LC3-dependent macro-autophagy (mitophagy) is critical for maintaining mitochondrial homeostasis. To identify alternate forms of mitochondrial quality control that functionally compensate if mitophagy is inactive, we selected for autophagy-dependent cancer cells that survived loss of LC3-dependent autophagosome formation caused by inactivation of ATG7 or RB1CC1/FIP200. We discovered rare surviving autophagy-deficient clones that adapted to maintain mitochondrial homeostasis after gene inactivation and identified two enhanced mechanisms affecting mitochondria including mitochondrial dynamics and mitochondrial-derived vesicles (MDVs). To further understand these mechanisms, we quantified MDVs via flow cytometry and confirmed an SNX9-mediated mechanism necessary for flux of MDVs to lysosomes. We show that the autophagy-dependent cells acquire unique dependencies on these processes, indicating that these alternate forms of mitochondrial homeostasis compensate for loss of autophagy to maintain mitochondrial health.
    Keywords:  ATG7; FIP200; SNX9; autophagy; cancer; late endosomes; mitochondria; mitochondrial dynamics; mitochondrial-derived vesicles; mitophagy
    DOI:  https://doi.org/10.1016/j.devcel.2021.06.003
  6. FASEB J. 2021 Jul;35(7): e21708
    Protein tyrosine phosphatome metabolic screen identifies TC-PTP as a positive regulator of cancer cell bioenergetics and mitochondrial dynamics.
    Valerie Vinette, Isabelle Aubry, Hayley Insull, Noriko Uetani, Serge Hardy, Michel L Tremblay.
      Metabolic reprogramming occurs in cancer cells and is regulated partly by the opposing actions of tyrosine kinases and tyrosine phosphatases. Several members of the protein tyrosine phosphatase (PTP) superfamily have been linked to cancer as either pro-oncogenic or tumor-suppressive enzymes. In order to investigate which PTPs can modulate the metabolic state of cancer cells, we performed an shRNA screen of PTPs in HCT116 human colorectal cancer cells. Among the 72 PTPs efficiently targeted, 24 were found to regulate mitochondrial respiration, 8 as negative and 16 as positive regulators. Of the latter, we selected TC-PTP (PTPN2) for further characterization since inhibition of this PTP resulted in major functional defects in oxidative metabolism without affecting glycolytic flux. Transmission electron microscopy revealed an increase in the number of damaged mitochondria in TC-PTP-null cells, demonstrating the potential role of this PTP in regulating mitochondrial homeostasis. Downregulation of STAT3 by siRNA-mediated silencing partially rescued the mitochondrial respiration defect observed in TC-PTP-deficient cells, supporting the role of this signaling axis in regulating mitochondrial activity. In addition, mitochondrial stress prevented an increased expression of electron transport chain-related genes in cells with TC-PTP silencing, correlating with decreased ATP production, cellular proliferation, and migration. Our shRNA-based metabolic screen revealed that PTPs can serve as either positive or negative regulators of cancer cell metabolism. Taken together, our findings uncover a new role for TC-PTP as an activator of mitochondrial metabolism, validating this PTP as a key target for cancer therapeutics.
    Keywords:  PTPN2; TC-PTP; cancer; metabolism; mitochondria; protein tyrosine phosphatases
    DOI:  https://doi.org/10.1096/fj.202100207R
  7. Math Biosci. 2021 Jun 16. pii: S0025-5564(21)00083-3. [Epub ahead of print] 108646
    Quantitative analysis of mitochondrial ATP synthesis.
    E Benjamin Randall, Marcus Hock, Rachel Lopez, Bahador Marzban, Collin Marshall, Daniel A Beard.
      We present a computational framework for analyzing and simulating mitochondrial ATP synthesis using basic thermodynamic and kinetic principles. The framework invokes detailed descriptions of the thermodynamic driving forces associated with the processes of the electron transport chain, mitochondrial ATP synthetase, and phosphate and adenine nucleotide transporters. Assembling models of these discrete processes into an integrated model of mitochondrial ATP synthesis, we illustrate how to analyze and simulate in vitro respirometry experiments and how models identified from in vitro experimental data effectively explain cardiac respiratory control in vivo. Computer codes for these analyses are embedded as Python scripts in a Jupyter Book to facilitate easy adoption and modification of the concepts developed here. This accessible framework may also prove useful in supporting educational applications. All source codes are available on at https://beards-lab.github.io/QAMAS_book/.
    Keywords:  Biochemical thermodynamics; Bioenergetics; Computational modeling; Metabolic pathways; Respiratory
    DOI:  https://doi.org/10.1016/j.mbs.2021.108646
  8. Chem Sci. 2021 Apr 28. 12(22): 7763-7769
    Tumor chemical suffocation therapy by dual respiratory inhibitions.
    Yingying Xu, Yuedong Guo, Lei Chen, Dalong Ni, Ping Hu, Jianlin Shi.
      The extraordinarily rapid growth of malignant tumors depends heavily on the glucose metabolism by the pathways of glycolysis and mitochondrial oxidative phosphorylation to generate adenosine 5'-triphosphate (ATP) for maintaining cell proliferation and tumor growth. This study reports a tumor chemical suffocation therapeutic strategy by concurrently suppressing both glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) via the co-deliveries of EDTA and rotenone into a glutathione (GSH)-overexpressed tumor microenvironment. EDTA is to block the glycolytic pathway through inhibiting the activity of glycolytic enzymes via the chelation of magnesium ion, a co-worker of glycolytic enzymes, despite the presence of Ca2+. Meanwhile rotenone is to inhibit the mitochondrial OXPHOS. This work provides a novel tumor suffocation strategy by the co-deliveries of glucose metabolism inhibitors, especially by de-functioning glycolytic enzymes via eliminating their co-worker magnesium.
    DOI:  https://doi.org/10.1039/d1sc00929j
  9. Cancer Commun (Lond). 2021 Jun 23.
    Mitochondrial transcription factor A plays opposite roles in the initiation and progression of colitis-associated cancer.
    Shirong Yang, Xianli He, Jing Zhao, Dalin Wang, Shanshan Guo, Tian Gao, Gang Wang, Chao Jin, Zeyu Yan, Nan Wang, Yongxing Wang, Yilin Zhao, Jinliang Xing, Qichao Huang.
       BACKGROUND: Mitochondria are key regulators in cell proliferation and apoptosis. Alterations in mitochondrial function are closely associated with inflammation and tumorigenesis. This study aimed to investigate whether mitochondrial transcription factor A (TFAM), a key regulator of mitochondrial DNA transcription and replication, is involved in the initiation and progression of colitis-associated cancer (CAC).
    METHODS: TFAM expression was examined in tissue samples of inflammatory bowel diseases (IBD) and CAC by immunohistochemistry. Intestinal epithelial cell (IEC)-specific TFAM-knockout mice (TFAM△IEC ) and colorectal cancer (CRC) cells with TFAM knockdown or overexpression were used to evaluate the role of TFAM in colitis and the initiation and progression of CAC. The underlying mechanisms of TFAM were also explored by analyzing mitochondrial respiration function and biogenesis.
    RESULTS: The expression of TFAM was downregulated in active IBD and negatively associated with the disease activity. The downregulation of TFAM in IECs was induced by interleukin-6 in a signal transducer and activator of transcription 3 (STAT3)/miR-23b-dependent manner. In addition, TFAM knockout impaired IEC turnover to promote dextran sulfate sodium (DSS)-induced colitis in mice. Of note, TFAM knockout increased the susceptibility of mice to azoxymethane/DSS-induced CAC and TFAM overexpression protected mice from intestinal inflammation and colitis-associated tumorigenesis. By contrast, TFAM expression was upregulated in CAC tissues and contributed to cell growth. Furthermore, it was demonstrated that β-catenin induced the upregulation of TFAM through c-Myc in CRC cells. Mechanistically, TFAM promoted the proliferation of both IECs and CRC cells by increasing mitochondrial biogenesis and activity.
    CONCLUSIONS: TFAM plays a dual role in the initiation and progression of CAC, providing a novel understanding of CAC pathogenesis.
    Keywords:  colitis; colitis-associated cancer; colorectal cancer; energy metabolism; inflammatory bowel diseases; intestinal homeostasis; mitochondrial transcription factor A (TFAM)
    DOI:  https://doi.org/10.1002/cac2.12184
  10. Comp Biochem Physiol C Toxicol Pharmacol. 2021 Jun 16. pii: S1532-0456(21)00138-1. [Epub ahead of print] 109111
    Anoxia-reoxygenation alters H2O2 efflux and sensitivity of redox centers to copper in heart mitochondria.
    Michael O Isei, Nirmala Chinnappareddy, Don Stevens, Collins Kamunde.
      Mitochondrial reactive oxygen species (ROS) have been implicated in organ damage caused by environmental stressors, prompting studies on the effect of oxygen deprivation and metal exposure on ROS metabolism. However, how anoxia and copper (Cu) jointly influence heart mitochondrial ROS metabolism is not understood. We used rainbow trout heart mitochondria to probe the effects of anoxia-reoxygenation and Cu on hydrogen peroxide (H2O2) emission during oxidation of palmitoylcarnitine (PC), succinate, and glutamate-malate. In addition, we examined the influence of anoxia-reoxygenation and Cu on site-specific H2O2 emission capacities and key antioxidant enzymes, glutathione peroxidase (GPx) and thioredoxin reductase (TrxR). Results showed that anoxia-reoxygenation suppressed H2O2 emission regardless of substrate type and duration of anoxia. Anoxia-reoxygenation reduced mitochondrial sensitivity to Cu during oxidation of succinate or glutamate-malate whereas high Cu concentration additively stimulated H2O2 emission in mitochondria oxidizing PC. Prolonged anoxia-reoxygenation stimulated H2O2 emission from sites OF and IF, inhibited emission from sites IQ, IIF and IIIQo, and disparately altered the sensitivity of the sites to Cu. Interestingly, anoxia-reoxygenation increased GPx and TrxR activities, more prominently when reoxygenation followed a short duration of anoxia. Cu did not alter GPx but reduced TrxR activity in normoxic and anoxic-reoxygenated mitochondria. Overall, our study revealed potential mechanisms that may prevent oxidative damage associated with anoxia-reoxygenation and Cu exposure in heart mitochondria. The increased and decreased H2O2 emission from NADH/NAD+ and QH2/Q isopotential sites, respectively, may represent a balance between H2O2 required for oxygen deprivation-induced signaling and prevention of ROS burst associated with anoxia-reoxygenation.
    Keywords:  Anoxia-reoxygenation; Antioxidant enzymes; Copper; H(2)O(2) emission; Heart mitochondria
    DOI:  https://doi.org/10.1016/j.cbpc.2021.109111
  11. Proc Natl Acad Sci U S A. 2021 Jun 22. pii: e2023752118. [Epub ahead of print]118(25):
    Fever supports CD8+ effector T cell responses by promoting mitochondrial translation.
    David O'Sullivan, Michal A Stanczak, Matteo Villa, Franziska M Uhl, Mauro Corrado, Ramon I Klein Geltink, David E Sanin, Petya Apostolova, Nisha Rana, Joy Edwards-Hicks, Katarzyna M Grzes, Agnieszka M Kabat, Ryan L Kyle, Mario Fabri, Jonathan D Curtis, Michael D Buck, Annette E Patterson, Annamaria Regina, Cameron S Field, Francesc Baixauli, Daniel J Puleston, Edward J Pearce, Robert Zeiser, Erika L Pearce.
      Fever can provide a survival advantage during infection. Metabolic processes are sensitive to environmental conditions, but the effect of fever on T cell metabolism is not well characterized. We show that in activated CD8+ T cells, exposure to febrile temperature (39 °C) augmented metabolic activity and T cell effector functions, despite having a limited effect on proliferation or activation marker expression. Transcriptional profiling revealed an up-regulation of mitochondrial pathways, which was consistent with increased mass and metabolism observed in T cells exposed to 39 °C. Through in vitro and in vivo models, we determined that mitochondrial translation is integral to the enhanced metabolic activity and function of CD8+ T cells exposed to febrile temperature. Transiently exposing donor lymphocytes to 39 °C prior to infusion in a myeloid leukemia mouse model conferred enhanced therapeutic efficacy, raising the possibility that exposure of T cells to febrile temperatures could have clinical potential.
    Keywords:  T cell; fever; immunology; metabolism; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2023752118
  12. Redox Biol. 2021 Jun 16. pii: S2213-2317(21)00203-2. [Epub ahead of print]45 102044
    An update on methods and approaches for interrogating mitochondrial reactive oxygen species production.
    Ryan J Mailloux.
      The chief ROS formed by mitochondria are superoxide (O2·-) and hydrogen peroxide (H2O2). Superoxide is converted rapidly to H2O2 and therefore the latter is the chief ROS emitted by mitochondria into the cell. Once considered an unavoidable by-product of aerobic respiration, H2O2 is now regarded as a central mitokine used in mitochondrial redox signaling. However, it has been postulated that O2·- can also serve as a signal in mammalian cells. Progress in understanding the role of mitochondrial H2O2 in signaling is due to significant advances in the development of methods and technologies for its detection. Unfortunately, the development of techniques to selectively measure basal O2·- changes has been met with more significant hurdles due to its short half-life and the lack of specific probes. The development of sensitive techniques for the selective and real time measure of O2·- and H2O2 has come on two fronts: development of genetically encoded fluorescent proteins and small molecule reporters. In 2015, I published a detailed comprehensive review on the state of knowledge for mitochondrial ROS production and how it is controlled, which included an in-depth discussion of the up-to-date methods utilized for the detection of both superoxide (O2·-) and H2O2. In the article, I presented the challenges associated with utilizing these probes and their significance in advancing our collective understanding of ROS signaling. Since then, many other authors in the field of Redox Biology have published articles on the challenges and developments detecting O2·- and H2O2 in various organisms [1-3]. There has been significant advances in this state of knowledge, including the development of novel genetically encoded fluorescent H2O2 probes, several O2·- sensors, and the establishment of a toolkit of inhibitors and substrates for the interrogation of mitochondrial H2O2 production and the antioxidant defenses utilized to maintain the cellular H2O2 steady-state. Here, I provide an update on these methods and their implementation in furthering our understanding of how mitochondria serve as cell ROS stabilizing devices for H2O2 signaling.
    Keywords:  Methods for measuring ROS; Mitochondria; Peroxide detectors; Reactive oxygen species; Superoxide probes
    DOI:  https://doi.org/10.1016/j.redox.2021.102044
  13. ChemMedChem. 2021 Jun 23.
    Water-soluble gold(III)-Metformin complex alters mitochondrial bioenergetics in breast cancer cells.
    Samuel G Awuah, Jong Hyun Kim, Samuel Ofori, R Tyler Mertens, Sean Parkin.
      Chemical control of mitochondrial dynamics and bioenergetics can unravel fundamental biological mechanisms and therapeutics for several diseases including, diabetes and cancer. We synthesized stable, water-soluble gold(III) complexes (Auraformin) supported by biguanide metformin or phenylmetformin for efficacious inhibition of mitochondrial respiration. The new compounds were characterized following the reaction of [C^N]-cyclometalated gold(III) compounds with respective biguanides. Auraformin is solution stable in a physiologically relevant environment.  We show that auraformin decreases mitochondrial respiration efficiently in comparison to the clinically used metformin by 100-fold. The compound displays significant mitochondrial uptake and induce antiproliferative activity in the micromolar range. Our results shed light on the development of new scaffolds as improved inhibitors of mitochondrial respiration.
    Keywords:  Anticancer, Gold(III)-Metformin Complexes, Mitochondria Inhibition, OXPHOS, Auraformin
    DOI:  https://doi.org/10.1002/cmdc.202100233
  14. Front Immunol. 2021 ;12 666231
    Optical Control of CD8+ T Cell Metabolism and Effector Functions.
    Andrea M Amitrano, Brandon J Berry, Kihong Lim, Kyun-Do Kim, Richard E Waugh, Andrew P Wojtovich, Minsoo Kim.
      Although cancer immunotherapy is effective against hematological malignancies, it is less effective against solid tumors due in part to significant metabolic challenges present in the tumor microenvironment (TME), where infiltrated CD8+ T cells face fierce competition with cancer cells for limited nutrients. Strong metabolic suppression in the TME is often associated with impaired T cell recruitment to the tumor site and hyporesponsive effector function via T cell exhaustion. Increasing evidence suggests that mitochondria play a key role in CD8+ T cell activation, effector function, and persistence in tumors. In this study, we showed that there was an increase in overall mitochondrial function, including mitochondrial mass and membrane potential, during both mouse and human CD8+ T cell activation. CD8+ T cell mitochondrial membrane potential was closely correlated with granzyme B and IFN-γ production, demonstrating the significance of mitochondria in effector T cell function. Additionally, activated CD8+ T cells that migrate on ICAM-1 and CXCL12 consumed significantly more oxygen than stationary CD8+ T cells. Inhibition of mitochondrial respiration decreased the velocity of CD8+ T cell migration, indicating the importance of mitochondrial metabolism in CD8+ T cell migration. Remote optical stimulation of CD8+ T cells that express our newly developed "OptoMito-On" successfully enhanced mitochondrial ATP production and improved overall CD8+ T cell migration and effector function. Our study provides new insight into the effect of the mitochondrial membrane potential on CD8+ T cell effector function and demonstrates the development of a novel optogenetic technique to remotely control T cell metabolism and effector function at the target tumor site with outstanding specificity and temporospatial resolution.
    Keywords:  T cell migration; cancer immunotherapy; effector T cell; metabolism; optogenetics
    DOI:  https://doi.org/10.3389/fimmu.2021.666231
  15. Cell Death Dis. 2021 Jun 19. 12(7): 634
    Mitochondrial STAT5A promotes metabolic remodeling and the Warburg effect by inactivating the pyruvate dehydrogenase complex.
    Liang Zhang, Jianong Zhang, Yan Liu, Pingzhao Zhang, Ji Nie, Rui Zhao, Qin Shi, Huiru Sun, Dongyue Jiao, Yingji Chen, Xiaying Zhao, Yan Huang, Yao Li, Jian-Yuan Zhao, Wei Xu, Shi-Min Zhao, Chenji Wang.
      Signal transducer and activator 5a (STAT5A) is a classical transcription factor that plays pivotal roles in various biological processes, including tumor initiation and progression. A fraction of STAT5A is localized in the mitochondria, but the biological functions of mitochondrial STAT5A remain obscure. Here, we show that STAT5A interacts with pyruvate dehydrogenase complex (PDC), a mitochondrial gatekeeper enzyme connecting two key metabolic pathways, glycolysis and the tricarboxylic acid cycle. Mitochondrial STAT5A disrupts PDC integrity, thereby inhibiting PDC activity and remodeling cellular glycolysis and oxidative phosphorylation. Mitochondrial translocation of STAT5A is increased under hypoxic conditions. This strengthens the Warburg effect in cancer cells and promotes in vitro cell growth under hypoxia and in vivo tumor growth. Our findings indicate distinct pro-oncogenic roles of STAT5A in energy metabolism, which is different from its classical function as a transcription factor.
    DOI:  https://doi.org/10.1038/s41419-021-03908-0
  16. Prostate. 2021 Jun 25.
    Prostate cancer cells survive anti-androgen and mitochondrial metabolic inhibitors by modulating glycolysis and mitochondrial metabolic activities.
    Hirak S Basu, Nathaniel Wilganowski, Samantha Robertson, James M Reuben, Evan N Cohen, Amado Zurita, Sumankalai Ramachandran, Lian-Chun Xiao, Mark Titus, George Wilding.
       BACKGROUND: Most cancer cells are more glycolytic even under aerobic conditions compared with their normal counterparts. Recent evidence of tumor cell metabolism, however, shows that some tumors also increase mitochondrial oxidative phosphorylation (ox-phos) at some disease states during progression and/or development of drug resistance. Our data show that anti-androgen enzalutamide (ENZA) resistant prostate cancer (PCa) cells use more mitochondrial metabolism leading to higher ox-phos as compared to the ENZA-sensitive cells and can become vulnerable to mitochondrial metabolism targeted therapies.
    METHODS: Seahorse assay, mass spectrometry and high resolution fluorescence confocal microscopy coupled with image analysis has been used to compare mitochondrial metabolism in ENZA-treated and -untreated anti-androgen-sensitive LNCaP and -resistant C4-2, CWR22ν1, and PCa2b cells. Ex vivo fluorescence microscopy and image analysis has been standardized to monitor mitochondrial electron transport (ETS) activity that likely increases ox-phos in circulating tumor cells (CTCs) isolated fom patients undergoing AR-targeted therapies.
    RESULTS: Our data show that PCa cells that are resistant to anti-androgen ENZA switch from glycolysis to ox-phos leading to an increased ETS activity. ENZA pretreated cells are more vulnerable to ETS component complex I inhibitor IACS-010759 (IACS) and mitochondrial glutaminase inhibitor CB-839 that reduces glutamate supply to tricarboxylic acid cycle. CTCs isolated from 6 of 20 patient blood samples showed relatively higher ETS activity than the rest of the patients. All six patients have developed ENZA resistance within less than 6 months of the sample collection.
    CONCLUSION: The enhanced growth inhibitory effects of mitochondrial metabolic inhibitors IACS and CB-839 in ENZA pretreated PCa cells provides a rationale for designing a drug combination trial. Patients can be selected for such trials by monitoring the mitochondrial ETS activities in their CTCs to maximize success.
    DOI:  https://doi.org/10.1002/pros.24146
  17. J Exp Clin Cancer Res. 2021 Jun 23. 40(1): 206
    Metformin induces Ferroptosis by inhibiting UFMylation of SLC7A11 in breast cancer.
    Jingjing Yang, Yulu Zhou, Shuduo Xie, Ji Wang, Zhaoqing Li, Lini Chen, Misha Mao, Cong Chen, Aihua Huang, Yongxia Chen, Xun Zhang, Noor Ul Hassan Khan, Linbo Wang, Jichun Zhou.
       BACKGROUND: Ferroptosis is a newly defined form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxidation and is involved in various pathophysiological conditions, including cancer. Targeting ferroptosis is considered to be a novel anti-cancer strategy. The identification of FDA-approved drugs as ferroptosis inducers is proposed to be a new promising approach for cancer treatment. Despite a growing body of evidence indicating the potential efficacy of the anti-diabetic metformin as an anti-cancer agent, the exact mechanism underlying this efficacy has not yet been fully elucidated.
    METHODS: The UFMylation of SLC7A11 is detected by immunoprecipitation and the expression of UFM1 and SLC7A11 in tumor tissues was detected by immunohistochemical staining. The level of ferroptosis is determined by the level of free iron, total/lipid Ros and GSH in the cells and the morphological changes of mitochondria are observed by transmission electron microscope. The mechanism in vivo was verified by in situ implantation tumor model in nude mice.
    RESULTS: Metformin induces ferroptosis in an AMPK-independent manner to suppress tumor growth. Mechanistically, we demonstrate that metformin increases the intracellular Fe2+ and lipid ROS levels. Specifically, metformin reduces the protein stability of SLC7A11, which is a critical ferroptosis regulator, by inhibiting its UFMylation process. Furthermore, metformin combined with sulfasalazine, the system xc- inhibitor, can work in a synergistic manner to induce ferroptosis and inhibit the proliferation of breast cancer cells.
    CONCLUSIONS: This study is the first to demonstrate that the ability of metformin to induce ferroptosis may be a novel mechanism underlying its anti-cancer effect. In addition, we identified SLC7A11 as a new UFMylation substrate and found that targeting the UFM1/SLC7A11 pathway could be a promising cancer treatment strategy.
    Keywords:  Breast cancer; Ferroptosis; Metformin; SLC7A11; UFMylation
    DOI:  https://doi.org/10.1186/s13046-021-02012-7
  18. Sci Rep. 2021 Jun 23. 11(1): 13163
    Differences in molecular phenotype in mouse and human hypertrophic cardiomyopathy.
    Styliani Vakrou, Yamin Liu, Li Zhu, Gabriela V Greenland, Bahadir Simsek, Virginia B Hebl, Yufan Guan, Kirubel Woldemichael, Conover C Talbot, Miguel A Aon, Ryuya Fukunaga, M Roselle Abraham.
      Hypertrophic cardiomyopathy (HCM) is characterized by phenotypic heterogeneity. We investigated the molecular basis of the cardiac phenotype in two mouse models at established disease stage (mouse-HCM), and human myectomy tissue (human-HCM). We analyzed the transcriptome in 2 mouse models with non-obstructive HCM (R403Q-MyHC, R92W-TnT)/littermate-control hearts at 24 weeks of age, and in myectomy tissue of patients with obstructive HCM/control hearts (GSE36961, GSE36946). Additionally, we examined myocyte redox, cardiac mitochondrial DNA copy number (mtDNA-CN), mt-respiration, mt-ROS generation/scavenging and mt-Ca2+ handling in mice. We identified distinct allele-specific gene expression in mouse-HCM, and marked differences between mouse-HCM and human-HCM. Only two genes (CASQ1, GPT1) were similarly dysregulated in both mutant mice and human-HCM. No signaling pathway or transcription factor was predicted to be similarly dysregulated (by Ingenuity Pathway Analysis) in both mutant mice and human-HCM. Losartan was a predicted therapy only in TnT-mutant mice. KEGG pathway analysis revealed enrichment for several metabolic pathways, but only pyruvate metabolism was enriched in both mutant mice and human-HCM. Both mutant mouse myocytes demonstrated evidence of an oxidized redox environment. Mitochondrial complex I RCR was lower in both mutant mice compared to controls. MyHC-mutant mice had similar mtDNA-CN and mt-Ca2+ handling, but TnT-mutant mice exhibited lower mtDNA-CN and impaired mt-Ca2+ handling, compared to littermate-controls. Molecular profiling reveals differences in gene expression, transcriptional regulation, intracellular signaling and mt-number/function in 2 mouse models at established disease stage. Further studies are needed to confirm differences in gene expression between mouse and human-HCM, and to examine whether cardiac phenotype, genotype and/or species differences underlie the divergence in molecular profiles.
    DOI:  https://doi.org/10.1038/s41598-021-89451-6
  19. Cell Chem Biol. 2021 Jun 08. pii: S2451-9456(21)00260-9. [Epub ahead of print]
    Light-inducible deformation of mitochondria in live cells.
    Yutong Song, Peiyuan Huang, Xiaoying Liu, Zhihao Zhao, Yijin Wang, Bianxiao Cui, Liting Duan.
      Mitochondria, the powerhouse of the cell, are dynamic organelles that undergo constant morphological changes. Increasing evidence indicates that mitochondria morphologies and functions can be modulated by mechanical cues. However, the mechano-sensing and -responding properties of mitochondria and the relation between mitochondrial morphologies and functions are unclear due to the lack of methods to precisely exert mechano-stimulation on and deform mitochondria inside live cells. Here, we present an optogenetic approach that uses light to induce deformation of mitochondria by recruiting molecular motors to the outer mitochondrial membrane via light-activated protein-protein hetero-dimerization. Mechanical forces generated by motor proteins distort the outer membrane, during which the inner mitochondrial membrane can also be deformed. Moreover, this optical method can achieve subcellular spatial precision and be combined with different optical dimerizers and molecular motors. This method presents a mitochondria-specific mechano-stimulator for studying mitochondria mechanobiology and the interplay between mitochondria shapes and functions.
    Keywords:  cryptochrome 2; light-gated hetero-dimerization; mitochondria; mitochondrial morphology; molecular motor; optical dimerizer; optogenetics; organelle mechanobiology
    DOI:  https://doi.org/10.1016/j.chembiol.2021.05.015
  20. Cancer Lett. 2021 Jun 21. pii: S0304-3835(21)00300-1. [Epub ahead of print]
    Suppression of oxidative phosphorylation and IDH2 sensitizes colorectal cancer to a naphthalimide derivative and mitoxantrone.
    Chaochao Ge, Yuxia Wang, Yongli Feng, Senzhen Wang, Kemeng Zhang, Xiaojuan Xu, Zhiyang Zhang, Yuan Zhao, Yanming Wang, Lei Gao, Fujun Dai, Songqiang Xie, Chaojie Wang.
      Colorectal cancer (CRC) is one of the most prevalent cancers worldwide. Oxidative phosphorylation (OXPHOS) has attracted a considerable attention in CRC. It is of great interest to explore novel therapies that inhibit OXPHOS for CRC treatment. Compound 6c is a novel naphthalimide derivative. However, the effects of 6c on CRC and the underlying mechanism are unclear. In this study, 6c suppressed CRC tumor growth and metastasis. RNA-seq data showed that 6c triggered the inhibition of OXPHOS and tricarboxylic acid cycle. 6c specifically inhibited mitochondrial complex III activity and the expression of isocitrate dehydrogenase 2 (IDH2), resulting in oxidative stress. Antioxidants reversed 6c-induced cell death, senescence, and autophagosomes formation. 6c inhibited autophagy flux; however, pretreatment with autophagy inhibitors resulted in the reduction of 6c-induced cytoplasmic vacuolization and proliferation inhibition. Moreover, combinatory treatment of 6c and mitoxantrone (MIT) showed stronger inhibitory effects on CRC compared with the single agent. Downregulation of IDH2 induced reactive oxygen species production, leading to MIT accumulation and autophagic cell death after co-treatment with 6c and MIT. In summary, our findings indicated 6c as a promising candidate for CRC treatment.
    Keywords:  Autophagy; Mitochondria; Reactive oxygen species; Senescence; Tricarboxylic acid cycle
    DOI:  https://doi.org/10.1016/j.canlet.2021.06.015
  21. iScience. 2021 Jun 25. 24(6): 102649
    KEAP1 deficiency drives glucose dependency and sensitizes lung cancer cells and tumors to GLUT inhibition.
    Pranavi Koppula, Kellen Olszewski, Yilei Zhang, Lavanya Kondiparthi, Xiaoguang Liu, Guang Lei, Molina Das, Bingliang Fang, Masha V Poyurovsky, Boyi Gan.
      Metabolic reprogramming in cancer cells can create metabolic liabilities. KEAP1-mutant lung cancer is refractory to most current therapies. Here we show that KEAP1 deficiency promotes glucose dependency in lung cancer cells, and KEAP1-mutant/deficient lung cancer cells are more vulnerable to glucose deprivation than their WT counterparts. Mechanistically, KEAP1 inactivation in lung cancer cells induces constitutive activation of NRF2 transcription factor and aberrant expression of NRF2 target cystine transporter SLC7A11; under glucose limitation, high cystine uptake in KEAP1-inactivated lung cancer cells stimulates toxic intracellular disulfide buildup, NADPH depletion, and cell death, which can be rescued by genetic ablation of NRF2-SLC7A11 axis or treatments inhibiting disulfide accumulation. Finally, we show that KEAP1-inactivated lung cancer cells or xenograft tumors are sensitive to glucose transporter inhibitor. Together, our results reveal that KEAP1 deficiency induces glucose dependency in lung cancer cells and uncover a therapeutically relevant metabolic liability.
    Keywords:  cancer; cell biology; physiology
    DOI:  https://doi.org/10.1016/j.isci.2021.102649
  22. Redox Biol. 2021 Jun 12. pii: S2213-2317(21)00188-9. [Epub ahead of print]45 102030
    Compensatory expression of NRF2-dependent antioxidant genes is required to overcome the lethal effects of Kv11.1 activation in breast cancer cells and PDOs.
    Vitalyi Senyuk, Najmeh Eskandari, Ying Jiang, Rebeca Garcia-Varela, Rachel Sundstrom, Luigi Leanza, Roberta Peruzzo, Mark Burkard, Richard D Minshall, Saverio Gentile.
      Potassium channels are important regulators of cellular homeostasis and targeting these proteins pharmacologically is unveiling important mechanisms in cancer cell biology. Here we demonstrate that pharmacological stimulation of the Kv11.1 potassium channel activity results in mitochondrial reactive oxygen species (ROS) production and fragmentation in breast cancer cell lines and patient-derived organoids independent of breast cancer subtype. mRNA expression profiling revealed that Kv11.1 activity significantly altered expression of genes controlling the production of ROS and endoplasmic-reticulum (ER) stress. Characterization of the transcriptional signature of breast cancer cells treated with Kv11.1 potassium channel activators strikingly revealed an adaptive response to the potentially lethal augmentation of ROS by increasing Nrf2-dependent transcription of antioxidant genes. Nrf2 in this context was shown to promote survival in breast cancer, whereas knockdown of Nrf2 lead to Kv11.1-induced cell death. In conclusion, we found that the Kv11.1 channel activity promotes oxidative stress in breast cancer cells and that suppression of the Nrf2-mediated anti-oxidant survival mechanism strongly sensitized breast cancer cells to a lethal effect of pharmacological activation of Kv11.1.
    Keywords:  Cancer cell survival; Mitochondria; NRF2; Potassium channels
    DOI:  https://doi.org/10.1016/j.redox.2021.102030
  23. JCI Insight. 2021 Jun 22. pii: 143540. [Epub ahead of print]
    Lupus susceptibility gene Esrrg modulates regulatory T cells through mitochondrial metabolism.
    Wei Li, Minghao Gong, Yuk-Pheel Park, Ahmed S Elshikha, Seung-Chul Choi, Josephine Brown, Nathalie Kanda, Wen-I Yeh, Leeana Peters, Anton A Titov, Xiangyu Teng, Todd M Brusko, Laurence Morel.
      Estrogen-related receptor gamma (Esrrg) is a murine lupus susceptibility gene associated with T cell activation. Here, we report that Esrrg controls regulatory T cells (Treg) through mitochondria homeostasis. Esrrg deficiency impaired the maintenance and function of Treg cells, leading to global T cell activation and autoimmunity in aged mice. Further, Esrrg-deficient Treg cells presented an impaired differentiation into follicular Treg (Tfr) cells that enhanced follicular helper T cells (Tfh) responses. Mechanistically, Esrrg-deficient Treg cells presented with dysregulated mitochondria with decreased oxygen consumption as well as ATP and NAD+ production. In addition, Esrrg-deficient Treg cells exhibited decreased phosphatidylinositol and TGF-β signaling pathways and increased mTORC1 activation. We found that the expression of human ESRRG, which is high in Treg cells, was lower in CD4+ T cells from lupus patients than in healthy controls. Finally, knocking down ESRRG in Jurkat T cells decreased their metabolism. Together, our results reveal a critical role of Esrrg in the maintenance and metabolism of Treg cells, which may provide a genetic link between lupus pathogenesis and mitochondrial dysfunction in T cells.
    Keywords:  Autoimmunity; Lupus; Mitochondria; T cells
    DOI:  https://doi.org/10.1172/jci.insight.143540
  24. Nat Commun. 2021 06 21. 12(1): 3820
    Composition and stage dynamics of mitochondrial complexes in Plasmodium falciparum.
    Felix Evers, Alfredo Cabrera-Orefice, Dei M Elurbe, Mariska Kea-Te Lindert, Sylwia D Boltryk, Till S Voss, Martijn A Huynen, Ulrich Brandt, Taco W A Kooij.
      Our current understanding of mitochondrial functioning is largely restricted to traditional model organisms, which only represent a fraction of eukaryotic diversity. The unusual mitochondrion of malaria parasites is a validated drug target but remains poorly understood. Here, we apply complexome profiling to map the inventory of protein complexes across the pathogenic asexual blood stages and the transmissible gametocyte stages of Plasmodium falciparum. We identify remarkably divergent composition and clade-specific additions of all respiratory chain complexes. Furthermore, we show that respiratory chain complex components and linked metabolic pathways are up to 40-fold more prevalent in gametocytes, while glycolytic enzymes are substantially reduced. Underlining this functional switch, we find that cristae are exclusively present in gametocytes. Leveraging these divergent properties and stage dynamics for drug development presents an attractive opportunity to discover novel classes of antimalarials and increase our repertoire of gametocytocidal drugs.
    DOI:  https://doi.org/10.1038/s41467-021-23919-x
  25. Biochim Biophys Acta Mol Cell Biol Lipids. 2021 Jun 17. pii: S1388-1981(21)00120-7. [Epub ahead of print]1866(10): 158992
    Comparative proteomics reveals that lipid droplet-anchored mitochondria are more sensitive to cold in brown adipocytes.
    Ahmed Hammad Mirza, Liujuan Cui, Shuyan Zhang, Pingsheng Liu.
      Brown adipose tissue (BAT) is specialized for uncoupled heat production through mitochondrion fueled majorly from fatty acids (FAs) of lipid droplets (LDs). How the interaction between the two organelles contributes the generation of heat remains elusive. Here, we report that LD-anchored mitochondria (LDAM) were observed in the BAT of mice raised at three different temperatures, 30 °C, 23 °C, and 6 °C. The biochemical analyses including Western blotting of electron transport chain subunits showed that LDAM were functional. Comparative proteomics analysis was conducted, which revealed differential expressions of proteins between LDAM and cytoplasmic mitochondria (CM) at different temperatures. Higher expressions of proteins at low temperature were observed for i) FA β-oxidation in LDAM including FA synthesis and uncoupling, ii) pseudo-futile cycle in CM, and iii) two shuttle systems: glycerol 3-phosphate in both CM and LDAM and citrate malate in CM. Together, these results suggest that LDs and LDAM form a preorganized and functional organelle complex that permits the rapid response to cold.
    Keywords:  BAT; Comparative proteomics; FA β-oxidation; Lipid droplet-anchored mitochondria
    DOI:  https://doi.org/10.1016/j.bbalip.2021.158992
  26. J Biol Chem. 2021 Jun 16. pii: S0021-9258(21)00684-0. [Epub ahead of print] 100884
    mTORC1 Activation is Not Sufficient to Suppress Hepatic PPARα Signaling or Ketogenesis.
    Ebru S Selen, Michael J Wolfgang.
      The mechanistic target of rapamycin (mTOR) is often referred to as a master regulator of cellular metabolism that can integrate growth factor and nutrient signaling. Fasting suppresses hepatic mTORC1 activity via the activity of the Tuberous Sclerosis Complex (TSC), a negative regulator of mTORC1, in order to suppress anabolic metabolism. The loss of TSC1 in the liver locks the liver in a constitutively anabolic state even during fasting, which was suggested to regulate PPARα signaling and ketogenesis, but the molecular determinants of this regulation are unknown. Here, we examined if the activation of the mTORC1 complex in mice by the liver-specific deletion of TSC1 (TSC1L-/-) is sufficient to suppress PPARα signaling and therefore ketogenesis in the fasted state. We found that the activation of mTORC1 in the fasted state is not sufficient to repress PPARα-responsive genes or ketogenesis. Further, we examined whether the activation of the anabolic program mediated by mTORC1 complex activation in the fasted state could suppress the robust catabolic programming and enhanced PPARα transcriptional response of mice with a liver-specific defect in mitochondrial long-chain fatty acid oxidation using Cpt2L-/- mice. We generated liver-specific Cpt2L-/-; Tsc1L-/- double knockout mice and showed that the activation of mTORC1 by deletion of TSC1 could not suppress the catabolic PPARα-mediated phenotype of Cpt2L-/- mice. These data demonstrate that the activation of mTORC1 by the deletion of TSC1 is not sufficient to suppress a PPARα transcriptional program or ketogenesis following fasting.
    Keywords:  Ketogenesis; carnitine palmitoyltransferase 2 (Cpt2); fatty acid oxidation; mTOR; metabolism; peroxisome proliferator-activated receptor alpha (PPARα); β-hydroxybutyrate (βHB)
    DOI:  https://doi.org/10.1016/j.jbc.2021.100884
  27. Cancer Metab. 2021 Jun 25. 9(1): 27
    Impaired anaplerosis is a major contributor to glycolysis inhibitor toxicity in glioma.
    Sunada Khadka, Kenisha Arthur, Yasaman Barekatain, Eliot Behr, Mykia Washington, Jeffrey Ackroyd, Kaitlyn Crowley, Pornpa Suriyamongkol, Yu-Hsi Lin, Cong-Dat Pham, Rafal Zielinski, Marissa Trujillo, James Galligan, Dimitra K Georgiou, John Asara, Florian Muller.
       BACKGROUND: Reprogramming of metabolic pathways is crucial to satisfy the bioenergetic and biosynthetic demands and maintain the redox status of rapidly proliferating cancer cells. In tumors, the tricarboxylic acid (TCA) cycle generates biosynthetic intermediates and must be replenished (anaplerosis), mainly from pyruvate and glutamine. We recently described a novel enolase inhibitor, HEX, and its pro-drug POMHEX. Since glycolysis inhibition would deprive the cell of a key source of pyruvate, we hypothesized that enolase inhibitors might inhibit anaplerosis and synergize with other inhibitors of anaplerosis, such as the glutaminase inhibitor, CB-839.
    METHODS: We analyzed polar metabolites in sensitive (ENO1-deleted) and resistant (ENO1-WT) glioma cells treated with enolase and glutaminase inhibitors. We investigated whether sensitivity to enolase inhibitors could be attenuated by exogenous anaplerotic metabolites. We also determined the synergy between enolase inhibitors and the glutaminase inhibitor CB-839 in glioma cells in vitro and in vivo in both intracranial and subcutaneous tumor models.
    RESULTS: Metabolomic profiling of ENO1-deleted glioma cells treated with the enolase inhibitor revealed a profound decrease in the TCA cycle metabolites with the toxicity reversible upon exogenous supplementation of supraphysiological levels of anaplerotic substrates, including pyruvate. ENO1-deleted cells also exhibited selective sensitivity to the glutaminase inhibitor CB-839, in a manner rescuable by supplementation of anaplerotic substrates or plasma-like media PlasmaxTM. In vitro, the interaction of these two drugs yielded a strong synergistic interaction but the antineoplastic effects of CB-839 as a single agent in ENO1-deleted xenograft tumors in vivo were modest in both intracranial orthotopic tumors, where the limited efficacy could be attributed to the blood-brain barrier (BBB), and subcutaneous xenografts, where BBB penetration is not an issue. This contrasts with the enolase inhibitor HEX, which, despite its negative charge, achieved antineoplastic effects in both intracranial and subcutaneous tumors.
    CONCLUSION: Together, these data suggest that at least for ENO1-deleted gliomas, tumors in vivo-unlike cells in culture-show limited dependence on glutaminolysis and instead primarily depend on glycolysis for anaplerosis. Our findings reinforce the previously reported metabolic idiosyncrasies of in vitro culture and suggest that cell culture media nutrient composition more faithful to the in vivo environment will more accurately predict in vivo efficacy of metabolism targeting drugs.
    Keywords:  Anaplerosis; CB-839; Cancer metabolism; Collateral lethality; Enolase inhibitor; Glutaminolysis; Glycolysis; POMHEX
    DOI:  https://doi.org/10.1186/s40170-021-00259-4
  28. Hum Mol Genet. 2021 Jun 24. pii: ddab168. [Epub ahead of print]
    Coordinated pyruvate kinase activity is crucial for metabolic adaptation and cell survival during mitochondrial dysfunction.
    Xiaoshan Zhou, Flora Mikaeloff, Sophie Curbo, Qian Zhao, Raoul V Kuiper, Ákos Végvári, Ujjwal Neogi, Anna Karlsson.
      Deoxyguanosine kinase (DGUOK) deficiency causes mtDNA depletion and mitochondrial dysfunction. We reported long survival of DGUOK knockout (Dguok-/-) mice despite low (<5%) mtDNA content in liver tissue. However, the molecular mechanisms enabling the extended survival remain unknown. Using transcriptomics, proteomics and metabolomics followed by in vitro assays, we aimed to identify the molecular pathways involved in the extended survival of the Dguok-/- mice. At the early stage, the serine synthesis and folate cycle were activated but declined later. Increased activity of the mitochondrial citric acid cycle (TCA cycle) and the urea cycle and degradation of branched chain amino acids were hallmarks of the extended lifespan in DGUOK deficiency. Furthermore, the increased synthesis of TCA cycle intermediates was supported by coordination of two pyruvate kinase genes, PKLR and PKM, indicating a central coordinating role of pyruvate kinases to support the long-term survival in mitochondrial dysfunction.
    DOI:  https://doi.org/10.1093/hmg/ddab168
  29. Antioxid Redox Signal. 2021 Jun 22.
    Mitochondrial NAD(P)+ transhydrogenase: from molecular features to physiology and disease.
    Annelise Francisco, Tiago Rezende Figueira, Roger Frigerio Castilho.
       SIGNIFICANCE: Proton-translocating NAD(P)+ transhydrogenase, also known as nicotinamide nucleotide transhydrogenase (NNT), catalyzes a reversible reaction coupling the protonmotive force across the inner mitochondrial membrane and hydride (H-, a proton plus two electrons) transfer between the mitochondrial pools of NAD(H) and NADP(H). The forward NNT reaction is a source of NADPH in the mitochondrial matrix, fueling antioxidant and biosynthetic pathways with reductive potential. Despite the greater emphasis given to the net forward reaction, the reverse NNT reaction that oxidizes NADPH also occurs in physiological and pathological conditions. Recent Advances: NNT (dys)function has been linked to various metabolic pathways and disease phenotypes. Most of these findings have been based on spontaneous loss-of-function Nnt mutations found in the C57BL/6J mouse strain (NntC57BL/6J mutation) and disease-causing Nnt mutations in humans. The present review focuses on recent advances based on the mouse NntC57BL/6J mutation.
    CRITICAL ISSUES: Most studies associating NNT function with disease phenotypes have been based on comparisons of inbred mouse strains (with or without the NntC57BL/6J mutation), which creates uncertainties over the actual contribution of NNT in the context of other potential genetic modifiers.
    FUTURE DIRECTIONS: Future research might contribute to understanding the role of NNT in pathological conditions and elucidate how NNT regulates physiological signaling through its forward and reverse reactions. The importance of NNT in redox balance and tumor cell proliferation makes it a potential target of new therapeutic strategies for oxidative-stress-mediated diseases and cancer.
    DOI:  https://doi.org/10.1089/ars.2021.0111
  30. FEBS J. 2021 Jun 26.
    A guide to genetically encoded tools for the study of H2 O2.
    Daria D Smolyarova, Oleg V Podgorny, Dmitry S Bilan, Vsevolod V Belousov.
      Cell metabolism heavily relies on the redox reactions that inevitably generate reactive oxygen species (ROS). It is now well established that ROS fluctuations near basal levels coordinate numerous physiological processes in living organisms, thus exhibiting regulatory functions. Hydrogen peroxide, the most long-lived ROS, is a key contributor to ROS-dependent signal transduction in the cell. H2 O2 is known to impact various targets in the cell, therefore the question of how H2 O2 modulates physiological processes in a highly specific manner is central in redox biology. To resolve this question, novel genetic tools have recently been created for detecting H2 O2 and emulating its generation in living organisms with unmatched spatiotemporal resolution. Here, we review H2 O2 -sensitive genetically encoded fluorescent sensors and opto- and chemogenetic tools for controlled H2 O2 generation.
    Keywords:  D-amino acid oxidase; HyPer; Reactive oxygen species; genetically encoded fluorescent sensors; hydrogen peroxide; roGFP2-based sensors
    DOI:  https://doi.org/10.1111/febs.16088
  31. Dis Model Mech. 2021 Jun 01. pii: dmm048912. [Epub ahead of print]14(6):
    Mitochondrial function in development and disease.
    Marlies P Rossmann, Sonia M Dubois, Suneet Agarwal, Leonard I Zon.
      Mitochondria are organelles with vital functions in almost all eukaryotic cells. Often described as the cellular 'powerhouses' due to their essential role in aerobic oxidative phosphorylation, mitochondria perform many other essential functions beyond energy production. As signaling organelles, mitochondria communicate with the nucleus and other organelles to help maintain cellular homeostasis, allow cellular adaptation to diverse stresses, and help steer cell fate decisions during development. Mitochondria have taken center stage in the research of normal and pathological processes, including normal tissue homeostasis and metabolism, neurodegeneration, immunity and infectious diseases. The central role that mitochondria assume within cells is evidenced by the broad impact of mitochondrial diseases, caused by defects in either mitochondrial or nuclear genes encoding for mitochondrial proteins, on different organ systems. In this Review, we will provide the reader with a foundation of the mitochondrial 'hardware', the mitochondrion itself, with its specific dynamics, quality control mechanisms and cross-organelle communication, including its roles as a driver of an innate immune response, all with a focus on development, disease and aging. We will further discuss how mitochondrial DNA is inherited, how its mutation affects cell and organismal fitness, and current therapeutic approaches for mitochondrial diseases in both model organisms and humans.
    Keywords:  Mitochondrial diseases; Mitochondrial fusion and fission; Mitochondrial unfolded protein response; Mitophagy; mtDNA heteroplasmy and inheritance; mtDNA-mediated innate immune response
    DOI:  https://doi.org/10.1242/dmm.048912
  32. iScience. 2021 Jun 25. 24(6): 102651
    Combined epigenetic and metabolic treatments overcome differentiation blockade in acute myeloid leukemia.
    Barry M Zee, Kamrine E Poels, Cong-Hui Yao, Kimihito C Kawabata, Gongwei Wu, Cihangir Duy, William D Jacobus, Elizabeth Senior, Jennifer E Endress, Ashwini Jambhekar, Scott B Lovitch, Jiexian Ma, Abhinav Dhall, Isaac S Harris, M Andres Blanco, David B Sykes, Jonathan D Licht, David M Weinstock, Ari Melnick, Marcia C Haigis, Franziska Michor, Yang Shi.
      A hallmark of acute myeloid leukemia (AML) is the inability of self-renewing malignant cells to mature into a non-dividing terminally differentiated state. This differentiation block has been linked to dysregulation of multiple cellular processes, including transcriptional, chromatin, and metabolic regulation. The transcription factor HOXA9 and the histone demethylase LSD1 are examples of such regulators that promote differentiation blockade in AML. To identify metabolic targets that interact with LSD1 inhibition to promote myeloid maturation, we screened a small molecule library to identify druggable substrates. We found that differentiation caused by LSD1 inhibition is enhanced by combined perturbation of purine nucleotide salvage and de novo lipogenesis pathways, and identified multiple lines of evidence to support the specificity of these pathways and suggest a potential basis of how perturbation of these pathways may interact synergistically to promote myeloid differentiation. In sum, these findings suggest potential drug combination strategies in the treatment of AML.
    Keywords:  molecular biology; stem cell research; systems biology
    DOI:  https://doi.org/10.1016/j.isci.2021.102651
  33. Nat Commun. 2021 06 23. 12(1): 3896
    Single cell derived mRNA signals across human kidney tumors.
    Matthew D Young, Thomas J Mitchell, Lars Custers, Thanasis Margaritis, Francisco Morales-Rodriguez, Kwasi Kwakwa, Eleonora Khabirova, Gerda Kildisiute, Thomas R W Oliver, Ronald R de Krijger, Marry M van den Heuvel-Eibrink, Federico Comitani, Alice Piapi, Eva Bugallo-Blanco, Christine Thevanesan, Christina Burke, Elena Prigmore, Kirsty Ambridge, Kenny Roberts, Felipe A Vieira Braga, Tim H H Coorens, Ignacio Del Valle, Anna Wilbrey-Clark, Lira Mamanova, Grant D Stewart, Vincent J Gnanapragasam, Dyanne Rampling, Neil Sebire, Nicholas Coleman, Liz Hook, Anne Warren, Muzlifah Haniffa, Marcel Kool, Stefan M Pfister, John C Achermann, Xiaoling He, Roger A Barker, Adam Shlien, Omer A Bayraktar, Sarah A Teichmann, Frank C Holstege, Kerstin B Meyer, Jarno Drost, Karin Straathof, Sam Behjati.
      Tumor cells may share some patterns of gene expression with their cell of origin, providing clues into the differentiation state and origin of cancer. Here, we study the differentiation state and cellular origin of 1300 childhood and adult kidney tumors. Using single cell mRNA reference maps of normal tissues, we quantify reference "cellular signals" in each tumor. Quantifying global differentiation, we find that childhood tumors exhibit fetal cellular signals, replacing the presumption of "fetalness" with a quantitative measure of immaturity. By contrast, in adult cancers our assessment refutes the suggestion of dedifferentiation towards a fetal state in most cases. We find an intimate connection between developmental mesenchymal populations and childhood renal tumors. We demonstrate the diagnostic potential of our approach with a case study of a cryptic renal tumor. Our findings provide a cellular definition of human renal tumors through an approach that is broadly applicable to human cancer.
    DOI:  https://doi.org/10.1038/s41467-021-23949-5
  34. EMBO Mol Med. 2021 Jun 21. e14323
    Very-low-carbohydrate diet enhances human T-cell immunity through immunometabolic reprogramming.
    Simon Hirschberger, Gabriele Strauß, David Effinger, Xaver Marstaller, Alicia Ferstl, Martin B Müller, Tingting Wu, Max Hübner, Tim Rahmel, Hannah Mascolo, Nicole Exner, Julia Heß, Friedrich W Kreth, Kristian Unger, Simone Kreth.
      Very-low-carbohydrate diet triggers the endogenous production of ketone bodies as alternative energy substrates. There are as yet unproven assumptions that ketone bodies positively affect human immunity. We have investigated this topic in an in vitro model using primary human T cells and in an immuno-nutritional intervention study enrolling healthy volunteers. We show that ketone bodies profoundly impact human T-cell responses. CD4+ , CD8+ , and regulatory T-cell capacity were markedly enhanced, and T memory cell formation was augmented. RNAseq and functional metabolic analyses revealed a fundamental immunometabolic reprogramming in response to ketones favoring mitochondrial oxidative metabolism. This confers superior respiratory reserve, cellular energy supply, and reactive oxygen species signaling. Our data suggest a very-low-carbohydrate diet as a clinical tool to improve human T-cell immunity. Rethinking the value of nutrition and dietary interventions in modern medicine is required.
    Keywords:  T-cell immunity; immunometabolism; ketogenic diet; metabolic therapy; nutritional intervention
    DOI:  https://doi.org/10.15252/emmm.202114323
  35. Cell Death Dis. 2021 Jun 19. 12(7): 632
    Mitochondrial Ca2+ oscillation induces mitophagy initiation through the PINK1-Parkin pathway.
    Zhengying Yu, Haipeng Wang, Wanyi Tang, Shaoyang Wang, Xiaoying Tian, Yujie Zhu, Hao He.
      Dysregulation of the PINK1/Parkin-mediated mitophagy is essential to Parkinson's disease. Although important progress has been made in previous researches, the biochemical reagents that induce global and significant mitochondrial damage may still hinder deeper insights into the mechanisms of mitophagy. The origin of PINK1/Parkin pathway activation in mitophagy remains elusive. In this study, we develop an optical method, ultra-precise laser stimulation (UPLaS) that delivers a precise and noninvasive stimulation onto a submicron region in a single mitochondrial tubular structure. UPLaS excites localized mitochondrial Ca2+ (mitoCa2+) oscillations with tiny perturbation to mitochondrial membrane potential (MMP) or mitochondrial reactive oxygen species. The UPLaS-induced mitoCa2+ oscillations can directly induce PINK1 accumulation and Parkin recruitment on mitochondria. The Parkin recruitment by UPLaS requires PINK1. Our results provide a precise and noninvasive technology for research on mitophagy, which stimulates target mitochondria with little damage, and reveal mitoCa2+ oscillation directly initiates the PINK1-Parkin pathway for mitophagy without MMP depolarization.
    DOI:  https://doi.org/10.1038/s41419-021-03913-3
  36. Sci Adv. 2021 Jun;pii: eabg3012. [Epub ahead of print]7(26):
    Systemic regulation of mitochondria by germline proteostasis prevents protein aggregation in the soma of C. elegans.
    Giuseppe Calculli, Hyun Ju Lee, Koning Shen, Uyen Pham, Marija Herholz, Aleksandra Trifunovic, Andrew Dillin, David Vilchez.
      Protein aggregation causes intracellular changes in neurons, which elicit signals to modulate proteostasis in the periphery. Beyond the nervous system, a fundamental question is whether other organs also communicate their proteostasis status to distal tissues. Here, we examine whether proteostasis of the germ line influences somatic tissues. To this end, we induce aggregation of germline-specific PGL-1 protein in germline stem cells of Caenorhabditis elegans Besides altering the intracellular mitochondrial network of germline cells, PGL-1 aggregation also reduces the mitochondrial content of somatic tissues through long-range Wnt signaling pathway. This process induces the unfolded protein response of the mitochondria in the soma, promoting somatic mitochondrial fragmentation and aggregation of proteins linked with neurodegenerative diseases such as Huntington's and amyotrophic lateral sclerosis. Thus, the proteostasis status of germline stem cells coordinates mitochondrial networks and protein aggregation through the organism.
    DOI:  https://doi.org/10.1126/sciadv.abg3012
  37. Cell Rep. 2021 Jun 22. pii: S2211-1247(21)00642-2. [Epub ahead of print]35(12): 109275
    Identification and functional validation of FDA-approved positive and negative modulators of the mitochondrial calcium uniporter.
    Agnese De Mario, Anna Tosatto, Julia Marie Hill, Janos Kriston-Vizi, Robin Ketteler, Denis Vecellio Reane, Gino Cortopassi, Gyorgy Szabadkai, Rosario Rizzuto, Cristina Mammucari.
      The mitochondrial calcium uniporter (MCU), the highly selective channel responsible for mitochondrial Ca2+ entry, plays important roles in physiology and pathology. However, only few pharmacological compounds directly and selectively modulate its activity. Here, we perform high-throughput screening on a US Food and Drug Administration (FDA)-approved drug library comprising 1,600 compounds to identify molecules modulating mitochondrial Ca2+ uptake. We find amorolfine and benzethonium to be positive and negative MCU modulators, respectively. In agreement with the positive effect of MCU in muscle trophism, amorolfine increases muscle size, and MCU silencing is sufficient to blunt amorolfine-induced hypertrophy. Conversely, in the triple-negative breast cancer cell line MDA-MB-231, benzethonium delays cell growth and migration in an MCU-dependent manner and protects from ceramide-induced apoptosis, in line with the role of mitochondrial Ca2+ uptake in cancer progression. Overall, we identify amorolfine and benzethonium as effective MCU-targeting drugs applicable to a wide array of experimental and disease conditions.
    Keywords:  FDA-approved drugs; MCU; amorolfine; benzethonium; high-throughput screening; mitochondrial Ca(2+) uptake; mitochondrial calcium uniporter; skeletal muscle hypertrophy; triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.celrep.2021.109275
  38. Mitochondrion. 2021 Jun 19. pii: S1567-7249(21)00083-0. [Epub ahead of print]
    Blood Mitochondrial DNA Copy Number: What Are We Counting?
    Martin Picard.
      There is growing scientific interest to develop scalable biological measures that capture mitochondrial (dys)function. Mitochondria have their own genome, the mitochondrial DNA (mtDNA), and it has been proposed that the number of mtDNA copies per cell (mtDNA copy number; mtDNAcn) reflects mitochondrial health. The common availability of stored DNA material or existing DNA sequencing data, especially from blood and other easy-to-collect samples, has made its quantification a popular approach in clinical and epidemiological studies. However, the interpretation of mtDNAcn is not univocal, and either a reduction or elevation in mtDNAcn can indicate dysfunction. The major determinants of blood-derived mtDNAcn are the heterogeneous cell type composition of leukocytes and platelet abundance, which can change with time of day, aging, and with disease. Hematopoiesis as a likely driver of blood mtDNAcn. Here we discuss the rationale and available methods to quantify mtDNAcn, the influence of blood cell type variations, and consider important gaps in knowledge that need to be resolved to maximize the scientific output around the investigation of blood mtDNAcn in humans.
    Keywords:  White blood cells; biomarker; count; leukocytes; mitochondrial function; mitochondrial genome; mitochondrion
    DOI:  https://doi.org/10.1016/j.mito.2021.06.010
  39. Clin Cancer Res. 2021 Jun 25. pii: clincanres.5020.2020. [Epub ahead of print]
    PGC1α-Mediated Metabolic Reprogramming Drives the Stemness of Pancreatic Precursor Lesions.
    Rama Krishna Nimmakayala, Sanchita Rauth, Ramakanth Chirravuri Venkata, Saravanakumar Marimuthu, Palanisamy Nallasamy, Raghupathy Vengoji, Subodh M Lele, Satyanarayana Rachagani, Kavita Mallya, Mokenge P Malafa, Moorthy P Ponnusamy, Surinder K Batra.
       PURPOSE: Metabolic reprogramming and cancer stem cells (CSCs) drive the aggressiveness of pancreatic ductal adenocarcinoma (PDAC). However, the metabolic and stemness programs of pancreatic precursor lesions (PPLs), considered early PDAC development events, have not been thoroughly explored.
    EXPERIMENTAL DESIGN: Meta-analyses using gene expression profile data from NCBI GEO and immunohistochemistry on tissue microarrays (TMAs) were performed. The following animal and cellular models were used: cerulean-induced KrasG12D; Pdx1 Cre (KC) acinar-to-ductal metaplasia (ADM) mice, KrasG12D; Smad4Loss; Pdx-1 Cre (KCSmad4-) intraductal papillary mucinous neoplasm (IPMN) mice, LGKC1 cell line derived from the doxycycline-inducible Gnas IPMN model, and human IPMN organoids. Flow cytometry, Seahorse extracellular flux analyzer, qRT-PCR, and sphere assay were used to analyze metabolic and stemness features. SR18292 was used to inhibit PGC1α, and shRNA was used to knockdown (KD) PGC1α.
    RESULTS: The meta-analysis revealed a significant upregulation of specific stemness genes in ADM-mediated pancreatic intraepithelial neoplasms (PanINs) and IPMN. Meta- and TMA analyses followed by in vitro and in vivo validation revealed that ADM/PanIN exhibit increased PGC1α and oxidative phosphorylation (OXPhos) but reduced CPT1A. IPMN showed elevated PGC1α, fatty acid β-oxidation (FAO) gene expression, and FAO-OXPhos. PGC1α was co-overexpressed with its coactivator NRF1 in ADM/PanINs and with PPARγ in IPMN. PGC1α KD or SR18292 inhibited the specific metabolic and stemness features of PPLs and repressed IPMN organoid growth.
    CONCLUSIONS: ADM/PanINs and IPMNs show specific stemness signatures with unique metabolisms. Inhibition of PGC1α using SR18292 diminishes the specific stemness by targeting FAO-independent and FAO-dependent OXPhos of ADM/PanINs and IPMNs, respectively.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-5020
  40. Cell Chem Biol. 2021 Jun 12. pii: S2451-9456(21)00261-0. [Epub ahead of print]
    Intracellular H2S production is an autophagy-dependent adaptive response to DNA damage.
    Xiaofeng Jiang, Michael R MacArthur, J Humberto Treviño-Villarreal, Peter Kip, C Keith Ozaki, Sarah J Mitchell, James R Mitchell.
      Hydrogen sulfide (H2S) is a gasotransmitter with broad physiological activities, including protecting cells against stress, but little is known about the regulation of cellular H2S homeostasis. We have performed a high-content small-molecule screen and identified genotoxic agents, including cancer chemotherapy drugs, as activators of intracellular H2S levels. DNA damage-induced H2S in vitro and in vivo. Mechanistically, DNA damage elevated autophagy and upregulated H2S-generating enzyme CGL; chemical or genetic disruption of autophagy or CGL impaired H2S induction. Importantly, exogenous H2S partially rescued autophagy-deficient cells from genotoxic stress. Furthermore, stressors that are not primarily genotoxic (growth factor depletion and mitochondrial uncoupler FCCP) increased intracellular H2S in an autophagy-dependent manner. Our findings highlight the role of autophagy in H2S production and suggest that H2S generation may be a common adaptive response to DNA damage and other stressors.
    Keywords:  CGL enzyme; DNA damage response; P3 probe; SF7-AM probe; autophagy; cancer chemotherapy; high-throughput screening; hydrogen sulfide; stress response; sulfide metabolism
    DOI:  https://doi.org/10.1016/j.chembiol.2021.05.016
  41. Front Oncol. 2021 ;11 694594
    Anti-Tumor Effects of BDH1 in Acute Myeloid Leukemia.
    Fei Han, Huanhuan Zhao, Jun Lu, Weina Yun, Lingling Yang, Yude Lou, Dan Su, Xin Chen, Shixuan Zhang, Hanwei Jin, Xiang Li, Jie Sun, He Huang, Qishan Wang, Xi Jiang.
      Dysregulation of ketone metabolism has been reported in various types of cancer. In order to find out its role in acute myeloid leukemia (AML) pathogenesis, we first analyzed the expression levels of 10 key genes involved in ketone metabolism in AML blasts and CD34+ hematopoietic stem cells (HSCs) from healthy donors. We found that the expression level of BDH1 was significantly lower in AML than in normal HSCs. The downregulation of BDH1 gene expression in AML cell lines as compared with normal HSCs was further confirmed with real-time RT-PCR. Analysis of TCGA and other database revealed that the downregulation of BDH1 was associated with worse prognosis in AML patients. In addition, we showed that overexpression of BDH1 inhibited the viability and proliferation of AML cells. In contrast, BDH1 knock-down promoted AML cell growth. Collectively, our results suggest the previously unappreciated anti-tumor role of BDH1 in AML, and low BDH1 expression predicts poor survival.
    Keywords:  AML - acute myeloid leukemia; BDH1; ketone; metabolism; prognostic factors; tumor suppressor
    DOI:  https://doi.org/10.3389/fonc.2021.694594
  42. Nat Commun. 2021 06 22. 12(1): 3830
    LINC00842 inactivates transcription co-regulator PGC-1α to promote pancreatic cancer malignancy through metabolic remodelling.
    Xudong Huang, Ling Pan, Zhixiang Zuo, Mei Li, Lingxing Zeng, Rui Li, Ying Ye, Jialiang Zhang, Guandi Wu, Ruihong Bai, Lisha Zhuang, Lusheng Wei, Yanfen Zheng, Jiachun Su, Junge Deng, Shuang Deng, Shaoping Zhang, Shihao Zhu, Xu Che, Chengfeng Wang, Chen Wu, Rufu Chen, Dongxin Lin, Jian Zheng.
      The molecular mechanism underlying pancreatic ductal adenocarcinoma (PDAC) malignancy remains unclear. Here, we characterize a long intergenic non-coding RNA LINC00842 that plays a role in PDAC progression. LINC00842 expression is upregulated in PDAC and induced by high concentration of glucose via transcription factor YY1. LINC00842 binds to and prevents acetylated PGC-1α from deacetylation by deacetylase SIRT1 to form PGC-1α, an important transcription co-factor in regulating cellular metabolism. LINC00842 overexpression causes metabolic switch from mitochondrial oxidative catabolic process to fatty acid synthesis, enhancing the malignant phenotypes of PDAC cells. High LINC00842 levels are correlated with elevated acetylated- PGC-1α levels in PDAC and poor patient survival. Decreasing LINC00842 level and inhibiting fatty acid synthase activity significantly repress PDAC growth and invasiveness in mouse pancreatic xenograft or patient-derived xenograft models. These results demonstrate that LINC00842 plays a role in promoting PDAC malignancy and thus might serve as a druggable target.
    DOI:  https://doi.org/10.1038/s41467-021-23904-4
  43. Sci Rep. 2021 Jun 24. 11(1): 13236
    Fms-like tyrosine kinase 3-internal tandem duplications epigenetically activates checkpoint kinase 1 in acute myeloid leukemia cells.
    Yudong Zhang, Lingli Yuan.
      It is not clear how Fms-like tyrosine kinase 3-internal tandem duplications (FLT3-ITD) regulates checkpoint kinase 1 (CHK1) in acute myeloid leukemia (AML). In this study, we investigated the regulatory effect of FLT3-ITD on CHK1. Our results showed that CHK1 was highly expressed in FLT3-ITD positive AML. The overall survival rate and disease-free survival rate of AML patients with high CHK1 level were lower than those of patients with low CHK1 level. Mechanistically, FLT3-ITD recruited p300 to the CHK1 promoter and subsequently acetylated H3K27, thereby enhancing the transcription of CHK1. Interfering with the expression of CHK1 significantly inhibited the cell proliferation and induced cell apoptosis in FLT3-ITD positive MV4-11 cells. In addition, CHK1 knockdown promoted the sensitivity of MV4-11 cells to the epigenetic inhibitors JQ1 and C646. This study discovers a new therapeutic target for FLT3-ITD + AML and provided evidence for the combination of epigenetic inhibitors for AML treatment.
    DOI:  https://doi.org/10.1038/s41598-021-92566-5
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