bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2022‒10‒23
25 papers selected by
Kelsey Fisher-Wellman, East Carolina University
  1. Single protonation of the reduced quinone in respiratory complex I drives four-proton pumping.
  2. HIRA loss transforms FH-deficient cells.
  3. The cholesterol transport protein GRAMD1C regulates autophagy initiation and mitochondrial bioenergetics.
  4. The metabolite-controlled ubiquitin conjugase Ubc8 promotes mitochondrial protein import.
  5. Assessment of Mitochondrial Dysfunctions After Sirtuin Inhibition.
  6. Nitric oxide-driven modifications of lipoic arm inhibit α-ketoacid dehydrogenases.
  7. Inhibiting glutamine utilization creates a synthetic lethality for suppression of ATP citrate lyase in KRas-driven cancer cells.
  8. Lipids reroute mitochondria.
  9. Tumor-produced and aging-associated oncometabolite methylmalonic acid promotes cancer-associated fibroblast activation to drive metastatic progression.
  10. HSF1 is a driver of leukemia stem cell self-renewal in acute myeloid leukemia.
  11. Parkin coordinates mitochondrial lipid remodeling to execute mitophagy.
  12. Glutamine synthetase limits b-catenin-mutated liver cancer growth by maintaining nitrogen homeostasis and suppressing mTORC1.
  13. Therapeutic resistance in acute myeloid leukemia cells is mediated by a novel ATM/mTOR pathway regulating oxidative phosphorylation.
  14. p53 mutation in normal esophagus promotes multiple stages of carcinogenesis but is constrained by clonal competition.
  15. NAC, NAC, Knockin' on Heaven's door: Interpreting the mechanism of action of N-acetylcysteine in tumor and immune cells.
  16. MTCH2 is a mitochondrial outer membrane protein insertase.
  17. BCAT1 redox function maintains mitotic fidelity.
  18. Gene signature predicting recurrence in oral squamous cell carcinoma is characterized by increased oxidative phosphorylation.
  19. Clinical significance of mitochondrial DNA content in acute promyelocytic leukaemia.
  20. Mammalian oocytes store mRNAs in a mitochondria-associated membraneless compartment.
  21. Purine nucleoside phosphorylase controls nicotinamide riboside metabolism in mammalian cells.
  22. Circulating mitochondrial DNA is associated with anemia in newly diagnosed hematologic malignancies.
  23. Sirtuin5 protects colorectal cancer from DNA damage by keeping nucleotide availability.
  24. Fructose-1,6-bisphosphatase 1 functions as a protein phosphatase to dephosphorylate histone H3 and suppresses PPARα-regulated gene transcription and tumour growth.
  25. Beyond ATP, new roles of mitochondria.
  1. FEBS Lett. 2022 Oct 17.
    Single protonation of the reduced quinone in respiratory complex I drives four-proton pumping.
    Alexei A Stuchebrukhov, Tomoyuki Hayashi.
      Complex I is a key proton-pumping enzyme in bacterial and mitochondrial respiratory electron transport chains. Using quantum chemistry and electrostatic calculations, we have examined the pKa of the reduced quinone QH-/QH2 in the catalytic cavity of complex I. We find that pKa(QH-/QH2) is very high, above 20. This means that the energy of a single protonation reaction of the doubly reduced quinone (i.e. the reduced semiquinone QH-) is sufficient to drive four protons across the membrane with a potential of 180mV. Based on these calculations, we propose a possible scheme of redox-linked proton pumping by complex I. The model explains how the energy of the protonation reaction can be divided equally between four pumping units of the pump, and how a single proton can drive translocation of four additional protons in multiple pumping blocks.
    Keywords:  Mitochondria; NADH dehydrogenase; coupled electron-proton transfer; proton pumping; proton translocation; respiratory complex I
    DOI:  https://doi.org/10.1002/1873-3468.14518
  2. Sci Adv. 2022 Oct 21. 8(42): eabq8297
    HIRA loss transforms FH-deficient cells.
    Lorea Valcarcel-Jimenez, Connor Rogerson, Cissy Yong, Christina Schmidt, Ming Yang, Monica Cremades-Rodelgo, Victoria Harle, Victoria Offord, Kim Wong, Ariane Mora, Alyson Speed, Veronica Caraffini, Maxine Gia Binh Tran, Eamonn R Maher, Grant D Stewart, Sakari Vanharanta, David J Adams, Christian Frezza.
      Fumarate hydratase (FH) is a mitochondrial enzyme that catalyzes the reversible hydration of fumarate to malate in the tricarboxylic acid (TCA) cycle. Germline mutations of FH lead to hereditary leiomyomatosis and renal cell carcinoma (HLRCC), a cancer syndrome characterized by a highly aggressive form of renal cancer. Although HLRCC tumors metastasize rapidly, FH-deficient mice develop premalignant cysts in the kidneys, rather than carcinomas. How Fh1-deficient cells overcome these tumor-suppressive events during transformation is unknown. Here, we perform a genome-wide CRISPR-Cas9 screen to identify genes that, when ablated, enhance the proliferation of Fh1-deficient cells. We found that the depletion of the histone cell cycle regulator (HIRA) enhances proliferation and invasion of Fh1-deficient cells in vitro and in vivo. Mechanistically, Hira loss activates MYC and its target genes, increasing nucleotide metabolism specifically in Fh1-deficient cells, independent of its histone chaperone activity. These results are instrumental for understanding mechanisms of tumorigenesis in HLRCC and the development of targeted treatments for patients.
    DOI:  https://doi.org/10.1126/sciadv.abq8297
  3. Nat Commun. 2022 Oct 21. 13(1): 6283
    The cholesterol transport protein GRAMD1C regulates autophagy initiation and mitochondrial bioenergetics.
    Matthew Yoke Wui Ng, Chara Charsou, Ana Lapao, Sakshi Singh, Laura Trachsel-Moncho, Sebastian W Schultz, Sigve Nakken, Michael J Munson, Anne Simonsen.
      During autophagy, cytosolic cargo is sequestered into double-membrane vesicles called autophagosomes. The contributions of specific lipids, such as cholesterol, to the membranes that form the autophagosome, remain to be fully characterized. Here, we demonstrate that short term cholesterol depletion leads to a rapid induction of autophagy and a corresponding increase in autophagy initiation events. We further show that the ER-localized cholesterol transport protein GRAMD1C functions as a negative regulator of starvation-induced autophagy and that both its cholesterol transport VASt domain and membrane binding GRAM domain are required for GRAMD1C-mediated suppression of autophagy initiation. Similar to its yeast orthologue, GRAMD1C associates with mitochondria through its GRAM domain. Cells lacking GRAMD1C or its VASt domain show increased mitochondrial cholesterol levels and mitochondrial oxidative phosphorylation, suggesting that GRAMD1C may facilitate cholesterol transfer at ER-mitochondria contact sites. Finally, we demonstrate that expression of GRAMD family proteins is linked to clear cell renal carcinoma survival, highlighting the pathophysiological relevance of cholesterol transport proteins.
    DOI:  https://doi.org/10.1038/s41467-022-33933-2
  4. Life Sci Alliance. 2023 Jan;pii: e202201526. [Epub ahead of print]6(1):
    The metabolite-controlled ubiquitin conjugase Ubc8 promotes mitochondrial protein import.
    Saskia Rödl, Fabian den Brave, Markus Räschle, Büsra Kizmaz, Svenja Lenhard, Carina Groh, Hanna Becker, Jannik Zimmermann, Bruce Morgan, Elke Richling, Thomas Becker, Johannes M Herrmann.
      Mitochondria play a key role in cellular energy metabolism. Transitions between glycolytic and respiratory conditions induce considerable adaptations of the cellular proteome. These metabolism-dependent changes are particularly pronounced for the protein composition of mitochondria. Here, we show that the yeast cytosolic ubiquitin conjugase Ubc8 plays a crucial role in the remodeling process when cells transition from respiratory to fermentative conditions. Ubc8 is a conserved and well-studied component of the catabolite control system that is known to regulate the stability of gluconeogenic enzymes. Unexpectedly, we found that Ubc8 also promotes the assembly of the translocase of the outer membrane of mitochondria (TOM) and increases the levels of its cytosol-exposed receptor subunit Tom22. Ubc8 deficiency results in compromised protein import into mitochondria and reduced steady-state levels of mitochondrial proteins. Our observations show that Ubc8, which is controlled by the prevailing metabolic conditions, promotes the switch from glucose synthesis to glucose usage in the cytosol and induces the biogenesis of the mitochondrial TOM machinery to improve mitochondrial protein import during phases of metabolic transition.
    DOI:  https://doi.org/10.26508/lsa.202201526
  5. Methods Mol Biol. 2023 ;2589 269-291
    Assessment of Mitochondrial Dysfunctions After Sirtuin Inhibition.
    Christian Marx, Lisa Marx-Blümel, Jürgen Sonnemann, Zhao-Qi Wang.
      Posttranslational modifications are important for protein functions and cellular signaling pathways. The acetylation of lysine residues is catalyzed by histone acetyltransferases (HATs) and removed by histone deacetylases (HDACs), with the latter being grouped into four phylogenetic classes. The class III of the HDAC family, the sirtuins (SIRTs), contributes to gene expression, genomic stability, cell metabolism, and tumorigenesis. Thus, several specific SIRT inhibitors (SIRTi) have been developed to target cancer cell proliferation. Here we provide an overview of methods to study SIRT-dependent cell metabolism and mitochondrial functionality. The chapter describes metabolic flux analysis using Seahorse analyzers, methods for normalization of Seahorse data, flow cytometry and fluorescence microscopy to determine the mitochondrial membrane potential, mitochondrial content per cell and mitochondrial network structures, and Western blot analysis to measure mitochondrial proteins.
    Keywords:  Flow cytometry; Metabolism; Mitochondria; SIRT; Seahorse analysis; Sirtuin inhibition; Western blot
    DOI:  https://doi.org/10.1007/978-1-0716-2788-4_18
  6. Nat Chem Biol. 2022 Oct 20.
    Nitric oxide-driven modifications of lipoic arm inhibit α-ketoacid dehydrogenases.
    Gretchen L Seim, Steven V John, Nicholas L Arp, Zixiang Fang, David J Pagliarini, Jing Fan.
      Pyruvate dehydrogenase complex (PDHC) and oxoglutarate dehydrogenase complex (OGDC), which belong to the mitochondrial α-ketoacid dehydrogenase family, play crucial roles in cellular metabolism. These multi-subunit enzyme complexes use lipoic arms covalently attached to their E2 subunits to transfer an acyl group to coenzyme A (CoA). Here, we report a novel mechanism capable of substantially inhibiting PDHC and OGDC: reactive nitrogen species (RNS) can covalently modify the thiols on their lipoic arms, generating a series of adducts that block catalytic activity. S-Nitroso-CoA, a product between RNS and the E2 subunit's natural substrate, CoA, can efficiently deliver these modifications onto the lipoic arm. We found RNS-mediated inhibition of PDHC and OGDC occurs during classical macrophage activation, driving significant rewiring of cellular metabolism over time. This work provides a new mechanistic link between RNS and mitochondrial metabolism with potential relevance for numerous physiological and pathological conditions in which RNS accumulate.
    DOI:  https://doi.org/10.1038/s41589-022-01153-w
  7. PLoS One. 2022 ;17(10): e0276579
    Inhibiting glutamine utilization creates a synthetic lethality for suppression of ATP citrate lyase in KRas-driven cancer cells.
    Ahmet Hatipoglu, Deepak Menon, Talia Levy, Maria A Frias, David A Foster.
      Metabolic reprogramming is now considered a hallmark of cancer cells. KRas-driven cancer cells use glutaminolysis to generate the tricarboxylic acid cycle intermediate α-ketoglutarate via a transamination reaction between glutamate and oxaloacetate. We reported previously that exogenously supplied unsaturated fatty acids could be used to synthesize phosphatidic acid-a lipid second messenger that activates both mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and mTOR complex 2 (mTORC2). A key target of mTORC2 is Akt-a kinase that promotes survival and regulates cell metabolism. We report here that mono-unsaturated oleic acid stimulates the phosphorylation of ATP citrate lyase (ACLY) at the Akt phosphorylation site at S455 in an mTORC2 dependent manner. Inhibition of ACLY in KRas-driven cancer cells in the absence of serum resulted in loss of cell viability. We examined the impact of glutamine (Gln) deprivation in combination with inhibition of ACLY on the viability of KRas-driven cancer cells. While Gln deprivation was somewhat toxic to KRas-driven cancer cells by itself, addition of the ACLY inhibitor SB-204990 increased the loss of cell viability. However, the transaminase inhibitor aminooxyacetate was minimally toxic and the combination of SB-204990 and aminooxtacetate led to significant loss of cell viability and strong cleavage of poly-ADP ribose polymerase-indicating apoptotic cell death. This effect was not observed in MCF7 breast cancer cells that do not have a KRas mutation or in BJ-hTERT human fibroblasts which have no oncogenic mutation. These data reveal a synthetic lethality between inhibition of glutamate oxaloacetate transaminase and ACLY inhibition that is specific for KRas-driven cancer cells and the apparent metabolic reprogramming induced by activating mutations to KRas.
    DOI:  https://doi.org/10.1371/journal.pone.0276579
  8. Nat Metab. 2022 Oct;4(10): 1218
    Lipids reroute mitochondria.
    Michael Attwaters.
      
    DOI:  https://doi.org/10.1038/s42255-022-00662-1
  9. Nat Commun. 2022 Oct 20. 13(1): 6239
    Tumor-produced and aging-associated oncometabolite methylmalonic acid promotes cancer-associated fibroblast activation to drive metastatic progression.
    Zhongchi Li, Vivien Low, Valbona Luga, Janet Sun, Ethan Earlie, Bobak Parang, Kripa Shobana Ganesh, Sungyun Cho, Jennifer Endress, Tanya Schild, Mengying Hu, David Lyden, Wenbing Jin, Chunjun Guo, Noah Dephoure, Lewis C Cantley, Ashley M Laughney, John Blenis.
      The systemic metabolic shifts that occur during aging and the local metabolic alterations of a tumor, its stroma and their communication cooperate to establish a unique tumor microenvironment (TME) fostering cancer progression. Here, we show that methylmalonic acid (MMA), an aging-increased oncometabolite also produced by aggressive cancer cells, activates fibroblasts in the TME, which reciprocally secrete IL-6 loaded extracellular vesicles (EVs) that drive cancer progression, drug resistance and metastasis. The cancer-associated fibroblast (CAF)-released EV cargo is modified as a result of reactive oxygen species (ROS) generation and activation of the canonical and noncanonical TGFβ signaling pathways. EV-associated IL-6 functions as a stroma-tumor messenger, activating the JAK/STAT3 and TGFβ signaling pathways in tumor cells and promoting pro-aggressive behaviors. Our findings define the role of MMA in CAF activation to drive metastatic reprogramming, unveiling potential therapeutic avenues to target MMA at the nexus of aging, the tumor microenvironment and metastasis.
    DOI:  https://doi.org/10.1038/s41467-022-33862-0
  10. Nat Commun. 2022 Oct 16. 13(1): 6107
    HSF1 is a driver of leukemia stem cell self-renewal in acute myeloid leukemia.
    Qianze Dong, Yan Xiu, Yang Wang, Christina Hodgson, Nick Borcherding, Craig Jordan, Jane Buchanan, Eric Taylor, Brett Wagner, Mariah Leidinger, Carol Holman, Dennis J Thiele, Sean O'Brien, Hai-Hui Xue, Jinming Zhao, Qingchang Li, Howard Meyerson, Brendan F Boyce, Chen Zhao.
      Acute myeloid leukemia (AML) is maintained by self-renewing leukemic stem cells (LSCs). A fundamental problem in treating AML is that conventional therapy fails to eliminate LSCs, which can reinitiate leukemia. Heat shock transcription factor 1 (HSF1), a central regulator of the stress response, has emerged as an important target in cancer therapy. Using genetic Hsf1 deletion and a direct HSF1 small molecule inhibitor, we show that HSF1 is specifically required for the maintenance of AML, while sparing steady-state and stressed hematopoiesis. Mechanistically, deletion of Hsf1 dysregulates multifaceted genes involved in LSC stemness and suppresses mitochondrial oxidative phosphorylation through downregulation of succinate dehydrogenase C (SDHC), a direct HSF1 target. Forced expression of SDHC largely restores the Hsf1 ablation-induced AML developmental defect. Importantly, the growth and engraftment of human AML cells are suppressed by HSF1 inhibition. Our data provide a rationale for developing efficacious small molecules to specifically target HSF1 in AML.
    DOI:  https://doi.org/10.1038/s41467-022-33861-1
  11. EMBO Rep. 2022 Oct 18. e55191
    Parkin coordinates mitochondrial lipid remodeling to execute mitophagy.
    Chao-Chieh Lin, Jin Yan, Meghan D Kapur, Kristi L Norris, Cheng-Wei Hsieh, De Huang, Nicolas Vitale, Kah-Leong Lim, Ziqiang Guan, Xiao-Fan Wang, Jen-Tsan Chi, Wei-Yuan Yang, Tso-Pang Yao.
      Autophagy has emerged as the prime machinery for implementing organelle quality control. In the context of mitophagy, the ubiquitin E3 ligase Parkin tags impaired mitochondria with ubiquitin to activate autophagic degradation. Although ubiquitination is essential for mitophagy, it is unclear how ubiquitinated mitochondria activate autophagosome assembly locally to ensure efficient destruction. Here, we report that Parkin activates lipid remodeling on mitochondria targeted for autophagic destruction. Mitochondrial Parkin induces the production of phosphatidic acid (PA) and its subsequent conversion to diacylglycerol (DAG) by recruiting phospholipase D2 and activating the PA phosphatase, Lipin-1. The production of DAG requires mitochondrial ubiquitination and ubiquitin-binding autophagy receptors, NDP52 and optineurin (OPTN). Autophagic receptors, via Golgi-derived vesicles, deliver an autophagic activator, EndoB1, to ubiquitinated mitochondria. Inhibition of Lipin-1, NDP52/OPTN, or EndoB1 results in a failure to produce mitochondrial DAG, autophagosomes, and mitochondrial clearance, while exogenous cell-permeable DAG can induce autophagosome production. Thus, mitochondrial DAG production acts downstream of Parkin to enable the local assembly of autophagosomes for the efficient disposal of ubiquitinated mitochondria.
    Keywords:  Lipin-1; PLD2; Parkin; diacylglycerol; mitophagy
    DOI:  https://doi.org/10.15252/embr.202255191
  12. J Clin Invest. 2022 Oct 18. pii: e161408. [Epub ahead of print]
    Glutamine synthetase limits b-catenin-mutated liver cancer growth by maintaining nitrogen homeostasis and suppressing mTORC1.
    Weiwei Dai, Jianliang Shen, Junrong Yan, Alex J Bott, Sara Maimouni, Heineken Q Daguplo, Yujue Wang, Khoosheh Khayati, Jessie Yanxiang Guo, Lanjing Zhang, Yongbo Wang, Alexander Valvezan, Wen-Xing Ding, Xin Chen, Xiaoyang Su, Shenglan Gao, Wei-Xing Zong.
      Glutamine synthetase (GS) catalyzes de novo synthesis of glutamine that facilitates cancer cell growth. In the liver, GS functions next to the urea cycle to remove ammonia waste. As dysregulated urea cycle is implicated in cancer development, the impact of GS' ammonia clearance function has not been explored in cancer. Here we show that, oncogenic activation of beta-catenin led to decreased urea cycle and elevated ammonia waste burden. While beta-catenin induced the expression of GS, which is thought to be cancer-promoting, surprisingly, genetic ablation of hepatic GS accelerated the onset of liver tumors in several mouse models that involved β-catenin activation. Mechanistically, GS ablation exacerbated hyperammonemia and facilitated the production of glutamate-derived non-essential amino acids (NEAAs), which subsequently stimulated mTORC1. Pharmacological and genetic inhibition of mTORC1 and glutamic transaminases suppressed tumorigenesis facilitated by GS ablation. While HCC patients, especially those with CTNNB1 mutations, have an overall defective urea cycle and increased expression of GS, there exists a subset of patients with low GS expression that is associated with mTORC1 hyperactivation. Therefore, GS-mediated ammonia clearance serves as a tumor-suppressing mechanism in livers that harbor β-catenin activation mutations and a compromised urea cycle.
    Keywords:  Hepatology; Liver cancer; Metabolism
    DOI:  https://doi.org/10.1172/JCI161408
  13. Elife. 2022 Oct 19. pii: e79940. [Epub ahead of print]11
    Therapeutic resistance in acute myeloid leukemia cells is mediated by a novel ATM/mTOR pathway regulating oxidative phosphorylation.
    Hae J Park, Mark A Gregory, Vadym Zaberezhnyy, Andrew Goodspeed, Craig T Jordan, Jeffrey S Kieft, James DeGregori.
      While leukemic cells are susceptible to various therapeutic insults, residence in the bone marrow microenvironment typically confers protection from a wide range of drugs. Thus, understanding the unique molecular changes elicited by the marrow is of critical importance towards improving therapeutic outcomes. In the present study, we demonstrate that aberrant activation of oxidative phosphorylation serves to induce therapeutic resistance in FLT3 mutant human AML cells challenged with FLT3 inhibitor drugs. Importantly, our findings show that AML cells are protected from apoptosis following FLT3 inhibition due to marrow-mediated activation of ATM, which in turn up-regulates oxidative phosphorylation via mTOR signaling. mTOR is required for the bone marrow stroma-dependent maintenance of protein translation, with selective polysome enrichment of oxidative phosphorylation transcripts, despite FLT3 inhibition. To investigate the therapeutic significance of this finding, we tested the mTOR inhibitor everolimus in combination with the FLT3 inhibitor quizartinib in primary human AML xenograft models. While marrow resident AML cells were highly resistant to quizartinib alone, the addition of everolimus induced profound reduction in tumor burden and prevented relapse. Taken together, these data provide a novel mechanistic understanding of marrow-based therapeutic resistance, and a promising strategy for improved treatment of FLT3 mutant AML patients.
    Keywords:  cancer biology; human
    DOI:  https://doi.org/10.7554/eLife.79940
  14. Nat Commun. 2022 Oct 20. 13(1): 6206
    p53 mutation in normal esophagus promotes multiple stages of carcinogenesis but is constrained by clonal competition.
    Kasumi Murai, Stefan Dentro, Swee Hoe Ong, Roshan Sood, David Fernandez-Antoran, Albert Herms, Vasiliki Kostiou, Irina Abnizova, Benjamin A Hall, Moritz Gerstung, Philip H Jones.
      Aging normal human oesophagus accumulates TP53 mutant clones. These are the origin of most oesophageal squamous carcinomas, in which biallelic TP53 disruption is almost universal. However, how p53 mutant clones expand and contribute to cancer development is unclear. Here we show that inducing the p53R245W mutant in single oesophageal progenitor cells in transgenic mice confers a proliferative advantage and clonal expansion but does not disrupt normal epithelial structure. Loss of the remaining p53 allele in mutant cells results in genomically unstable p53R245W/null epithelium with giant polyaneuploid cells and copy number altered clones. In carcinogenesis, p53 mutation does not initiate tumour formation, but tumours developing from areas with p53 mutation and LOH are larger and show extensive chromosomal instability compared to lesions arising in wild type epithelium. We conclude that p53 has distinct functions at different stages of carcinogenesis and that LOH within p53 mutant clones in normal epithelium is a critical step in malignant transformation.
    DOI:  https://doi.org/10.1038/s41467-022-33945-y
  15. Redox Biol. 2022 Oct 09. pii: S2213-2317(22)00269-5. [Epub ahead of print]57 102497
    NAC, NAC, Knockin' on Heaven's door: Interpreting the mechanism of action of N-acetylcysteine in tumor and immune cells.
    Balaraman Kalyanaraman.
      N-acetylcysteine (NAC) has been used as a direct scavenger of reactive oxygen species (hydrogen peroxide, in particular) and an antioxidant in cancer biology and immuno-oncology. NAC is the antioxidant drug most frequently employed in studies using tumor cells, immune cells, and preclinical mouse xenografts. Most studies use redox-active fluorescent probes such as dichlorodihydrofluorescein, hydroethidine, mitochondria-targeted hydroethidine, and proprietary kit-based probes (i.e., CellROX Green and CellROX Red) for intracellular detection of superoxide or hydrogen peroxide. Inhibition of fluorescence by NAC was used as a key experimental observation to support the formation of reactive oxygen species and redox mechanisms proposed for ferroptosis, tumor metastasis, and redox signaling in the tumor microenvironment. Reactive oxygen species such as superoxide and hydrogen peroxide stimulate or abrogate tumor cells and immune cells depending on multiple factors. Understanding the mechanism of antioxidants is crucial for interpretation of the results. Because neither NAC nor the fluorescent probes indicated above react directly with hydrogen peroxide, it is critically important to reinterpret the results to advance our understanding of the mechanism of action of NAC and shed additional mechanistic insight on redox-regulated signaling in tumor biology. To this end, this review is focused on how NAC could affect multiple pathways in cancer cells, including iron signaling, ferroptosis, and the glutathione-dependent antioxidant and redox signaling mechanism, and how NAC could inhibit oxidation of the fluorescent probes through multiple mechanisms.
    Keywords:  Antioxidant thiols; Ferroptosis; Fluorescent probes; Mitochondrial reactive oxygen species; Transferrin iron; Tumor metastasis
    DOI:  https://doi.org/10.1016/j.redox.2022.102497
  16. Science. 2022 Oct 21. 378(6617): 317-322
    MTCH2 is a mitochondrial outer membrane protein insertase.
    Alina Guna, Taylor A Stevens, Alison J Inglis, Joseph M Replogle, Theodore K Esantsi, Gayathri Muthukumar, Kelly C L Shaffer, Maxine L Wang, Angela N Pogson, Jeff J Jones, Brett Lomenick, Tsui-Fen Chou, Jonathan S Weissman, Rebecca M Voorhees.
      In the mitochondrial outer membrane, α-helical transmembrane proteins play critical roles in cytoplasmic-mitochondrial communication. Using genome-wide CRISPR screens, we identified mitochondrial carrier homolog 2 (MTCH2), and its paralog MTCH1, and showed that it is required for insertion of biophysically diverse tail-anchored (TA), signal-anchored, and multipass proteins, but not outer membrane β-barrel proteins. Purified MTCH2 was sufficient to mediate insertion into reconstituted proteoliposomes. Functional and mutational studies suggested that MTCH2 has evolved from a solute carrier transporter. MTCH2 uses membrane-embedded hydrophilic residues to function as a gatekeeper for the outer membrane, controlling mislocalization of TAs into the endoplasmic reticulum and modulating the sensitivity of leukemia cells to apoptosis. Our identification of MTCH2 as an insertase provides a mechanistic explanation for the diverse phenotypes and disease states associated with MTCH2 dysfunction.
    DOI:  https://doi.org/10.1126/science.add1856
  17. Cell Rep. 2022 Oct 18. pii: S2211-1247(22)01379-1. [Epub ahead of print]41(3): 111524
    BCAT1 redox function maintains mitotic fidelity.
    Liliana Francois, Pavle Boskovic, Julian Knerr, Wei He, Gianluca Sigismondo, Carsten Schwan, Tushar H More, Magdalena Schlotter, Jeroen Krijgsveld, Karsten Hiller, Robert Grosse, Peter Lichter, Bernhard Radlwimmer.
      The metabolic enzyme branched-chain amino acid transaminase 1 (BCAT1) drives cell proliferation in aggressive cancers such as glioblastoma. Here, we show that BCAT1 localizes to mitotic structures and has a non-metabolic function as a mitotic regulator. Furthermore, BCAT1 is required for chromosome segregation in cancer and induced pluripotent stem cells and tumor growth in human cerebral organoid and mouse syngraft models. Applying gene knockout and rescue strategies, we show that the BCAT1 CXXC redox motif is crucial for controlling cysteine sulfenylation specifically in mitotic cells, promoting Aurora kinase B localization to centromeres, and securing accurate chromosome segregation. These findings offer an explanation for the well-established role of BCAT1 in promoting cancer cell proliferation. In summary, our data establish BCAT1 as a component of the mitotic apparatus that safeguards mitotic fidelity through a moonlighting redox functionality.
    Keywords:  BCAT1; CP: Cell biology; cancer; chromosome segregation; metabolism; mitosis; moonlighting function; redox; stem cells
    DOI:  https://doi.org/10.1016/j.celrep.2022.111524
  18. Mol Oncol. 2022 Oct 22.
    Gene signature predicting recurrence in oral squamous cell carcinoma is characterized by increased oxidative phosphorylation.
    Joo Kyung Noh, Seon Rang Woo, Moonkyoo Kong, Min Kyeong Lee, Jung Woo Lee, Young Chan Lee, Seong-Gyu Ko, Young-Gyu Eun.
      Although numerous studies have used systemic approaches to identify prognostic predictors in oral squamous cell carcinoma (OSCC), the effectiveness of these approaches has not been assessed clinically. Further, the mechanism underlying malignant behaviors in OSCC is poorly characterized. This study aimed to develop and verify accurate prognostic predictors for OSCC patients and assess the associated biology. We identified an OSCC-recurrence-related gene signature (ORGS) using a Cox regression analysis. Functional enrichment analysis was used to identify enriched pathways and biological processes to reveal the underlying mechanism of OSCC malignant behavior. The ORGS successfully divided OSCC patients into low- and high-risk groups with significantly different overall survivals. Pathway analysis revealed oxidative phosphorylation (OXPHOS) as a signaling pathway associated with the ORGS in OSCC. Interestingly, high OXPHOS status was strongly associated with poor overall survival in OSCC patients. Mediator complex subunit 30 (MED30) was a predicted upstream regulator of OXPHOS, and knockdown of MED30 reduced histone acetylation. We identified that the ORGS was strongly correlated with OXPHOS regulatory processes, suggesting OXPHOS as a key mechanism leading to poor prognosis in OSCC.
    Keywords:  MED30; gene signature; mitochondrial membrane potential; oral squamous cell carcinoma; oxidative phosphorylation
    DOI:  https://doi.org/10.1002/1878-0261.13328
  19. Br J Haematol. 2022 Oct 20.
    Clinical significance of mitochondrial DNA content in acute promyelocytic leukaemia.
    Diego A Pereira-Martins, Juan L Coelho-Silva, Isabel Weinhäuser, Pedro L Franca-Neto, Douglas R Silveira, César Ortiz, Amanda Moreira-Aguiar, Marinus M Lima, Luisa C Koury, Raul A de Melo, Ana B Glória, Evandro M Fagundes, Bruno K Lino, Katia Pagnano, Rosane Bittencourt, Elenaide Nunes, Fabiola Traina, Lorena Figueiredo-Pontes, Armand Keating, Martin S Tallman, Raul C Ribeiro, Richard Dilon, Arnold Ganser, Miguel A Sanz, Nancy Berliner, Peter Valk, Bob Löwenberg, Tiziana Ottone, Nelida I Noguera, Maria T Voso, Francesca Paoloni, Paola Fazi, Emanuele Ammatuna, Gerwin Huls, Jan Jacob Schuringa, Eduardo M Rego, Antonio R Lucena-Araujo.
      Although a growing body of evidence demonstrates that altered mtDNA content (mtDNAc) has clinical implications in several types of solid tumours, its prognostic relevance in acute promyelocytic leukaemia (APL) patients remains largely unknown. Here, we show that patients with higher-than-normal mtDNAc had better outcomes regardless of tumour burden. These results were more evident in patients with low-risk of relapse. The multivariate Cox proportional hazard model demonstrated that high mtDNAc was independently associated with a decreased cumulative incidence of relapse. Altogether, our data highlights the possible role of mitochondrial metabolism in APL patients treated with ATRA.
    Keywords:  ATRA; anthracycline-based chemotherapy; mtDNA content; oxidative phosphorylation
    DOI:  https://doi.org/10.1111/bjh.18510
  20. Science. 2022 Oct 21. 378(6617): eabq4835
    Mammalian oocytes store mRNAs in a mitochondria-associated membraneless compartment.
    Shiya Cheng, Gerrit Altmeppen, Chun So, Luisa M Welp, Sarah Penir, Torben Ruhwedel, Katerina Menelaou, Katarina Harasimov, Alexandra Stützer, Martyn Blayney, Kay Elder, Wiebke Möbius, Henning Urlaub, Melina Schuh.
      Full-grown oocytes are transcriptionally silent and must stably maintain the messenger RNAs (mRNAs) needed for oocyte meiotic maturation and early embryonic development. However, where and how mammalian oocytes store maternal mRNAs is unclear. Here, we report that mammalian oocytes accumulate mRNAs in a mitochondria-associated ribonucleoprotein domain (MARDO). MARDO assembly around mitochondria was promoted by the RNA-binding protein ZAR1 and directed by an increase in mitochondrial membrane potential during oocyte growth. MARDO foci coalesced into hydrogel-like matrices that clustered mitochondria. Maternal mRNAs stored in the MARDO were translationally repressed. Loss of ZAR1 disrupted the MARDO, dispersed mitochondria, and caused a premature loss of MARDO-localized mRNAs. Thus, a mitochondria-associated membraneless compartment controls mitochondrial distribution and regulates maternal mRNA storage, translation, and decay to ensure fertility in mammals.
    DOI:  https://doi.org/10.1126/science.abq4835
  21. J Biol Chem. 2022 Oct 17. pii: S0021-9258(22)01058-4. [Epub ahead of print] 102615
    Purine nucleoside phosphorylase controls nicotinamide riboside metabolism in mammalian cells.
    Andrey Kropotov, Veronika Kulikova, Ljudmila Solovjeva, Alexander Yakimov, Kirill Nerinovski, Maria Svetlova, Julia Sudnitsyna, Alena Plusnina, Maria Antipova, Mikhail Khodorkovskiy, Marie E Migaud, Stepan Gambaryan, Mathias Ziegler, Andrey Nikiforov.
      Nicotinamide riboside (NR) is an effective precursor of nicotinamide adenine dinucleotide (NAD) in human and animal cells. NR supplementation can increase the level of NAD in various tissues and thereby improve physiological functions that are weakened or lost in experimental models of aging or various human pathologies. However, there are also reports questioning the efficacy of NR supplementation. Indeed, the mechanisms of its utilization by cells are not fully understood. Herein, we investigated the role of purine nucleoside phosphorylase (PNP) in NR metabolism in mammalian cells. Using both PNP overexpression and genetic knockout, we show that after being imported into cells by members of the equilibrative nucleoside transporter family, NR is predominantly metabolized by PNP, resulting in nicotinamide (Nam) accumulation. Intracellular cleavage of NR to Nam is prevented by the potent PNP inhibitor Immucillin H in various types of mammalian cells. In turn, suppression of PNP activity potentiates NAD synthesis from NR. Combining pharmacological inhibition of PNP with NR supplementation in mice, we demonstrate that the cleavage of the riboside to Nam is strongly diminished, maintaining high levels of NR in blood, kidney and liver. Moreover, we show that PNP inhibition stimulates Nam mononucleotide and NAD+ synthesis from NR in vivo, in particular, in the kidney. Thus, we establish PNP as a major regulator of NR metabolism in mammals and provide evidence that the health benefits of NR supplementation could be greatly enhanced by concomitant downregulation of PNP activity.
    Keywords:  NAD biosynthesis; human; metabolism; mouse; nicotinamide adenine dinucleotide (NAD); nicotinamide riboside; purine nucleoside phosphorylase
    DOI:  https://doi.org/10.1016/j.jbc.2022.102615
  22. Leuk Lymphoma. 2022 Oct 19. 1-10
    Circulating mitochondrial DNA is associated with anemia in newly diagnosed hematologic malignancies.
    Liang Yue, Yu-Hang Li, Rui-Lin Ma, Jing-Wen Niu, Hong-Tu Cui, Yao Sun, Zhi-Min Yun, Hai-Long Zhuo, Lu-Ming Wan, Su-Bo Li, Xue Zhang, Cheng-Jun Wu, Liang-Ding Hu, Ying-Xia Tan.
      Recent reports discovered that red blood cells (RBCs) could scavenge cell-free mitochondrial DNA (mtDNA), which drives the accelerated erythrophagocytosis and innate immune activation characterized by anemia and inflammatory cytokine production. However, the clinical value of the circulating mtDNA copy number alterations in hematologic malignancies is poorly understood. Our data showed that in comparison to healthy group, the patients group had significantly higher mtDNA and histone H4 levels. Moreover, we observed that RBC-bound mtDNA and histone H4 were negatively correlated with hemoglobin in patients. In addition, cytokines and chemokines levels in patients differed significantly from normal controls (21 higher, 7 lower). Our study suggested that both circulating mtDNA and histone H4 were associated with anemia in hematologic malignancies, which helps to further understand the potential mechanism of anemia development in patients with hematologic malignancies. This information may play a vital role in the specific therapeutic interventions for leukemia in the future.
    Keywords:  Mitochondrial DNA; RBC; anemia; hematologic malignancies
    DOI:  https://doi.org/10.1080/10428194.2022.2133537
  23. Nat Commun. 2022 Oct 17. 13(1): 6121
    Sirtuin5 protects colorectal cancer from DNA damage by keeping nucleotide availability.
    Hao-Lian Wang, Yan Chen, Yun-Qian Wang, En-Wei Tao, Juan Tan, Qian-Qian Liu, Chun-Min Li, Xue-Mei Tong, Qin-Yan Gao, Jie Hong, Ying-Xuan Chen, Jing-Yuan Fang.
      In our previous study, we reported that sirtuin5 (SIRT5), a member of the NAD+-dependent class III histone deacetylase family, is highly expressed in colorectal cancer (CRC). Herein we show that SIRT5 knockdown impairs the production of ribose-5-phosphate, which is essential for nucleotide synthesis, resulting in continuous and irreparable DNA damage and consequently leading to cell cycle arrest and enhanced apoptosis in CRC cells. These SIRT5 silencing-induced effects can be reversed by nucleoside supplementation. Mechanistically, SIRT5 activates transketolase (TKT), a key enzyme in the non-oxidative pentose phosphate pathway, in a demalonylation-dependent manner. Furthermore, TKT is essential for SIRT5-induced malignant phenotypes of CRC both in vivo and in vitro. Altogether, SIRT5 silencing induces DNA damage in CRC via post-translational modifications and inhibits tumor growth, suggesting that SIRT5 can serve as a promising target for CRC treatment.
    DOI:  https://doi.org/10.1038/s41467-022-33903-8
  24. Nat Cell Biol. 2022 Oct 20.
    Fructose-1,6-bisphosphatase 1 functions as a protein phosphatase to dephosphorylate histone H3 and suppresses PPARα-regulated gene transcription and tumour growth.
    Zheng Wang, Min Li, Hongfei Jiang, Shudi Luo, Fei Shao, Yan Xia, Mengke Yang, Xiangle Ren, Tong Liu, Meisi Yan, Xu Qian, Haiyan He, Dong Guo, Yuran Duan, Ke Wu, Lei Wang, Guimei Ji, Yuli Shen, Lin Li, Peixiang Zheng, Bofei Dong, Jing Fang, Min Zheng, Tingbo Liang, Haitao Li, Rilei Yu, Daqian Xu, Zhimin Lu.
      Tumour cells exhibit greater metabolic plasticity than normal cells and possess selective advantages for survival and proliferation with unclearly defined mechanisms. Here we demonstrate that glucose deprivation in normal hepatocytes induces PERK-mediated fructose-1,6-bisphosphatase 1 (FBP1) S170 phosphorylation, which converts the FBP1 tetramer to monomers and exposes its nuclear localization signal for nuclear translocation. Importantly, nuclear FBP1 binds PPARα and functions as a protein phosphatase that dephosphorylates histone H3T11 and suppresses PPARα-mediated β-oxidation gene expression. In contrast, FBP1 S124 is O-GlcNAcylated by overexpressed O-linked N-acetylglucosamine transferase in hepatocellular carcinoma cells, leading to inhibition of FBP1 S170 phosphorylation and enhancement of β-oxidation for tumour growth. In addition, FBP1 S170 phosphorylation inversely correlates with β-oxidation gene expression in hepatocellular carcinoma specimens and patient survival duration. These findings highlight the differential role of FBP1 in gene regulation in normal and tumour cells through direct chromatin modulation and underscore the inactivation of its protein phosphatase function in tumour growth.
    DOI:  https://doi.org/10.1038/s41556-022-01009-4
  25. Biochem (Lond). 2022 Aug;44(4): 2-8
    Beyond ATP, new roles of mitochondria.
    Ram Prosad Chakrabarty, Navdeep S Chandel.
      Mitochondria, special double-membraned intracellular compartments or 'organelles', are popularly known as the 'powerhouses of the cell', as they generate the bulk of ATP used to fuel cellular biochemical reactions. Mitochondria are also well known for generating metabolites for the synthesis of macromolecules (e.g., carbohydrates, proteins, lipids and nucleic acids). In the mid-1990s, new evidence suggesting that mitochondria, beyond their canonical roles in bioenergetics and biosynthesis, can act as signalling organelles began to emerge, bringing a dramatic shift in our view of mitochondria's roles in controlling cell function. Over the next two and half decades, works from multiple groups have demonstrated how mitochondrial signalling can dictate diverse physiological and pathophysiological outcomes. In this article, we will briefly discuss different mechanisms by which mitochondria can communicate with cytosol and other organelles to regulate cell fate and function and exert paracrine effects. Our molecular understanding of mitochondrial communication with the rest of the cell, i.e. mitochondrial signalling, could reveal new therapeutic strategies to improve health and ameliorate diseases.
    DOI:  https://doi.org/10.1042/bio_2022_119
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