bims-mibica 2023-10-15 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2023‒10‒15
thirty-two papers selected by
Kelsey Fisher-Wellman, East Carolina University

Forward genetic screens identify mechanisms of resistance to small molecule lactate dehydrogenase inhibitors.
Structural rather than catalytic role for mitochondrial respiratory chain supercomplexes.
COX17 acetylation via MOF-KANSL complex promotes mitochondrial integrity and function.
ApoE enhances mitochondrial metabolism via microRNA-142a/146a-regulated circuits that suppress hematopoiesis and inflammation in hyperlipidemia.
Apoptotic stress causes mtDNA release during senescence and drives the SASP.
The functional significance of mitochondrial respiratory chain supercomplexes.
Inhibition of mitochondrial fission activates glycogen synthesis to support cell survival in colon cancer.
PPTC7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy.
The Pro-Oncogenic Protein IF1 Promotes Proliferation of Anoxic Cancer Cells during Re-Oxygenation.
Mitochondrial DNA breaks activate an integrated stress response to reestablish homeostasis.
Tetracyclines activate mitoribosome quality control and reduce ER stress to promote cell survival.
Profiling mitochondrial DNA mutations in tumors and circulating extracellular vesicles of triple-negative breast cancer patients for potential biomarker development.
Combined inhibition of pyruvate dehydrogenase kinase 1 and lactate dehydrogenase a induces metabolic and signaling reprogramming and enhances lung adenocarcinoma cell killing.
Positive regulation of oxidative phosphorylation by nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice.
STAT3 modulates CD4+ T mitochondrial dynamics and function in aging.
Improved CAR-T cell activity associated with increased mitochondrial function primed by galactose.
MYC is a regulator of androgen receptor inhibition-induced metabolic requirements in prostate cancer.
Identification of the mitochondrial protein POLRMT as a potential therapeutic target of prostate cancer.
The landscape of cell-free mitochondrial DNA in liquid biopsy for cancer detection.
Anti-leukemia effects of omipalisib in acute myeloid leukemia: inhibition of PI3K/AKT/mTOR signaling and suppression of mitochondrial biogenesis.
The known unknowns of mitochondrial carcinogenesis: de novo NUMTs and intercellular mitochondrial transfer.
Tumor Immunogenicity Is Enhanced by Altering Mitochondrial Electron Flow.
Higher-order structural organization of the mitochondrial proteome charted by in situ cross-linking mass spectrometry.
Systematic investigation of mitochondrial transfer between cancer cells and T cells at single-cell resolution.
HDGF Stimulates Liver Tumorigenesis by Enhancing Reactive Oxygen Species Generation in Mitochondria.
A concerted ATPase cycle of the protein transporter AAA-ATPase Bcs1.
BCL-xL Targeting to Induce Apoptosis and to Eliminate Chemotherapy-Induced Senescent Tumor Cells: From Navitoclax to Platelet-Sparing BCL-xL PROTACs.
Targeting pancreatic cancer metabolic dependencies through glutamine antagonism.
Intermittent fasting induced ketogenesis inhibits mouse epithelial ovarian cancer by promoting antitumor T cell response.
The Determination of Mitochondrial Mass Is a Prerequisite for Accurate Assessment of Peripheral Blood Mononuclear Cells' Oxidative Metabolism.
Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma.
Oncogenic context shapes the fitness landscape of tumor suppression.

bioRxiv. 2023 Sep 30. pii: 2023.09.30.560315. [Epub ahead of print]

Forward genetic screens identify mechanisms of resistance to small molecule lactate dehydrogenase inhibitors.

Anderson R Frank, Florentina Vandiver, David G McFadden.

Altered metabolism is a hallmark of cancer; however, it has been difficult to specifically target metabolism in cancer for therapeutic benefit. Cancers with genetically defined defects in metabolic enzymes constitute a subset of cancers where targeting metabolism is potentially accessible. Hürthle cell carcinoma of the thyroid (HTC) tumors frequently harbor deleterious mitochondrial DNA (mtDNA) mutations in subunits of complex I of the mitochondrial electron transport chain (ETC). Previous work has shown that HTC models with deleterious mtDNA mutations exhibit mitochondrial ETC defects that expose lactate dehydrogenase (LDH) as a therapeutic vulnerability. Here, we performed forward genetic screens to identify mechanisms of resistance to small molecule LDH inhibitors. We identified two distinct mechanisms of resistance: upregulation of an LDH isoform and a compound-specific resistance mutation. Using these tools, we demonstrate that the anti-cancer activity of LDH inhibitors in cell line and xenograft models of complex I-mutant HTC is through on-target LDH inhibition.

DOI: https://doi.org/10.1101/2023.09.30.560315
Elife. 2023 Oct 12. pii: RP88084. [Epub ahead of print]12

Structural rather than catalytic role for mitochondrial respiratory chain supercomplexes.

Michele Brischigliaro, Alfredo Cabrera-Orefice, Susanne Arnold, Carlo Viscomi, Massimo Zeviani, Erika Fernández-Vizarra.

  Mammalian mitochondrial respiratory chain (MRC) complexes are able to associate into quaternary structures named supercomplexes (SCs), which normally coexist with non-bound individual complexes. The functional significance of SCs has not been fully clarified and the debate has been centered on whether or not they confer catalytic advantages compared with the non-bound individual complexes. Mitochondrial respiratory chain organization does not seem to be conserved in all organisms. In fact, and differently from mammalian species, mitochondria from Drosophila melanogaster tissues are characterized by low amounts of SCs, despite the high metabolic demands and MRC activity shown by these mitochondria. Here, we show that attenuating the biogenesis of individual respiratory chain complexes was accompanied by increased formation of stable SCs, which are missing in Drosophila melanogaster in physiological conditions. This phenomenon was not accompanied by an increase in mitochondrial respiratory activity. Therefore, we conclude that SC formation is necessary to stabilize the complexes in suboptimal biogenesis conditions, but not for the enhancement of respiratory chain catalysis.

Keywords:  D. melanogaster; Drosophila; Mitochondria; OXPHOS; biochemistry; chemical biology; supercomplexes

DOI:  https://doi.org/10.7554/eLife.88084
Nat Metab. 2023 Oct 09.

COX17 acetylation via MOF-KANSL complex promotes mitochondrial integrity and function.

Sukanya Guhathakurta, Niyazi Umut Erdogdu, Juliane J Hoffmann, Iga Grzadzielewska, Alexander Schendzielorz, Janine Seyfferth, Christoph U Mårtensson, Mauro Corrado, Adam Karoutas, Bettina Warscheid, Nikolaus Pfanner, Thomas Becker, Asifa Akhtar.

Reversible acetylation of mitochondrial proteins is a regulatory mechanism central to adaptive metabolic responses. Yet, how such functionally relevant protein acetylation is achieved remains unexplored. Here we reveal an unprecedented role of the MYST family lysine acetyltransferase MOF in energy metabolism via mitochondrial protein acetylation. Loss of MOF-KANSL complex members leads to mitochondrial defects including fragmentation, reduced cristae density and impaired mitochondrial electron transport chain complex IV integrity in primary mouse embryonic fibroblasts. We demonstrate COX17, a complex IV assembly factor, as a bona fide acetylation target of MOF. Loss of COX17 or expression of its non-acetylatable mutant phenocopies the mitochondrial defects observed upon MOF depletion. The acetylation-mimetic COX17 rescues these defects and maintains complex IV activity even in the absence of MOF, suggesting an activatory role of mitochondrial electron transport chain protein acetylation. Fibroblasts from patients with MOF syndrome who have intellectual disability also revealed respiratory defects that could be restored by alternative oxidase, acetylation-mimetic COX17 or mitochondrially targeted MOF. Overall, our findings highlight the critical role of MOF-KANSL complex in mitochondrial physiology and provide new insights into MOF syndrome.

DOI: https://doi.org/10.1038/s42255-023-00904-w
Cell Rep. 2023 Oct 11. pii: S2211-1247(23)01218-4. [Epub ahead of print]42(10): 113206

ApoE enhances mitochondrial metabolism via microRNA-142a/146a-regulated circuits that suppress hematopoiesis and inflammation in hyperlipidemia.

Tuan Anh Phu, Ngan K Vu, Martin Ng, Alex S Gao, Joshua S Stoolman, Navdeep S Chandel, Robert L Raffai.

  Apolipoprotein E (ApoE) is recognized for its pleiotropic properties that suppress inflammation. We report that ApoE serves as a metabolic rheostat that regulates microRNA control of glycolytic and mitochondrial activity in myeloid cells and hematopoietic stem and progenitor cells (HSPCs). ApoE expression in myeloid cells increases microRNA-146a, which reduces nuclear factor κB (NF-κB)-driven GLUT1 expression and glycolytic activity. In contrast, ApoE expression reduces microRNA-142a, which increases carnitine palmitoyltransferase 1a (CPT1A) expression, fatty acid oxidation, and oxidative phosphorylation. Improved mitochondrial metabolism by ApoE expression causes an enrichment of tricarboxylic acid (TCA) cycle metabolites and nicotinamide adenine dinucleotide (NAD+) in macrophages. The study of mice with conditional ApoE expression supports the capacity of ApoE to foster microRNA-controlled immunometabolism. Modulation of microRNA-146a and -142a in the hematopoietic system of hyperlipidemic mice using RNA mimics and antagonists, respectively, improves mitochondrial metabolism, which suppresses inflammation and hematopoiesis. Our findings unveil microRNA regulatory circuits, controlled by ApoE, that exert metabolic control over hematopoiesis and inflammation in hyperlipidemia.

Keywords:  ApoE; CP: Metabolism; CPT1A; Glut1; fatty acid oxidation; hematopoiesis; inflammation; macrophage; microRNA-142a; microRNA-146a; mitochondrial metabolism

DOI:  https://doi.org/10.1016/j.celrep.2023.113206
Nature. 2023 Oct 11.

Apoptotic stress causes mtDNA release during senescence and drives the SASP.

Stella Victorelli, Hanna Salmonowicz, James Chapman, Helene Martini, Maria Grazia Vizioli, Joel S Riley, Catherine Cloix, Ella Hall-Younger, Jair Machado Espindola-Netto, Diana Jurk, Anthony B Lagnado, Lilian Sales Gomez, Joshua N Farr, Dominik Saul, Rebecca Reed, George Kelly, Madeline Eppard, Laura C Greaves, Zhixun Dou, Nicholas Pirius, Karolina Szczepanowska, Rebecca A Porritt, Huijie Huang, Timothy Y Huang, Derek A Mann, Claudio Akio Masuda, Sundeep Khosla, Haiming Dai, Scott H Kaufmann, Emmanouil Zacharioudakis, Evripidis Gavathiotis, Nathan K LeBrasseur, Xue Lei, Alva G Sainz, Viktor I Korolchuk, Peter D Adams, Gerald S Shadel, Stephen W G Tait, João F Passos.

Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS-STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.

DOI: https://doi.org/10.1038/s41586-023-06621-4
EMBO Rep. 2023 Oct 12. e57092

The functional significance of mitochondrial respiratory chain supercomplexes.

Andreas Kohler, Antoni Barrientos, Flavia Fontanesi, Martin Ott.

  The mitochondrial respiratory chain (MRC) is a key energy transducer in eukaryotic cells. Four respiratory chain complexes cooperate in the transfer of electrons derived from various metabolic pathways to molecular oxygen, thereby establishing an electrochemical gradient over the inner mitochondrial membrane that powers ATP synthesis. This electron transport relies on mobile electron carries that functionally connect the complexes. While the individual complexes can operate independently, they are in situ organized into large assemblies termed respiratory supercomplexes. Recent structural and functional studies have provided some answers to the question of whether the supercomplex organization confers an advantage for cellular energy conversion. However, the jury is still out, regarding the universality of these claims. In this review, we discuss the current knowledge on the functional significance of MRC supercomplexes, highlight experimental limitations, and suggest potential new strategies to overcome these obstacles.

Keywords:  Mitochondria; bioenergetics; electron transfer; respiratory chain; supercomplexes

DOI:  https://doi.org/10.15252/embr.202357092
Cell Death Dis. 2023 Oct 10. 14(10): 664

Inhibition of mitochondrial fission activates glycogen synthesis to support cell survival in colon cancer.

Sumati Hasani, Lyndsay E A Young, Warren Van Nort, Moumita Banerjee, Dylan R Rivas, Jinhwan Kim, Xiaopeng Xiong, Ramon C Sun, Matthew S Gentry, Hiromi Sesaki, Tianyan Gao.

Metabolic reprogramming has been recognized as one of the major mechanisms that fuel tumor initiation and progression. Our previous studies demonstrate that activation of Drp1 promotes fatty acid oxidation and downstream Wnt signaling. Here we investigate the role of Drp1 in regulating glycogen metabolism in colon cancer. Knockdown of Drp1 decreases mitochondrial respiration without increasing glycolysis. Analysis of cellular metabolites reveals that the levels of glucose-6-phosphate, a precursor for glycogenesis, are significantly elevated whereas pyruvate and other TCA cycle metabolites remain unchanged in Drp1 knockdown cells. Additionally, silencing Drp1 activates AMPK to stimulate the expression glycogen synthase 1 (GYS1) mRNA and promote glycogen storage. Using 3D organoids from Apcf/f/Villin-CreERT2 models, we show that glycogen levels are elevated in tumor organoids upon genetic deletion of Drp1. Similarly, increased GYS1 expression and glycogen accumulation are detected in xenograft tumors derived from Drp1 knockdown colon cancer cells. Functionally, increased glycogen storage provides survival advantage to Drp1 knockdown cells. Co-targeting glycogen phosphorylase-mediated glycogenolysis sensitizes Drp1 knockdown cells to chemotherapy drug treatment. Taken together, our results suggest that Drp1-loss activates glucose uptake and glycogenesis as compensative metabolic pathways to promote cell survival. Combined inhibition of glycogen metabolism may enhance the efficacy of chemotherapeutic agents for colon cancer treatment.

DOI: https://doi.org/10.1038/s41419-023-06202-3
Nat Commun. 2023 Oct 13. 14(1): 6431

PPTC7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy.

Natalie M Niemi, Lia R Serrano, Laura K Muehlbauer, Catherine E Balnis, Lianjie Wei, Andrew J Smith, Keri-Lyn Kozul, Merima Forny, Olivia M Connor, Edrees H Rashan, Evgenia Shishkova, Kathryn L Schueler, Mark P Keller, Alan D Attie, Jonathan R Friedman, Julia K Pagan, Joshua J Coon, David J Pagliarini.

PPTC7 is a resident mitochondrial phosphatase essential for maintaining proper mitochondrial content and function. Newborn mice lacking Pptc7 exhibit aberrant mitochondrial protein phosphorylation, suffer from a range of metabolic defects, and fail to survive beyond one day after birth. Using an inducible knockout model, we reveal that loss of Pptc7 in adult mice causes marked reduction in mitochondrial mass and metabolic capacity with elevated hepatic triglyceride accumulation. Pptc7 knockout animals exhibit increased expression of the mitophagy receptors BNIP3 and NIX, and Pptc7-/- mouse embryonic fibroblasts (MEFs) display a major increase in mitophagy that is reversed upon deletion of these receptors. Our phosphoproteomics analyses reveal a common set of elevated phosphosites between perinatal tissues, adult liver, and MEFs, including multiple sites on BNIP3 and NIX, and our molecular studies demonstrate that PPTC7 can directly interact with and dephosphorylate these proteins. These data suggest that Pptc7 deletion causes mitochondrial dysfunction via dysregulation of several metabolic pathways and that PPTC7 may directly regulate mitophagy receptor function or stability. Overall, our work reveals a significant role for PPTC7 in the mitophagic response and furthers the growing notion that management of mitochondrial protein phosphorylation is essential for ensuring proper organelle content and function.

DOI: https://doi.org/10.1038/s41467-023-42069-w
Int J Mol Sci. 2023 Sep 27. pii: 14624. [Epub ahead of print]24(19):

The Pro-Oncogenic Protein IF1 Promotes Proliferation of Anoxic Cancer Cells during Re-Oxygenation.

Riccardo Righetti, Silvia Grillini, Valentina Del Dotto, Anna Costanzini, Francesca Liuzzi, Claudia Zanna, Gianluca Sgarbi, Giancarlo Solaini, Alessandra Baracca.

  Cancer cells overexpress IF1, the endogenous protein that inhibits the hydrolytic activity of ATP synthase when mitochondrial membrane potential (ΔμH+) falls, as in ischemia. Other roles have been ascribed to IF1, but the associated molecular mechanisms are still under debate. We investigated the ability of IF1 to promote survival and proliferation in osteosarcoma and colon carcinoma cells exposed to conditions mimicking ischemia and reperfusion, as occurs in vivo, particularly in solid tumors. IF1-silenced and parental cells were exposed to the FCCP uncoupler to collapse ΔμH+ and the bioenergetics of cell models were validated. All the uncoupled cells preserved mitochondrial mass, but the implemented mechanisms differed in IF1-expressing and IF1-silenced cells. Indeed, the membrane potential collapse and the energy charge preservation allowed an increase in both mitophagy and mitochondrial biogenesis in IF1-expressing cells only. Interestingly, the presence of IF1 also conferred a proliferative advantage to cells highly dependent on oxidative phosphorylation when the uncoupler was washed out, mimicking cell re-oxygenation. Overall, our results indicate that IF1, by allowing energy preservation and promoting mitochondrial renewal, can favor proliferation of anoxic cells and tumor growth. Therefore, hindering the action of IF1 may be promising for the therapy of tumors that rely on oxidative phosphorylation for energy production.

Keywords:  143B osteosarcoma cells; ATP synthase; HCT116 colon carcinoma cells; anoxia; autophagy; biogenesis; metabolism; mitochondria; mitophagy; oxidative phosphorylation

DOI:  https://doi.org/10.3390/ijms241914624
Mol Cell. 2023 Oct 08. pii: S1097-2765(23)00753-0. [Epub ahead of print]

Mitochondrial DNA breaks activate an integrated stress response to reestablish homeostasis.

Yi Fu, Olivia Sacco, Emily DeBitetto, Evgeny Kanshin, Beatrix Ueberheide, Agnel Sfeir.

  Mitochondrial DNA double-strand breaks (mtDSBs) lead to the degradation of circular genomes and a reduction in copy number; yet, the cellular response in human cells remains elusive. Here, using mitochondrial-targeted restriction enzymes, we show that a subset of cells with mtDSBs exhibited defective mitochondrial protein import, reduced respiratory complexes, and loss of membrane potential. Electron microscopy confirmed the altered mitochondrial membrane and cristae ultrastructure. Intriguingly, mtDSBs triggered the integrated stress response (ISR) via the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) by DELE1 and heme-regulated eIF2α kinase (HRI). When ISR was inhibited, the cells experienced intensified mitochondrial defects and slower mtDNA recovery post-breakage. Lastly, through proteomics, we identified ATAD3A-a membrane-bound protein interacting with nucleoids-as potentially pivotal in relaying signals from impaired genomes to the inner mitochondrial membrane. In summary, our study delineates the cascade connecting damaged mitochondrial genomes to the cytoplasm and highlights the significance of the ISR in maintaining mitochondrial homeostasis amid genome instability.

Keywords:  ATAD3A; double-strand breaks; integrated stress response; mitochondrial DNA; protein import

DOI:  https://doi.org/10.1016/j.molcel.2023.09.026
EMBO Rep. 2023 Oct 11. e57228

Tetracyclines activate mitoribosome quality control and reduce ER stress to promote cell survival.

Conor T Ronayne, Thomas D Jackson, Christopher F Bennett, Elizabeth A Perry, Noa Kantorovic, Pere Puigserver.

  Mitochondrial diseases are a group of disorders defined by defects in oxidative phosphorylation caused by nuclear- or mitochondrial-encoded gene mutations. A main cellular phenotype of mitochondrial disease mutations is redox imbalances and inflammatory signaling underlying pathogenic signatures of these patients. One method to rescue this cell death vulnerability is the inhibition of mitochondrial translation using tetracyclines. However, the mechanisms whereby tetracyclines promote cell survival are unknown. Here, we show that tetracyclines inhibit the mitochondrial ribosome and promote survival through suppression of endoplasmic reticulum (ER) stress. Tetracyclines increase mitochondrial levels of the mitoribosome quality control factor MALSU1 (Mitochondrial Assembly of Ribosomal Large Subunit 1) and promote its recruitment to the mitoribosome large subunit, where MALSU1 is necessary for tetracycline-induced survival and suppression of ER stress. Glucose starvation induces ER stress to activate the unfolded protein response and IRE1α-mediated cell death that is inhibited by tetracyclines. These studies establish a new interorganelle communication whereby inhibition of the mitoribosome signals to the ER to promote survival, implicating basic mechanisms of cell survival and treatment of mitochondrial diseases.

Keywords:  IRE1α; MALSU1; mitochondrial disease; mitoribosome; tetracyclines

DOI:  https://doi.org/10.15252/embr.202357228
FASEB Bioadv. 2023 Oct;5(10): 412-426

Profiling mitochondrial DNA mutations in tumors and circulating extracellular vesicles of triple-negative breast cancer patients for potential biomarker development.

Kunwar Somesh Vikramdeo, Shashi Anand, Sarabjeet Kour Sudan, Paramahansa Pramanik, Seema Singh, Andrew K Godwin, Ajay Pratap Singh, Santanu Dasgupta.

  Early detection and recurrence prediction are challenging in triple-negative breast cancer (TNBC) patients. We aimed to develop mitochondrial DNA (mtDNA)-based liquid biomarkers to improve TNBC management. Mitochondrial genome (MG) enrichment and next-generation sequencing mapped the entire MG in 73 samples (64 tissues and 9 extracellular vesicles [EV] samples) from 32 metastatic TNBCs. We measured mtDNA and cardiolipin (CL) contents, NDUFB8, and SDHB protein expression in tumors and in corresponding circulating EVs. We identified 168 nonsynonymous mtDNA mutations, with 73% (123/186) coding and 27% (45/168) noncoding in nature. Twenty percent of mutations were nucleotide transversions. Respiratory complex I (RCI) was the key target, which harbored 44% (74/168) of the overall mtDNA mutations. A panel of 11 hotspot mtDNA mutations was identified among 19%-38% TNBCs, which were detectable in the serum-derived EVs with 82% specificity. Overall, 38% of the metastatic tumor-signature mtDNA mutations were traceable in the EVs. An appreciable number of mtDNA mutations were homoplasmic (18%, 31/168), novel (14%, 23/168), and potentially pathogenic (9%, 15/168). The overall and RCI-specific mtDNA mutational load was higher in women with African compared to European ancestry accompanied by an exclusive abundance of respiratory complex (RC) protein NDUFB8 (RCI) and SDHB (RCII) therein. Increased mtDNA (p < 0.0001) content was recorded in both tumors and EVs along with an abundance of CL (p = 0.0001) content in the EVs. Aggressive tumor-signature mtDNA mutation detection and measurement of mtDNA and CL contents in the EVs bear the potential to formulate noninvasive early detection and recurrence prediction strategies.

Keywords:  extracellular vesicles; liquid biomarker; mitochondrial DNA; mutation; triple‐negative breast cancer

DOI:  https://doi.org/10.1096/fba.2023-00070
Cancer Lett. 2023 Oct 05. pii: S0304-3835(23)00376-2. [Epub ahead of print] 216425

Combined inhibition of pyruvate dehydrogenase kinase 1 and lactate dehydrogenase a induces metabolic and signaling reprogramming and enhances lung adenocarcinoma cell killing.

Yan Zhou, Yizhen Guo, Maoxin Ran, Wenying Shan, Carlotta Granchi, Elisa Giovannetti, Filippo Minutolo, Godefridus J Peters, Kin Yip Tam.

  Lung adenocarcinoma (LUAD) is one of the most prevalent and aggressive types of lung cancer. Metabolic reprogramming plays a critical role in the development and progression of LUAD. Pyruvate dehydrogenase kinase 1 (PDK1) and lactate dehydrogenase A (LDHA) are two key enzymes involved in glucose metabolism, whilst their aberrant expressions are often associated with tumorigenesis. Herein, we investigated the anticancer effects of combined inhibition of PDK1 and LDHA in LUAD in vitro and in vivo and its underlying mechanisms of action. The combination of a PDK1 inhibitor, 64, and a LDHA inhibitor, NHI-Glc-2, led to a synergistic growth inhibition in 3 different LUAD cell lines and more than additively suppressed tumor growth in the LUAD xenograft H1975 model. This combination also inhibited cellular migration and colony formation, while it induced a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) resulting in mitochondrial depolarization and apoptosis in LUAD cells. These effects were related to modulation of multiple cell signaling pathways, including AMPK, RAS/ERK, and AKT/mTOR. Our findings demonstrate that simultaneous inhibition of multiple glycolytic enzymes (PDK1 and LDHA) is a promising novel therapeutic approach for LUAD.

Keywords:  Anticancer; Combination treatment; Non-small cell lung cancer; Warburg effect

DOI:  https://doi.org/10.1016/j.canlet.2023.216425
Nat Commun. 2023 Oct 10. 14(1): 6328

Positive regulation of oxidative phosphorylation by nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice.

Tomas Venit, Oscar Sapkota, Wael Said Abdrabou, Palanikumar Loganathan, Renu Pasricha, Syed Raza Mahmood, Nadine Hosny El Said, Shimaa Sherif, Sneha Thomas, Salah Abdelrazig, Shady Amin, Davide Bedognetti, Youssef Idaghdour, Mazin Magzoub, Piergiorgio Percipalle.

Metabolic reprogramming is one of the hallmarks of tumorigenesis. Here, we show that nuclear myosin 1 (NM1) serves as a key regulator of cellular metabolism. NM1 directly affects mitochondrial oxidative phosphorylation (OXPHOS) by regulating mitochondrial transcription factors TFAM and PGC1α, and its deletion leads to underdeveloped mitochondria inner cristae and mitochondrial redistribution within the cell. These changes are associated with reduced OXPHOS gene expression, decreased mitochondrial DNA copy number, and deregulated mitochondrial dynamics, which lead to metabolic reprogramming of NM1 KO cells from OXPHOS to aerobic glycolysis.This, in turn, is associated with a metabolomic profile typical for cancer cells, namely increased amino acid-, fatty acid-, and sugar metabolism, and increased glucose uptake, lactate production, and intracellular acidity. NM1 KO cells form solid tumors in a mouse model, suggesting that the metabolic switch towards aerobic glycolysis provides a sufficient carcinogenic signal. We suggest that NM1 plays a role as a tumor suppressor and that NM1 depletion may contribute to the Warburg effect at the onset of tumorigenesis.

DOI: https://doi.org/10.1038/s41467-023-42093-w
Aging Cell. 2023 Oct 13. e13996

STAT3 modulates CD4+ T mitochondrial dynamics and function in aging.

Emelia Zukowski, Marco Sannella, Jack Donato Rockhold, Gabriella H Kalantar, Jingting Yu, Sara SantaCruz-Calvo, Madison K Kuhn, Nasun Hah, Ling Ouyang, Tzu-Wen Wang, Lyanne Murphy, Heather Marszalkowski, Kaleigh Gibney, Micah J Drummond, Elizabeth A Proctor, Hatice Hasturk, Barbara S Nikolajczyk, Leena P Bharath.

  Aging promotes numerous intracellular changes in T cells that impact their effector function. Our data show that aging promotes an increase in the localization of STAT3 to the mitochondria (mitoSTAT3), which promotes changes in mitochondrial dynamics and function and T-cell cytokine production. Mechanistically, mitoSTAT3 increased the activity of aging T-cell mitochondria by increasing complex II. Limiting mitoSTAT3 using a mitochondria-targeted STAT3 inhibitor, Mtcur-1 lowered complex II activity, prevented age-induced changes in mitochondrial dynamics and function, and reduced Th17 inflammation. Exogenous expression of a constitutively phosphorylated form of STAT3 in T cells from young adults mimicked changes in mitochondrial dynamics and function in T cells from older adults and partially recapitulated aging-related cytokine profiles. Our data show the mechanistic link among mitoSTAT3, mitochondrial dynamics, function, and T-cell cytokine production.

Keywords:  CD4+ T cells; Th17 cytokines; aging; cytokines; inflammaging; mitochondria; mitochondrial STAT3; naïve CD4+ T cells

DOI:  https://doi.org/10.1111/acel.13996
bioRxiv. 2023 Sep 25. pii: 2023.09.23.559091. [Epub ahead of print]

Improved CAR-T cell activity associated with increased mitochondrial function primed by galactose.

Golda Gross, Suha Alkadieri, Amilia Meir, Orit Itzhaki, Yarden Aharony-Tevet, Shahar Ben Yosef, Angi Zenab, Liat Shbiro, Amos Toren, Tal Yardeni, Elad Jacoby.

CD19 CAR-T cells have led to durable remissions in patients with refractory B-cell malignancies; nevertheless, most patients eventually relapse in the long term. Many interventions aimed at improving current products have been reported, with a subset of them focusing on a direct or indirect link to the metabolic state of the CAR-T cells. We assessed clinical products from an ongoing clinical trial utilizing CD19-28z CAR-T cells from patients with acute lymphoblastic leukemia. CAR-T clinical products leading to a complete response had significantly higher mitochondrial function (by oxygen consumption rate) irrespective of mitochondrial content. Next, we replaced the carbon source of the media from glucose to galactose to impact cellular metabolism. Galactose-containing media increased mitochondrial activity in CAR-T cells, and improved in vitro efficacy, without any consistent phenotypic change in memory profile. Finally, CAR-T cells produced in galactose-based glucose-free media resulted in increased mitochondrial activity. Using an in vivo model of Nalm6 injected mice, galactose-primed CAR-T cells significantly improved leukemia-free survival compared to standard glucose-cultured CAR-T cells. Our results prove the significance of mitochondrial metabolism on CAR-T cell efficacy and suggest a translational pathway to improve clinical products.

DOI: https://doi.org/10.1101/2023.09.23.559091
Cell Rep. 2023 Oct 09. pii: S2211-1247(23)01233-0. [Epub ahead of print]42(10): 113221

MYC is a regulator of androgen receptor inhibition-induced metabolic requirements in prostate cancer.

Preston D Crowell, Jenna M Giafaglione, Anthony E Jones, Nicholas M Nunley, Takao Hashimoto, Amelie M L Delcourt, Anton Petcherski, Raag Agrawal, Matthew J Bernard, Johnny A Diaz, Kylie Y Heering, Rong Rong Huang, Jin-Yih Low, Nedas Matulionis, Nora M Navone, Huihui Ye, Amina Zoubeidi, Heather R Christofk, Matthew B Rettig, Robert E Reiter, Michael C Haffner, Paul C Boutros, Orian S Shirihai, Ajit S Divakaruni, Andrew S Goldstein.

  Advanced prostate cancers are treated with therapies targeting the androgen receptor (AR) signaling pathway. While many tumors initially respond to AR inhibition, nearly all develop resistance. It is critical to understand how prostate tumor cells respond to AR inhibition in order to exploit therapy-induced phenotypes prior to the outgrowth of treatment-resistant disease. Here, we comprehensively characterize the effects of AR blockade on prostate cancer metabolism using transcriptomics, metabolomics, and bioenergetics approaches. The metabolic response to AR inhibition is defined by reduced glycolysis, robust elongation of mitochondria, and increased reliance on mitochondrial oxidative metabolism. We establish DRP1 activity and MYC signaling as mediators of AR-blockade-induced metabolic phenotypes. Rescuing DRP1 phosphorylation after AR inhibition restores mitochondrial fission, while rescuing MYC restores glycolytic activity and prevents sensitivity to complex I inhibition. Our study provides insight into the regulation of treatment-induced metabolic phenotypes and vulnerabilities in prostate cancer.

Keywords:  CP: Cancer; CP: Metabolism

DOI:  https://doi.org/10.1016/j.celrep.2023.113221
Cell Death Dis. 2023 10 10. 14(10): 665

Identification of the mitochondrial protein POLRMT as a potential therapeutic target of prostate cancer.

Xiaojun Li, Linya Yao, Tao Wang, Xiaolei Gu, Yufan Wu, Ting Jiang.

RNA polymerase mitochondria (POLRMT) is essential for mitochondrial transcription machinery and other mitochondrial functions. Its expression and potential functions in prostate cancer were explored here. The Cancer Genome Atlas prostate cancer cohort (TCGA PRAD) shows that POLRMT mRNA expression is upregulated in prostate cancer tissues and POLRMT upregulation is correlated with poor patients' survival. POLRMT mRNA and protein levels were upregulated in local prostate cancer tissues and different primary/immortalized prostate cancer cells. Genetic depletion of POLRMT, using viral shRNA or CRISPR/Cas9 gene editing methods, impaired mitochondrial functions in prostate cancer cells, leading to mitochondrial depolarization, oxidative stress, mitochondria complex I inhibition, and ATP depletion. Moreover, POLRMT depletion resulted in robust inhibition of prostate cancer cell viability, proliferation, and migration, and provoked apoptosis. Conversely, prostate cancer cell proliferation, migration, and ATP contents were strengthened following ectopic POLRMT overexpression. In vivo, intratumoral injection of POLRMT shRNA adeno-associated virus impeded prostate cancer xenograft growth in nude mice. POLRMT silencing, oxidative stress, and ATP depletion were detected in POLRMT shRNA-treated prostate cancer xenograft tissues. IMT1 (inhibitor of mitochondrial transcription 1), the first-in-class POLRMT inhibitor, inhibited prostate cancer cell growth in vitro and in vivo. Together, overexpressed POLRMT is an important mitochondrial protein for prostate cancer cell growth, representing a novel and promising diagnostic and therapeutic oncotarget.

DOI: https://doi.org/10.1038/s41419-023-06203-2
Genome Biol. 2023 Oct 12. 24(1): 229

The landscape of cell-free mitochondrial DNA in liquid biopsy for cancer detection.

Ymke van der Pol, Norbert Moldovan, Jip Ramaker, Sanne Bootsma, Kristiaan J Lenos, Louis Vermeulen, Shahneen Sandhu, Idris Bahce, D Michiel Pegtel, Stephen Q Wong, Sarah-Jane Dawson, Dineika Chandrananda, Florent Mouliere.

  BACKGROUND: Existing methods to detect tumor signal in liquid biopsy have focused on the analysis of nuclear cell-free DNA (cfDNA). However, non-nuclear cfDNA and in particular mitochondrial DNA (mtDNA) has been understudied. We hypothesize that an increase in mtDNA in plasma could reflect the presence of cancer, and that leveraging cell-free mtDNA could enhance cancer detection.RESULTS: We survey 203 healthy and 664 cancer plasma samples from three collection centers covering 12 cancer types with whole genome sequencing to catalogue the plasma mtDNA fraction. The mtDNA fraction is increased in individuals with cholangiocarcinoma, colorectal, liver, pancreatic, or prostate cancer, in comparison to that in healthy individuals. We detect almost no increase of mtDNA fraction in individuals with other cancer types. The mtDNA fraction in plasma correlates with the cfDNA tumor fraction as determined by somatic mutations and/or copy number aberrations. However, the mtDNA fraction is also elevated in a fraction of patients without an apparent increase in tumor-derived cfDNA. A predictive model integrating mtDNA and copy number analysis increases the area under the curve (AUC) from 0.73 when using copy number alterations alone to an AUC of 0.81.
CONCLUSIONS: The mtDNA signal retrieved by whole genome sequencing has the potential to boost the detection of cancer when combined with other tumor-derived signals in liquid biopsies.

Keywords:  Cancer; Cell-free DNA; Liquid biopsy; Mitochondrial DNA; Sequencing

DOI:  https://doi.org/10.1186/s13059-023-03074-w
Cancer Gene Ther. 2023 Oct 11.

Anti-leukemia effects of omipalisib in acute myeloid leukemia: inhibition of PI3K/AKT/mTOR signaling and suppression of mitochondrial biogenesis.

Chi-Yang Tseng, Yu-Hsuan Fu, Da-Liang Ou, Jeng-Wei Lu, Hsin-An Hou, Liang-In Lin.

Omipalisib (GSK2126458), a potent dual PI3K/mTOR inhibitor, is reported to exhibit anti-tumor effect in several kinds of cancers. More than 50% of acute myeloid leukemia (AML) patients display a hyperactivation of PI3K/AKT/mTOR signaling. We investigated the anti-proliferative effect of omipalisib in AML cell lines with varied genetic backgrounds. The OCI-AML3 and THP-1 cell lines had a significant response to omipalisib, with IC50 values of 17.45 nM and 8.93 nM, respectively. We integrated transcriptomic profile and metabolomic analyses, and followed by gene set enrichment analysis (GSEA) and metabolite enrichment analysis. Our findings showed that in addition to inhibiting PI3K/AKT/mTOR signaling and inducing cell cycle arrest at the G0/G1 phase, omipalisib also suppressed mitochondrial respiration and biogenesis. Furthermore, omipalisib downregulated several genes associated with serine, glycine, threonine, and glutathione metabolism, and decreased their protein and glutathione levels. In vivo experiments revealed that omipalisib significantly inhibited tumor growth and prolonged mouse survival without weight loss. Gedatolisib and dactolisib, another two PI3K/mTOR inhibitors, exerted similar effects without affecting mitochondria biogenesis. These results highlight the multifaceted anti-leukemic effect of omipalisib, revealing its potential as a novel therapeutic agent in AML treatment.

DOI: https://doi.org/10.1038/s41417-023-00675-2
Mutagenesis. 2023 Oct 07. pii: gead031. [Epub ahead of print]

The known unknowns of mitochondrial carcinogenesis: de novo NUMTs and intercellular mitochondrial transfer.

Tigran Harutyunyan.

  The translocation of mitochondrial DNA (mtDNA) sequences into the nuclear genome, resulted in the occurrence of nuclear sequences of mitochondrial origin (NUMTs) which can be detected in nearly all sequenced eukaryotes. However, de novo mtDNA insertions can contribute to the development of pathological conditions including cancer. Recent data indicate that de novo mtDNA translocation into chromosomes can occur due to genotoxic influence of DNA double-strand break (DSB)-inducing environmental mutagens. This confirms the hypothesis of the involvement of genome instability in the occurrence of mtDNA fragments in chromosomes. Mounting evidence indicates that mitochondria can be transferred from normal cells to cancer cells and recover cellular respiration. These exchanged mitochondria can facilitate cancer progression and metastasis. This review article provides a comprehensive overview of the potential carcinogenicity of mtDNA insertions, and the relevance of mtDNA escape in cancer progression, metastasis, and treatment resistance in humans. Potential molecular targets involved in mtDNA escape and exchange of mitochondria that can be of possible clinical benefits are presented and discussed. Understanding these processes could lead to improved diagnostic approaches, novel therapeutic strategies, and a deeper understanding of the intricate relationship between mitochondria, nuclear DNA, and cancer biology.

Keywords:  doxorubicin; genomic instability; mitochondrial carcinogenesis; mtDNA insertions; numtogenesis

DOI:  https://doi.org/10.1093/mutage/gead031
Cancer Discov. 2023 Oct 13. OF1

Tumor Immunogenicity Is Enhanced by Altering Mitochondrial Electron Flow.

Mitochondrial CII loss reduces tumor growth by increasing antigen presentation and T cell-mediated killing.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2023-160
Mol Cell Proteomics. 2023 Oct 05. pii: S1535-9476(23)00168-8. [Epub ahead of print] 100657

Higher-order structural organization of the mitochondrial proteome charted by in situ cross-linking mass spectrometry.

Johannes F Hevler, Albert J R Heck.

  Mitochondria are densely packed with proteins, of which most are involved physically or more transiently in protein-protein interactions (PPIs). Mitochondria host among others all enzymes of the Krebs cycle and the oxidative phosphorylation (OXPHOS) pathway and are foremost associated with cellular bioenergetics (1, 2). However, mitochondria are also important contributors to apoptotic cell death (3) and contain their own genome (4) indicating that they play additionally an eminent role in processes beyond bioenergetics (5). Despite intense efforts in identifying and characterizing mitochondrial protein complexes by structural biology and proteomics techniques, many PPIs have remained elusive. Several of these (membrane embedded) PPIs are less stable in-vitro hampering their characterization by most contemporary methods in structural biology. Particularly in these cases, cross-linking mass spectrometry (XL-MS) has proven valuable for the in-depth characterization of mitochondrial protein complexes in situ. Here, we highlight experimental strategies for the analysis of proteome-wide protein-protein interactions in mitochondria using XL-MS. We showcase the ability of in situ XL-MS as a tool to map sub-organelle interactions and topologies, and aid in refining structural models of protein complexes. We describe some of the most recent technological advances in XL-MS that may benefit the in situ characterization of PPIs even further, especially when combined with electron microscopy and structural modelling.

Keywords:  In situ cross-linking mass spectrometry; cross-linking reagents; membrane complexes; mitochondria; protein localization; protein-protein interactions

DOI:  https://doi.org/10.1016/j.mcpro.2023.100657
Cancer Cell. 2023 Oct 09. pii: S1535-6108(23)00319-7. [Epub ahead of print]41(10): 1788-1802.e10

Systematic investigation of mitochondrial transfer between cancer cells and T cells at single-cell resolution.

Hongyi Zhang, Xuexin Yu, Jianfeng Ye, Huiyu Li, Jing Hu, Yuhao Tan, Yan Fang, Esra Akbay, Fulong Yu, Chen Weng, Vijay G Sankaran, Robert M Bachoo, Elizabeth Maher, John Minna, Anli Zhang, Bo Li.

  Mitochondria (MT) participate in most metabolic activities of mammalian cells. A near-unidirectional mitochondrial transfer from T cells to cancer cells was recently observed to "metabolically empower" cancer cells while "depleting immune cells," providing new insights into tumor-T cell interaction and immune evasion. Here, we leverage single-cell RNA-seq technology and introduce MERCI, a statistical deconvolution method for tracing and quantifying mitochondrial trafficking between cancer and T cells. Through rigorous benchmarking and validation, MERCI accurately predicts the recipient cells and their relative mitochondrial compositions. Application of MERCI to human cancer samples identifies a reproducible MT transfer phenotype, with its signature genes involved in cytoskeleton remodeling, energy production, and TNF-α signaling pathways. Moreover, MT transfer is associated with increased cell cycle activity and poor clinical outcome across different cancer types. In summary, MERCI enables systematic investigation of an understudied aspect of tumor-T cell interactions that may lead to the development of therapeutic opportunities.

Keywords:  Mitochondrial Transfer; Statistical Deconvolution; T cell dysfunction; Tumor-Immune Interaction; mtDNA sequencing.; single cell genomics

DOI:  https://doi.org/10.1016/j.ccell.2023.09.003
J Biol Chem. 2023 Oct 10. pii: S0021-9258(23)02363-3. [Epub ahead of print] 105335

HDGF Stimulates Liver Tumorigenesis by Enhancing Reactive Oxygen Species Generation in Mitochondria.

Tsung-Hui Hu, Jian-Ching Wu, Shih-Tsung Huang, Tian-Huei Chu, Ai-Jie Han, Ting-Wei Shih, Yi-Chen Chang, Shih-Ming Yang, Chou-Yuan Ko, Yu-Wei Lin, Mei-Lang Kung, Ming-Hong Tai.

  Hepatoma-derived growth factor (HDGF) overexpression and uncontrolled ROS accumulation are involved in malignant transformation and poor prognosis in various types of cancer. However, the interplay between HDGF and ROS generation has not been elucidated in hepatocellular carcinoma. Here, we first analyzed the profile of HDGF expression and ROS production in newly generated orthotopic hepatomas by ultrasound-guided implantation. In situ superoxide detection showed that HDGF-overexpressing hepatomas had significantly elevated ROS levels compared with adjacent nontumor tissues. Consistently, liver tissues from HDGF-deficient mice exhibited lower ROS fluorescence than those from age- and sex-matched wild-type mice. ROS-detecting fluorescent dyes and flow cytometry revealed that recombinant HDGF stimulated the production of superoxide anion, hydrogen peroxide, and mitochondrial ROS generation in cultured hepatoma cells in a dose-dependent manner. In contrast, the inactive Ser103Ala rHDGF mutant failed to promote ROS generation or oncogenic behaviors. Seahorse metabolic flux assays revealed that rHDGF dose-dependently upregulated bioenergetics through enhanced basal and total oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and oxidative phosphorylation in hepatoma cells. Moreover, antioxidants of NAC and MitoQ treatment significantly inhibited HDGF-mediated cell proliferation and invasive capacity. Genetic silencing of SOD2 augmented the HDGF-induced ROS generation and oncogenic behaviors of hepatoma cells. Finally, genetic knockdown nucleolin (NCL) and antibody neutralization of surface NCL, the HDGF receptor, abolished the HDGF-induced increase in ROS and mitochondrial energetics. In conclusion, this study has demonstrated for the first time that the HDGF/NCL signaling axis induces ROS generation by elevating ROS generation in mitochondria, thereby stimulating liver carcinogenesis.

Keywords:  Hepatoma-derived growth factor; Nucleolin; ROS (reactive oxygen species); SOD2 (superoxide dismutase 2); mitochondrial energetics

DOI:  https://doi.org/10.1016/j.jbc.2023.105335
Nat Commun. 2023 Oct 11. 14(1): 6369

A concerted ATPase cycle of the protein transporter AAA-ATPase Bcs1.

Yangang Pan, Jingyu Zhan, Yining Jiang, Di Xia, Simon Scheuring.

Bcs1, a homo-heptameric transmembrane AAA-ATPase, facilitates folded Rieske iron-sulfur protein translocation across the inner mitochondrial membrane. Structures in different nucleotide states (ATPγS, ADP, apo) provided conformational snapshots, but the kinetics and structural transitions of the ATPase cycle remain elusive. Here, using high-speed atomic force microscopy (HS-AFM) and line scanning (HS-AFM-LS), we characterized single-molecule Bcs1 ATPase cycling. While the ATP conformation had ~5600 ms lifetime, independent of the ATP-concentration, the ADP/apo conformation lifetime was ATP-concentration dependent and reached ~320 ms at saturating ATP-concentration, giving a maximum turnover rate of 0.17 s-1. Importantly, Bcs1 ATPase cycle conformational changes occurred in concert. Furthermore, we propose that the transport mechanism involves opening the IMS gate through energetically costly straightening of the transmembrane helices, potentially driving rapid gate resealing. Overall, our results establish a concerted ATPase cycle mechanism in Bcs1, distinct from other AAA-ATPases that use a hand-over-hand mechanism.

DOI: https://doi.org/10.1038/s41467-023-41806-5
Cancer Res. 2023 Oct 12. OF1-OF3

BCL-xL Targeting to Induce Apoptosis and to Eliminate Chemotherapy-Induced Senescent Tumor Cells: From Navitoclax to Platelet-Sparing BCL-xL PROTACs.

Anna Skwarska, Marina Konopleva.

Restoring apoptotic cell death is a critical goal for cancer therapy. One of the primary mechanisms by which cancer cells evade death and maintain survival in the face of stress signals is by overexpression of prosurvival B-cell lymphoma 2 (BCL2) family members such as BCL2, BCL-xL, and MCL1, which suppress the intrinsic (mitochondrial) pathway of apoptosis through complex protein and membrane interactions. While these antiapoptotic proteins have been validated as potent therapeutic targets, synthesis of their inhibitors remained challenging for decades mainly due to the presence of a difficult to target, highly hydrophobic groove on the surface. The groove serves as a binding site for the BH3 domain of corresponding proapoptotic partners, which leads to their sequestration and prevents apoptosis. In 2008, a Cancer Research article by Tse and colleagues, led by Dr. Steven Elmore from Abbott Laboratories, reported the discovery of the first orally bioavailable BCL2/BCL-xL inhibitor, navitoclax (ABT-263), marking the onset of an era of "BH3 mimetics" in cancer therapeutics and changing the therapeutic landscape especially for leukemia. Here, we reflect on how this landmark study fueled development of small-molecule BH3 mimetics like venetoclax and seek to indicate new strategies and future directions for improving the clinical activity of navitoclax for hematologic malignancies. See related article by Tse and colleagues, Cancer Res 2008;68:3421-3428.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-2804
Nat Cancer. 2023 Oct 09.

Targeting pancreatic cancer metabolic dependencies through glutamine antagonism.

Joel Encarnación-Rosado, Albert S W Sohn, Douglas E Biancur, Elaine Y Lin, Victoria Osorio-Vasquez, Tori Rodrick, Diana González-Baerga, Ende Zhao, Yumi Yokoyama, Diane M Simeone, Drew R Jones, Seth J Parker, Robert Wild, Alec C Kimmelman.

Pancreatic ductal adenocarcinoma (PDAC) cells use glutamine (Gln) to support proliferation and redox balance. Early attempts to inhibit Gln metabolism using glutaminase inhibitors resulted in rapid metabolic reprogramming and therapeutic resistance. Here, we demonstrated that treating PDAC cells with a Gln antagonist, 6-diazo-5-oxo-L-norleucine (DON), led to a metabolic crisis in vitro. In addition, we observed a profound decrease in tumor growth in several in vivo models using sirpiglenastat (DRP-104), a pro-drug version of DON that was designed to circumvent DON-associated toxicity. We found that extracellular signal-regulated kinase (ERK) signaling is increased as a compensatory mechanism. Combinatorial treatment with DRP-104 and trametinib led to a significant increase in survival in a syngeneic model of PDAC. These proof-of-concept studies suggested that broadly targeting Gln metabolism could provide a therapeutic avenue for PDAC. The combination with an ERK signaling pathway inhibitor could further improve the therapeutic outcome.

DOI: https://doi.org/10.1038/s43018-023-00647-3
iScience. 2023 Oct 20. 26(10): 107839

Intermittent fasting induced ketogenesis inhibits mouse epithelial ovarian cancer by promoting antitumor T cell response.

Mary Priyanka Udumula, Harshit Singh, Faraz Rashid, Laila Poisson, Nivedita Tiwari, Irina Dimitrova, Miriana Hijaz, Radhika Gogoi, Margaret Swenor, Adnan Munkarah, Shailendra Giri, Ramandeep Rattan.

  In various cancer models, dietary interventions have been shown to inhibit tumor growth, improve anticancer drug efficacy, and enhance immunity, but no such evidence exists for epithelial ovarian cancer (EOC), the most lethal gynecologic cancer. The anticancer immune responses induced by 16-h intermittent fasting (IF) were studied in mice with EOC. IF consistently reduced metabolic growth factors and cytokines that stimulate tumor growth, creating a tumor-hostile environment. Immune profiling showed that IF dramatically alters anti-cancer immunity by increasing CD4+ and CD8+ cells, Th1 and cytotoxic responses, and metabolic fitness. β-hydroxy butyrate (BHB), a bioactive metabolite produced by IF, partially imitates its anticancer effects by inducing CD8+ effector function. In a direct comparison, IF outperformed exogenous BHB treatment in survival and anti-tumor immune response, probably due to increased ketogenesis. Thus, IF and one of its metabolic mediators BHB suppress EOC growth and sustain a potent anti-tumor T cell response.

Keywords:  Biological sciences; Cancer; Immunology; Physiology

DOI:  https://doi.org/10.1016/j.isci.2023.107839
Int J Mol Sci. 2023 Oct 02. pii: 14824. [Epub ahead of print]24(19):

The Determination of Mitochondrial Mass Is a Prerequisite for Accurate Assessment of Peripheral Blood Mononuclear Cells' Oxidative Metabolism.

Belay Tessema, Janine Haag, Ulrich Sack, Brigitte König.

  Mitochondria are responsible for ATP synthesis through oxidative phosphorylation in cells. However, there are limited data on the influence of mitochondrial mass (MM) in the adequate assessment of cellular stress assay (CSA) results in human peripheral blood mononuclear cells (PBMCs). Therefore, the aim of this study was to determine MM in PBMCS and assess its influence on the results of CSA measurements. Blood samples were collected and sent to the laboratory for MM and CSA measurements during different seasons of the year. The mitochondrial mass was determined based on the mtDNA:nDNA ratio in PBMCs using quantitative real-time PCR (qRT-PCR). CSA was measured using Seahorse technology. The MM was significantly lower during summer and autumn compared to winter and spring (p < 0.0001). On the contrary, we found that the maximal respiration per mitochondrion (MP) was significantly higher in summer and autumn compared to winter and spring (p < 0.0001). The estimated effect of MM on mitochondrial performance was -0.002 pmol/min/mitochondrion (p < 0.0001) and a correlation coefficient (r) of -0.612. Similarly, MM was negatively correlated with maximal respiration (r = -0.12) and spare capacity (in % r = -0.05, in pmol/min r = -0.11). In conclusion, this study reveals that MM changes significantly with seasons and is negatively correlated with CSA parameters and MP. Our findings indicate that the mitochondrial mass is a key parameter for determination of mitochondrial fitness. Therefore, we recommend the determination of MM during the measurement of CSA parameters for the correct interpretation and assessment of mitochondrial function.

Keywords:  cellular stress assay; mitochondrial mass; peripheral blood mononuclear cells; seasonal variation

DOI:  https://doi.org/10.3390/ijms241914824
Nat Cancer. 2023 Oct 09.

Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma.

Maria Victoria Recouvreux, Shea F Grenier, Yijuan Zhang, Edgar Esparza, Guillem Lambies, Cheska Marie Galapate, Swetha Maganti, Karen Duong-Polk, Deepika Bhullar, Razia Naeem, David A Scott, Andrew M Lowy, Hervé Tiriac, Cosimo Commisso.

In pancreatic ductal adenocarcinoma (PDAC), glutamine is a critical nutrient that drives a wide array of metabolic and biosynthetic processes that support tumor growth. Here, we elucidate how 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist that broadly inhibits glutamine metabolism, blocks PDAC tumor growth and metastasis. We find that DON significantly reduces asparagine production by inhibiting asparagine synthetase (ASNS), and that the effects of DON are rescued by asparagine. As a metabolic adaptation, PDAC cells upregulate ASNS expression in response to DON, and we show that ASNS levels are inversely correlated with DON efficacy. We also show that L-asparaginase (ASNase) synergizes with DON to affect the viability of PDAC cells, and that DON and ASNase combination therapy has a significant impact on metastasis. These results shed light on the mechanisms that drive the effects of glutamine mimicry and point to the utility of cotargeting adaptive responses to control PDAC progression.

DOI: https://doi.org/10.1038/s43018-023-00649-1
Nat Commun. 2023 Oct 12. 14(1): 6422

Oncogenic context shapes the fitness landscape of tumor suppression.

Lily M Blair, Joseph M Juan, Lafia Sebastian, Vy B Tran, Wensheng Nie, Gregory D Wall, Mehmet Gerceker, Ian K Lai, Edwin A Apilado, Gabriel Grenot, David Amar, Giorgia Foggetti, Mariana Do Carmo, Zeynep Ugur, Debbie Deng, Alex Chenchik, Maria Paz Zafra, Lukas E Dow, Katerina Politi, Jonathan J MacQuitty, Dmitri A Petrov, Monte M Winslow, Michael J Rosen, Ian P Winters.

Tumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the interactions between oncogenes and tumor suppressor genes that shape this landscape remain poorly resolved and cannot be revealed by human cancer genomics alone. Here, we use a multiplexed, autochthonous mouse platform to model and quantify the initiation and growth of more than one hundred genotypes of lung tumors across four oncogenic contexts: KRAS G12D, KRAS G12C, BRAF V600E, and EGFR L858R. We show that the fitness landscape is rugged-the effect of tumor suppressor inactivation often switches between beneficial and deleterious depending on the oncogenic context-and shows no evidence of diminishing-returns epistasis within variants of the same oncogene. These findings argue against a simple linear signaling relationship amongst these three oncogenes and imply a critical role for off-axis signaling in determining the fitness effects of inactivating tumor suppressors.

DOI: https://doi.org/10.1038/s41467-023-42156-y