bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2023‒12‒24
24 papers selected by
Kelsey Fisher-Wellman, East Carolina University
  1. Mitochondrial metabolism as a dynamic regulatory hub to malignant transformation and anti-cancer drug resistance.
  2. Mitochondrial quality control pathways sense mitochondrial protein import.
  3. Complex II ambiguities-FADH2 in the electron transfer system.
  4. Mitochondrial Functionality Is Regulated by Alkylphospholipids in Human Colon Cancer Cells.
  5. Chemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis.
  6. Mtfp1 ablation enhances mitochondrial respiration and protects against hepatic steatosis.
  7. Mitochondrial fatty acid synthesis is an emergent central regulator of mammalian oxidative metabolism.
  8. Beta-Hydroxybutyrate Augments Oxaliplatin-Induced Cytotoxicity by Altering Energy Metabolism in Colorectal Cancer Organoids.
  9. A gold-based inhibitor of oxidative phosphorylation is effective against triple negative breast cancer.
  10. Performance of TMRM and Mitotrackers in mitochondrial morphofunctional analysis of primary human skin fibroblasts.
  11. The centrosomal protein 131 participates in the regulation of mitochondrial apoptosis.
  12. Artesunate acts through cytochrome c to inhibit growth of pediatric AML cells.
  13. Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia.
  14. An overview of ATP synthase, inhibitors, and their toxicity.
  15. Confinement primes cells for faster migration by polarizing active mitochondria.
  16. DELE1 haploinsufficiency causes resistance to mitochondrial stress-induced apoptosis in monosomy 5/del(5q) AML.
  17. Mitochondrial dysfunction abrogates dietary lipid processing in enterocytes.
  18. Fasting-Mimicking Diet Inhibits Autophagy and Synergizes with Chemotherapy to Promote T-Cell-Dependent Leukemia-Free Survival.
  19. Need for speed: Human fast-twitch mitochondria favor power over efficiency.
  20. WNT4 regulates cellular metabolism via intracellular activity at the mitochondria in breast and gynecologic cancers.
  21. Aged intestinal stem cells propagate cell-intrinsic sources of inflammaging in mice.
  22. Inhibition of DHODH Enhances Replication-Associated Genomic Instability and Promotes Sensitivity in Endometrial Cancer.
  23. Repurposing Metabolic Inhibitors in the Treatment of Colon Adenocarcinoma Patient-Derived Models.
  24. Identifying metabolic features of colorectal cancer liability using Mendelian randomization.
  1. Biochem Biophys Res Commun. 2023 Dec 17. pii: S0006-291X(23)01476-6. [Epub ahead of print]694 149382
    Mitochondrial metabolism as a dynamic regulatory hub to malignant transformation and anti-cancer drug resistance.
    Manendra Singh Tomar, Ashok Kumar, Ashutosh Shrivastava.
      Glycolysis is the fundamental cellular process that permits cancer cells to convert energy and grow anaerobically. Recent developments in molecular biology have made it evident that mitochondrial respiration is critical to tumor growth and treatment response. As the principal organelle of cellular energy conversion, mitochondria can rapidly alter cellular metabolic processes, thereby fueling malignancies and contributing to treatment resistance. This review emphasizes the significance of mitochondrial biogenesis, turnover, DNA copy number, and mutations in bioenergetic system regulation. Tumorigenesis requires an intricate cascade of metabolic pathways that includes rewiring of the tricarboxylic acid (TCA) cycle, electron transport chain and oxidative phosphorylation, supply of intermediate metabolites of the TCA cycle through amino acids, and the interaction between mitochondria and lipid metabolism. Cancer recurrence or resistance to therapy often results from the cooperation of several cellular defense mechanisms, most of which are connected to mitochondria. Many clinical trials are underway to assess the effectiveness of inhibiting mitochondrial respiration as a potential cancer therapeutic. We aim to summarize innovative strategies and therapeutic targets by conducting a comprehensive review of recent studies on the relationship between mitochondrial metabolism, tumor development and therapeutic resistance.
    Keywords:  Cancer; Drug resistance; Electron transport chain; Metabolism; Mitochondria; Oxidative phosphorylation; TCA cycle
    DOI:  https://doi.org/10.1016/j.bbrc.2023.149382
  2. Trends Endocrinol Metab. 2023 Dec 15. pii: S1043-2760(23)00243-6. [Epub ahead of print]
    Mitochondrial quality control pathways sense mitochondrial protein import.
    Laurie P Lee-Glover, Timothy E Shutt.
      Mitochondrial quality control (MQC) mechanisms are required to maintain a functional proteome, which enables mitochondria to perform a myriad of important cellular functions from oxidative phosphorylation to numerous other metabolic pathways. Mitochondrial protein homeostasis begins with the import of over 1000 nuclear-encoded mitochondrial proteins and the synthesis of 13 mitochondrial DNA-encoded proteins. A network of chaperones and proteases helps to fold new proteins and degrade unnecessary, damaged, or misfolded proteins, whereas more extensive damage can be removed by mitochondrial-derived vesicles (MDVs) or mitochondrial autophagy (mitophagy). Here, focusing on mechanisms in mammalian cells, we review the importance of mitochondrial protein import as a sentinel of mitochondrial function that activates multiple MQC mechanisms when impaired.
    Keywords:  mitochondria; mitochondrial protein import; mitochondrial quality control; mitochondrial unfolded protein response; mitochondrial-derived vesicles; mitophagy
    DOI:  https://doi.org/10.1016/j.tem.2023.11.004
  3. J Biol Chem. 2023 Nov 22. pii: S0021-9258(23)02498-5. [Epub ahead of print]300(1): 105470
    Complex II ambiguities-FADH2 in the electron transfer system.
    Erich Gnaiger.
      The prevailing notion that reduced cofactors NADH and FADH2 transfer electrons from the tricarboxylic acid cycle to the mitochondrial electron transfer system creates ambiguities regarding respiratory Complex II (CII). CII is the only membrane-bound enzyme in the tricarboxylic acid cycle and is part of the electron transfer system of the mitochondrial inner membrane feeding electrons into the coenzyme Q-junction. The succinate dehydrogenase subunit SDHA of CII oxidizes succinate and reduces the covalently bound prosthetic group FAD to FADH2 in the canonical forward tricarboxylic acid cycle. However, several graphical representations of the electron transfer system depict FADH2 in the mitochondrial matrix as a substrate to be oxidized by CII. This leads to the false conclusion that FADH2 from the β-oxidation cycle in fatty acid oxidation feeds electrons into CII. In reality, dehydrogenases of fatty acid oxidation channel electrons to the Q-junction but not through CII. The ambiguities surrounding Complex II in the literature and educational resources call for quality control, to secure scientific standards in current communications of bioenergetics, and ultimately support adequate clinical applications. This review aims to raise awareness of the inherent ambiguity crisis, complementing efforts to address the well-acknowledged issues of credibility and reproducibility.
    Keywords:  Complex II; coenzyme Q; electron transfer system; fatty acid oxidation; flavin adenine dinucleotide; succinate dehydrogenase; tricarboxylic acid cycle
    DOI:  https://doi.org/10.1016/j.jbc.2023.105470
  4. Biology (Basel). 2023 Nov 22. pii: 1457. [Epub ahead of print]12(12):
    Mitochondrial Functionality Is Regulated by Alkylphospholipids in Human Colon Cancer Cells.
    Margalida Torrens-Mas, Alejandro Collado-Solé, Alberto Sola-Leyva, María Paz Carrasco-Jiménez, Jordi Oliver, Daniel Gabriel Pons, Pilar Roca, Jorge Sastre-Serra.
      Alkylphospholipids (APLs) have been studied as anticancer drugs that interfere with biological membranes without targeting DNA. Although their mechanism of action is not fully elucidated yet, it is known that they disrupt the intracellular trafficking of cholesterol and its metabolism. Here, we analyzed whether APLs could also interfere with mitochondrial function. For this purpose, we used HT29 colorectal cancer cells, derived from a primary tumor, and SW620 colorectal cancer cells, derived from a metastasis site. After treatment with the APLs miltefosine and perifosine, we analyzed various mitochondrial parameters, including mitochondrial mass, cardiolipin content, mitochondrial membrane potential, H2O2 production, the levels of oxidative phosphorylation (OXPHOS) complexes, metabolic enzymes activity, the oxygen consumption rate, and the levels of apoptosis and autophagy markers. APLs, especially perifosine, increased mitochondrial mass while OXPHOS complexes levels were decreased without affecting the total oxygen consumption rate. Additionally, we observed an increase in pyruvate dehydrogenase (PDH) and isocitrate dehydrogenase (IDH) levels and a decrease in lactate dehydrogenase (LDH) activity, suggesting a metabolic rewiring induced by perifosine. These alterations led to higher mitochondrial membrane potential, which was potentiated by decreased uncoupling protein 2 (UCP2) levels and increased reactive oxygen species (ROS) production. Consequently, perifosine induced an imbalance in mitochondrial function, resulting in higher ROS production that ultimately impacted cellular viability.
    Keywords:  Alkylphospholipids; colorectal cancer; mitochondrial function; perifosine
    DOI:  https://doi.org/10.3390/biology12121457
  5. Nat Commun. 2023 Dec 16. 14(1): 8381
    Chemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis.
    Nadege Gitego, Bogos Agianian, Oi Wei Mak, Vasantha Kumar Mv, Emily H Cheng, Evripidis Gavathiotis.
      The BCL-2 family protein BAX is a major regulator of physiological and pathological cell death. BAX predominantly resides in the cytosol in a quiescent state and upon stress, it undergoes conformational activation and mitochondrial translocation leading to mitochondrial outer membrane permeabilization, a critical event in apoptosis execution. Previous studies reported two inactive conformations of cytosolic BAX, a monomer and a dimer, however, it remains unclear how they regulate BAX. Here we show that, surprisingly, cancer cell lines express cytosolic inactive BAX dimers and/or monomers. Expression of inactive dimers, results in reduced BAX activation, translocation and apoptosis upon pro-apoptotic drug treatments. Using the inactive BAX dimer structure and a pharmacophore-based drug screen, we identify a small-molecule modulator, BDM19 that binds and activates cytosolic BAX dimers and prompts cells to apoptosis either alone or in combination with BCL-2/BCL-XL inhibitor Navitoclax. Our findings underscore the role of the cytosolic inactive BAX dimer in resistance to apoptosis and demonstrate a strategy to potentiate BAX-mediated apoptosis.
    DOI:  https://doi.org/10.1038/s41467-023-44084-3
  6. Nat Commun. 2023 Dec 20. 14(1): 8474
    Mtfp1 ablation enhances mitochondrial respiration and protects against hepatic steatosis.
    Cecilia Patitucci, Juan Diego Hernández-Camacho, Elodie Vimont, Sonny Yde, Thomas Cokelaer, Thibault Chaze, Quentin Giai Gianetto, Mariette Matondo, Anastasia Gazi, Ivan Nemazanyy, David A Stroud, Daniella H Hock, Erminia Donnarumma, Timothy Wai.
      Hepatic steatosis is the result of imbalanced nutrient delivery and metabolism in the liver and is the first hallmark of Metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD is the most common chronic liver disease and involves the accumulation of excess lipids in hepatocytes, inflammation, and cancer. Mitochondria play central roles in liver metabolism yet the specific mitochondrial functions causally linked to MASLD remain unclear. Here, we identify Mitochondrial Fission Process 1 protein (MTFP1) as a key regulator of mitochondrial and metabolic activity in the liver. Deletion of Mtfp1 in hepatocytes is physiologically benign in mice yet leads to the upregulation of oxidative phosphorylation (OXPHOS) activity and mitochondrial respiration, independently of mitochondrial biogenesis. Consequently, liver-specific knockout mice are protected against high fat diet-induced steatosis and metabolic dysregulation. Additionally, Mtfp1 deletion inhibits mitochondrial permeability transition pore opening in hepatocytes, conferring protection against apoptotic liver damage in vivo and ex vivo. Our work uncovers additional functions of MTFP1 in the liver, positioning this gene as an unexpected regulator of OXPHOS and a therapeutic candidate for MASLD.
    DOI:  https://doi.org/10.1038/s41467-023-44143-9
  7. Cell Metab. 2023 Dec 14. pii: S1550-4131(23)00449-7. [Epub ahead of print]
    Mitochondrial fatty acid synthesis is an emergent central regulator of mammalian oxidative metabolism.
    Riley J Wedan, Jacob Z Longenecker, Sara M Nowinski.
      Contrary to their well-known functions in nutrient breakdown, mitochondria are also important biosynthetic hubs and express an evolutionarily conserved mitochondrial fatty acid synthesis (mtFAS) pathway. mtFAS builds lipoic acid and longer saturated fatty acids, but its exact products, their ultimate destination in cells, and the cellular significance of the pathway are all active research questions. Moreover, why mitochondria need mtFAS despite their well-defined ability to import fatty acids is still unclear. The identification of patients with inborn errors of metabolism in mtFAS genes has sparked fresh research interest in the pathway. New mammalian models have provided insights into how mtFAS coordinates many aspects of oxidative mitochondrial metabolism and raise questions about its role in diseases such as obesity, diabetes, and heart failure. In this review, we discuss the products of mtFAS, their function, and the consequences of mtFAS impairment across models and in metabolic disease.
    Keywords:  fatty acids; inborn errors of metabolism; lipid metabolism; lipids; mitochondria; mitochondrial fatty acid synthesis; mouse models; mtFAS
    DOI:  https://doi.org/10.1016/j.cmet.2023.11.017
  8. Cancers (Basel). 2023 Dec 06. pii: 5724. [Epub ahead of print]15(24):
    Beta-Hydroxybutyrate Augments Oxaliplatin-Induced Cytotoxicity by Altering Energy Metabolism in Colorectal Cancer Organoids.
    Tolga Sever, Ender Berat Ellidokuz, Yasemin Basbinar, Hulya Ellidokuz, Ömer H Yilmaz, Gizem Calibasi-Kocal.
      Deregulation of cellular metabolism has recently emerged as a notable cancer characteristic. This reprogramming of key metabolic pathways supports tumor growth. Targeting cancer metabolism demonstrates the potential for managing colorectal cancer. Beta-hydroxybutyrate (BOHB) acts as an acetyl-CoA source for the tricarboxylic acid (TCA) cycle, possibly redirecting energy metabolic pathways towards the TCA cycle that could enhance sensitivity to oxaliplatin, through the generation of reactive oxygen species (ROS). This study explores the potential of BOHB to enhance oxaliplatin's cytotoxic effect by altering the energy metabolism in colorectal cancer. The study employed advanced in vitro organoid technology, which successfully emulates in vivo physiology. The combination treatment efficacy of BOHB and oxaliplatin was evaluated via cell viability assay. The levels of key proteins involved in energy metabolism, apoptotic pathways, DNA damage markers, and histone acetylation were analyzed via Western Blot. ROS levels were evaluated via flow cytometer. Non-toxic doses of BOHB with oxaliplatin significantly amplified cytotoxicity in colorectal cancer organoids. Treatment with BOHB and/or melatonin resulted in significantly decreased lactate dehydrogenase A and increased mitochondrial carrier protein 2 levels, indicating inhibited aerobic glycolysis and an increased oxidative phosphorylation rate. This metabolic shift induced apoptotic cell death mediated by oxaliplatin, owing to high levels of ROS. Melatonin counteracted this effect by protecting cancer cells from high oxidative stress conditions. BOHB may enhance the efficacy of chemotherapeutics with a similar mechanism of action to oxaliplatin in colorectal cancer treatment. These innovative combinations could improve treatment outcomes for colorectal cancer patients.
    Keywords:  beta-hydroxybutyrate; colorectal cancer; metabolic targeted therapy; organoid; oxaliplatin; reactive oxygen species
    DOI:  https://doi.org/10.3390/cancers15245724
  9. Biomed Pharmacother. 2023 Dec 20. pii: S0753-3322(23)01808-5. [Epub ahead of print]170 116010
    A gold-based inhibitor of oxidative phosphorylation is effective against triple negative breast cancer.
    R Tyler Mertens, Jong Hyun Kim, Samuel Ofori, Chibuzor Olelewe, Paul J Kamitsuka, Gunnar F Kwakye, Samuel G Awuah.
      Triple-negative breast cancer (TNBC) is associated with metabolic heterogeneity and poor prognosis with limited treatment options. New treatment paradigms for TNBC remains an unmet need. Thus, therapeutics that target metabolism are particularly attractive approaches. We previously designed organometallic Au(III) compounds capable of modulating mitochondrial respiration by ligand tuning with high anticancer potency in vitro and in vivo. Here, we show that an efficacious Au(III) dithiocarbamate (AuDTC) compound induce mitochondrial dysfunction and oxidative damage in cancer cells. Efficacy of AuDTC in TNBC mouse models harboring mitochondrial oxidative phosphorylation (OXPHOS) dependence and metabolic heterogeneity establishes its therapeutic potential following systemic delivery. This provides evidence that AuDTC is an effective modulator of mitochondrial respiration worthy of clinical development in the context of TNBC. ONE SENTENCE SUMMARY: Metabolic-targeting of triple-negative breast cancer by gold anticancer agent may provide efficacious therapy.
    Keywords:  Gold; Mitochondria; OXPHOS; Triple negative breast cancer
    DOI:  https://doi.org/10.1016/j.biopha.2023.116010
  10. Biochim Biophys Acta Bioenerg. 2023 Dec 16. pii: S0005-2728(23)00073-7. [Epub ahead of print] 149027
    Performance of TMRM and Mitotrackers in mitochondrial morphofunctional analysis of primary human skin fibroblasts.
    Shruti Desai, Sander Grefte, Els van de Westerlo, Susette Lauwen, Angela Paters, Jochen H M Prehn, Zhuohui Gan, Jaap Keijer, Merel J W Adjobo-Hermans, Werner J H Koopman.
      Mitochondrial membrane potential (Δψ) and morphology are considered key readouts of mitochondrial functional state. This morphofunction can be studied using fluorescent dyes ("probes") like tetramethylrhodamine methyl ester (TMRM) and Mitotracker (MT) dyes. Although these dyes are broadly used, information comparing their performance in mitochondrial morphology quantification and Δψ-sensitivity in the same cell model is still scarce. Here we applied epifluorescence microscopy of primary human skin fibroblasts to evaluate TMRM, Mitotracker Red CMXros (CMXros), Mitotracker Red CMH2Xros (CMH2Xros), Mitotracker Green FM (MG) and Mitotracker Deep Red FM (MDR). All probes were suited for automated quantification of mitochondrial morphology parameters when Δψ was normal, although they did not deliver quantitatively identical results. The mitochondrial localization of TMRM and MTs was differentially sensitive to carbonyl cyanide-4-phenylhydrazone (FCCP)-induced Δψ depolarization, decreasing in the order: TMRM ≫ CHM2Xros = CMXros = MDR > MG. To study the effect of reversible Δψ changes, the impact of photo-induced Δψ "flickering" was studied in cells co-stained with TMRM and MG. During a flickering event, individual mitochondria displayed subsequent TMRM release and uptake, whereas this phenomenon was not observed for MG. Spatiotemporal and computational analysis of the flickering event provided evidence that TMRM redistributes between adjacent mitochondria by a mechanism dependent on Δψ and TMRM concentration. In summary, this study demonstrates that: (1) TMRM and MTs are suited for automated mitochondrial morphology quantification, (2) numerical data obtained with different probes is not identical, and (3) all probes are sensitive to FCCP-induced Δψ depolarization, with TMRM and MG displaying the highest and lowest sensitivity, respectively. We conclude that TMRM is better suited for integrated analysis of Δψ and mitochondrial morphology than the tested MTs under conditions that Δψ is not substantially depolarized.
    Keywords:  FCCP; Flickering; Mitochondrial morphology; Mitotracker; TMRM
    DOI:  https://doi.org/10.1016/j.bbabio.2023.149027
  11. Commun Biol. 2023 Dec 15. 6(1): 1271
    The centrosomal protein 131 participates in the regulation of mitochondrial apoptosis.
    Clotilde C N Renaud, Kilian Trillet, Jane Jardine, Laura Merlet, Ophélie Renoult, Mélanie Laurent-Blond, Zoé Catinaud, Claire Pecqueur, Julie Gavard, Nicolas Bidère.
      Centriolar satellites are multiprotein aggregates that orbit the centrosome and govern centrosome homeostasis and primary cilia formation. In contrast to the scaffold PCM1, which nucleates centriolar satellites and has been linked to microtubule dynamics, autophagy, and intracellular trafficking, the functions of its interactant CEP131 beyond ciliogenesis remain unclear. Using a knockout strategy in a non-ciliary T-cell line, we report that, although dispensable for centriolar satellite assembly, CEP131 participates in optimal tubulin glycylation and polyglutamylation, and microtubule regrowth. Our unsupervised label-free proteomic analysis by quantitative mass spectrometry further uncovered mitochondrial and apoptotic signatures. CEP131-deficient cells showed an elongated mitochondrial network. Upon cell death inducers targeting mitochondria, knockout cells displayed delayed cytochrome c release from mitochondria, subsequent caspase activation, and apoptosis. This mitochondrial permeabilization defect was intrinsic, and replicable in vitro with isolated organelles. These findings extend CEP131 functions to life-and-death decisions and propose ways to interfere with mitochondrial apoptosis.
    DOI:  https://doi.org/10.1038/s42003-023-05676-3
  12. Sci Rep. 2023 Dec 16. 13(1): 22383
    Artesunate acts through cytochrome c to inhibit growth of pediatric AML cells.
    Kristen S Hill, Erin E Schuler, Sally R Ellingson, Jill M Kolesar.
      Artesunate is a derivative of artemisinin, an active compound isolated from Artemisia annua which has been used in Traditional Chinese Medicine and to treat malaria worldwide. Artemisinin derivatives have exhibited anti-cancer activity against both solid tumors and leukemia. The direct target(s) of artesunate are controversial; although, heme-bound proteins in the mitochondria have been implicated. We utilized computational modeling to calculate the predicted binding score of artesunate with heme-bound mitochondrial proteins and identified cytochrome c as potential artesunate target. UV-visible spectroscopy showed changes in the absorbance spectrum, and thus protein structure, when cytochrome c was incubated with artesunate. Artesunate induces apoptosis, disrupts mitochondrial membrane potential, and is antagonized by methazolamide in pediatric AML cells indicating a probable mechanism of action involving cytochrome c. We utilized a multi-disciplinary approach to show that artesunate can interact with and is dependent on cytochrome c release to induce cell death in pediatric AML cell lines.
    DOI:  https://doi.org/10.1038/s41598-023-49928-y
  13. Cancers (Basel). 2023 Dec 15. pii: 5866. [Epub ahead of print]15(24):
    Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia.
    Johnson Ung, Su-Fern Tan, Todd E Fox, Jeremy J P Shaw, Maansi Taori, Bethany J Horton, Upendarrao Golla, Arati Sharma, Zdzislaw M Szulc, Hong-Gang Wang, Charles E Chalfant, Myles C Cabot, David F Claxton, Thomas P Loughran, David J Feith.
      Acute myeloid leukemia (AML) is an aggressive hematologic malignancy requiring urgent treatment advancements. Ceramide is a cell-death-promoting signaling lipid that plays a central role in therapy-induced cell death. We previously determined that acid ceramidase (AC), a ceramide-depleting enzyme, is overexpressed in AML and promotes leukemic survival and drug resistance. The ceramidase inhibitor B-13 and next-generation lysosomal-localizing derivatives termed dimethylglycine (DMG)-B-13 prodrugs have been developed but remain untested in AML. Here, we report the in vitro anti-leukemic efficacy and mechanism of DMG-B-13 prodrug LCL-805 across AML cell lines and primary patient samples. LCL-805 inhibited AC enzymatic activity, increased total ceramides, and reduced sphingosine levels. A median EC50 value of 11.7 μM was achieved for LCL-805 in cell viability assays across 32 human AML cell lines. As a single agent tested across a panel of 71 primary AML patient samples, a median EC50 value of 15.8 μM was achieved. Exogenous ceramide supplementation with C6-ceramide nanoliposomes, which is entering phase I/II clinical trial for relapsed/refractory AML, significantly enhanced LCL-805 killing. Mechanistically, LCL-805 antagonized Akt signaling and led to iron-dependent cell death distinct from canonical ferroptosis. These findings elucidated key factors involved in LCL-805 cytotoxicity and demonstrated the potency of combining AC inhibition with exogenous ceramide.
    Keywords:  Akt; C6-ceramide nanoliposome; LCL-805; acid ceramidase; acute myeloid leukemia; ceramide; dimethylglycine-B-13 prodrug; iron chelation; sphingolipids
    DOI:  https://doi.org/10.3390/cancers15245866
  14. Heliyon. 2023 Nov;9(11): e22459
    An overview of ATP synthase, inhibitors, and their toxicity.
    Arwa R Althaher, Mohammad Alwahsh.
      Mitochondrial complex V (ATP synthase) is a remarkable molecular motor crucial in generating ATP and sustaining mitochondrial function. Its importance in cellular metabolism cannot be overstated, as malfunction of ATP synthase has been linked to various pathological conditions. Both natural and synthetic ATP synthase inhibitors have been extensively studied, revealing their inhibitory sites and modes of action. These findings have opened exciting avenues for developing new therapeutics and discovering new pesticides and herbicides to safeguard global food supplies. However, it is essential to remember that these compounds can also adversely affect human and animal health, impacting vital organs such as the nervous system, heart, and kidneys. This review aims to provide a comprehensive overview of mitochondrial ATP synthase, its structural and functional features, and the most common inhibitors and their potential toxicities.
    Keywords:  ATP synthase; ATP synthase inhibitors; Electron transport chain; Proton motive force; Rotational catalysis
    DOI:  https://doi.org/10.1016/j.heliyon.2023.e22459
  15. Nanoscale Adv. 2023 Dec 19. 6(1): 209-220
    Confinement primes cells for faster migration by polarizing active mitochondria.
    Jenna A Mosier, Emily D Fabiano, Catherine M Ludolph, Addison E White, Cynthia A Reinhart-King.
      Mechanical cues in the tumor microenvironment interplay with internal cellular processes to control cancer cell migration. Microscale pores present in tumor tissue confer varying degrees of confinement on migrating cells, increasing matrix contact and inducing cytoskeletal rearrangement. Previously, we observed that increased collagen matrix contact significantly increased cell migration speed and cell-induced strains within the matrix. However, the effects of this confinement on future cell migration are not fully understood. Here, we use a collagen microtrack platform to determine the effect of confinement on priming MDA-MB-231 cancer cells for fast migration. We show that migration through a confined track results in increased speed and accumulation of migratory machinery, including actin and active mitochondria, in the front of migrating breast cancer cells. By designing microtracks that allow cells to first navigate a region of high confinement, then a region of low confinement, we assessed whether migration in high confinement changes future migratory behavior. Indeed, cells maintain their speed attained in high confinement even after exiting to a region of low confinement, indicating that cells maintain memory of previous matrix cues to fuel fast migration. Active mitochondria maintain their location at the front of the cell even after cells leave high confinement. Furthermore, knocking out vinculin to disrupt focal adhesions disrupts active mitochondrial localization and disrupts the fast migration seen upon release from confinement. Together, these data suggest that active mitochondrial localization in confinement may facilitate fast migration post-confinement. By better understanding how confinement contributes to future cancer cell migration, we can identify potential therapeutic targets to inhibit breast cancer metastasis.
    DOI:  https://doi.org/10.1039/d3na00478c
  16. Leukemia. 2023 Dec 15.
    DELE1 haploinsufficiency causes resistance to mitochondrial stress-induced apoptosis in monosomy 5/del(5q) AML.
    Jean-François Spinella, Jalila Chagraoui, Céline Moison, Vincent P Lavallée, Isabel Boivin, Deanne Gracias, Sylvie Lavallée, Guillaume Richard Carpentier, François Beliveau, Josée Hébert, Guy Sauvageau.
      Monosomy 5 and deletions of the chromosome 5q (-5/del(5q)) are recurrent events in de novo adult acute myeloid leukemia (AML), reaching up to 40% of cases in secondary AML. These chromosome anomalies are associated with TP53 mutations and with very poor prognosis. Using the large Leucegene genomic and transcriptomic dataset composed of 48 -5/del(5q) patient specimens and 367 control AML, we identified DELE1 - located in the common deleted region - as the most consistently downregulated gene in these leukemias. DELE1 encodes a mitochondrial protein recently characterized as the relay of mitochondrial stress to the cytosol through a newly defined OMA1-DELE1-HRI pathway which ultimately leads to the activation of ATF4, the master transcription factor of the integrated stress response. Here, we showed that the partial loss of DELE1 expression observed in -5/del(5q) patients was sufficient to significantly reduce the sensitivity to mitochondrial stress in AML cells. Overall, our results suggest that DELE1 haploinsufficiency could represent a new driver mechanism in -5/del(5q) AML.
    DOI:  https://doi.org/10.1038/s41375-023-02107-4
  17. Nature. 2023 Dec 20.
    Mitochondrial dysfunction abrogates dietary lipid processing in enterocytes.
    Chrysanthi Moschandrea, Vangelis Kondylis, Ioannis Evangelakos, Marija Herholz, Farina Schneider, Christina Schmidt, Ming Yang, Sandra Ehret, Markus Heine, Michelle Y Jaeckstein, Karolina Szczepanowska, Robin Schwarzer, Linda Baumann, Theresa Bock, Efterpi Nikitopoulou, Susanne Brodesser, Marcus Krüger, Christian Frezza, Joerg Heeren, Aleksandra Trifunovic, Manolis Pasparakis.
      Digested dietary fats are taken up by enterocytes where they are assembled into pre-chylomicrons in the endoplasmic reticulum followed by transport to the Golgi for maturation and subsequent secretion to the circulation1. The role of mitochondria in dietary lipid processing is unclear. Here we show that mitochondrial dysfunction in enterocytes inhibits chylomicron production and the transport of dietary lipids to peripheral organs. Mice with specific ablation of the mitochondrial aspartyl-tRNA synthetase DARS2 (ref. 2), the respiratory chain subunit SDHA3 or the assembly factor COX10 (ref. 4) in intestinal epithelial cells showed accumulation of large lipid droplets (LDs) in enterocytes of the proximal small intestine and failed to thrive. Feeding a fat-free diet suppressed the build-up of LDs in DARS2-deficient enterocytes, which shows that the accumulating lipids derive mostly from digested fat. Furthermore, metabolic tracing studies revealed an impaired transport of dietary lipids to peripheral organs in mice lacking DARS2 in intestinal epithelial cells. DARS2 deficiency caused a distinct lack of mature chylomicrons concomitant with a progressive dispersal of the Golgi apparatus in proximal enterocytes. This finding suggests that mitochondrial dysfunction results in impaired trafficking of chylomicrons from the endoplasmic reticulum to the Golgi, which in turn leads to storage of dietary lipids in large cytoplasmic LDs. Taken together, these results reveal a role for mitochondria in dietary lipid transport in enterocytes, which might be relevant for understanding the intestinal defects observed in patients with mitochondrial disorders5.
    DOI:  https://doi.org/10.1038/s41586-023-06857-0
  18. Cancers (Basel). 2023 Dec 16. pii: 5870. [Epub ahead of print]15(24):
    Fasting-Mimicking Diet Inhibits Autophagy and Synergizes with Chemotherapy to Promote T-Cell-Dependent Leukemia-Free Survival.
    Roberta Buono, Jonathan Tucci, Raffaello Cutri, Novella Guidi, Serghei Mangul, Franca Raucci, Matteo Pellegrini, Steven D Mittelman, Valter D Longo.
      Fasting mimicking diets (FMDs) are effective in the treatment of many solid tumors in mouse models, but their effect on hematologic malignancies is poorly understood, particularly in combination with standard therapies. Here we show that cycles of a 3-day FMD given to high-fat-diet-fed mice once a week increased the efficacy of vincristine to improve survival from BCR-ABL B acute lymphoblastic leukemia (ALL). In mice fed a standard diet, FMD cycles in combination with vincristine promoted cancer-free survival. RNA seq and protein assays revealed a vincristine-dependent decrease in the expression of multiple autophagy markers, which was exacerbated by the fasting/FMD conditions. The autophagy inhibitor chloroquine could substitute for fasting/FMD to promote cancer-free survival in combination with vincristine. In vitro, targeted inhibition of autophagy genes ULK1 and ATG9a strongly potentiated vincristine's toxicity. Moreover, anti-CD8 antibodies reversed the effects of vincristine plus fasting/FMD in promoting leukemia-free survival in mice, indicating a central role of the immune system in this response. Thus, the inhibition of autophagy and enhancement of immune responses appear to be mediators of the fasting/FMD-dependent cancer-free survival in ALL mice.
    Keywords:  Leukemia; autophagy; cancer treatment; fasting-mimicking diet; pre-B-ALL
    DOI:  https://doi.org/10.3390/cancers15245870
  19. Mol Metab. 2023 Dec 15. pii: S2212-8778(23)00188-6. [Epub ahead of print] 101854
    Need for speed: Human fast-twitch mitochondria favor power over efficiency.
    Sebastian Edman, Mikael Flockhart, Filip J Larsen, William Apró.
      OBJECTIVE: Human skeletal muscle consists of a mixture of slow- and fast-twitch fibers with distinct capacities for contraction mechanics, fermentation, and oxidative phosphorylation (OXPHOS). While the divergence in mitochondrial volume favoring slow-twitch fibers is well established, data on the fiber type-specific intrinsic mitochondrial function and morphology are highly limited with existing data mainly being generated in animal models. This highlights the need for more human data on the topic.METHODS: Here, we utilized THRIFTY, a rapid fiber type identification protocol to detect, sort, and pool fast- and slow-twitch fibers within 6 h of muscle biopsy sampling. Respiration of permeabilized fast- and slow-twitch fiber pools was then analyzed with high-resolution respirometry. Using standardized western blot procedures, muscle fiber pools were subsequently analyzed for control proteins and key proteins related to respiratory capacity.
    RESULTS: Maximal complex I CI+II respiration was 25% higher in human slow-twitch fibers compared to fast-twitch fibers. However, per volume, the respiratory rate of mitochondria in fast-twitch fibers was approximately 50% higher for CI+II, which was primarily mediated through elevated CII respiration, but not CI or. Furthermore, the abundance of CII protein and proteins regulating cristae structure were disproportionally elevated in mitochondria of the fast-twitch fibers. The difference in intrinsic respiratory rate was not reflected in fatty acid-or complex I respiration.
    CONCLUSION: Mitochondria of human fast-twitch muscle fibers compensate for their lack of volume by substantially elevating intrinsic respiratory rate through increased reliance on complex II.
    DOI:  https://doi.org/10.1016/j.molmet.2023.101854
  20. Cancer Res Commun. 2023 Dec 19.
    WNT4 regulates cellular metabolism via intracellular activity at the mitochondria in breast and gynecologic cancers.
    Joseph L Sottnik, Madeleine T Shackleford, Sydney K Robinson, Fabian R Villagomez, Shaymaa Bahnassy, Steffi Oesterreich, Junxiao Hu, Zeynep Madak-Erdogan, Rebecca B Riggins, Bradley R Corr, Linda S Cook, Lindsey S Treviño, Benjamin G Bitler, Matthew J Sikora.
      Wnt ligand WNT4 is critical in female reproductive tissue development, with WNT4 dysregulation linked to related pathologies including breast cancer (invasive lobular carcinoma, ILC) and gynecologic cancers. WNT4 signaling in these contexts is distinct from canonical Wnt signaling yet inadequately understood. We previously identified atypical intracellular activity of WNT4 (independent of Wnt secretion) regulating mitochondrial function, and herein examine intracellular functions of WNT4. We further examine how convergent mechanisms of WNT4 dysregulation impact cancer metabolism. In ILC, WNT4 is co-opted by estrogen receptor α (ER) via genomic binding in WNT4 intron 1, while in gynecologic cancers, a common genetic polymorphism (rs3820282) at this ER binding site alters WNT4 regulation. Using proximity biotinylation (BioID), we show canonical Wnt ligand WNT3A is trafficked for secretion, but WNT4 is localized to the cytosol and mitochondria. We identified DHRS2, mTOR, and STAT1 as putative WNT4 cytosolic/mitochondrial signaling partners. Whole metabolite profiling, and integrated transcriptomic data, support that WNT4 mediates metabolic reprogramming via fatty acid and amino acid metabolism. Further, ovarian cancer cell lines with rs3820282 variant genotype are WNT4-dependent and have active WNT4 metabolic signaling. In protein array analyses of a cohort of 103 human gynecologic tumors enriched for patient diversity, germline rs3820282 genotype is associated with metabolic remodeling. Variant genotype tumors show increased AMPK activation and downstream signaling, with the highest AMPK signaling activity in variant genotype tumors from non-White patients. Taken together, atypical intracellular WNT4 signaling, in part via genetic dysregulation, regulate the distinct metabolic phenotypes of ILC and gynecologic cancers.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-23-0275
  21. Dev Cell. 2023 Dec 18. pii: S1534-5807(23)00611-1. [Epub ahead of print]58(24): 2914-2929.e7
    Aged intestinal stem cells propagate cell-intrinsic sources of inflammaging in mice.
    Maja C Funk, Jan G Gleixner, Florian Heigwer, Dominik Vonficht, Erica Valentini, Zeynep Aydin, Elena Tonin, Stefania Del Prete, Sylvia Mahara, Yannick Throm, Jenny Hetzer, Danijela Heide, Oliver Stegle, Duncan T Odom, Angelika Feldmann, Simon Haas, Mathias Heikenwalder, Michael Boutros.
      Low-grade chronic inflammation is a hallmark of ageing, associated with impaired tissue function and disease development. However, how cell-intrinsic and -extrinsic factors collectively establish this phenotype, termed inflammaging, remains poorly understood. We addressed this question in the mouse intestinal epithelium, using mouse organoid cultures to dissect stem cell-intrinsic and -extrinsic sources of inflammaging. At the single-cell level, we found that inflammaging is established differently along the crypt-villus axis, with aged intestinal stem cells (ISCs) strongly upregulating major histocompatibility complex class II (MHC-II) genes. Importantly, the inflammaging phenotype was stably propagated by aged ISCs in organoid cultures and associated with increased chromatin accessibility at inflammation-associated loci in vivo and ex vivo, indicating cell-intrinsic inflammatory memory. Mechanistically, we show that the expression of inflammatory genes is dependent on STAT1 signaling. Together, our data identify that intestinal inflammaging in mice is promoted by a cell-intrinsic mechanism, stably propagated by ISCs, and associated with a disbalance in immune homeostasis.
    Keywords:  ISC; ageing; epigenetics; inflammaging; inflammation; interferon; intestinal epithelium; intestinal stem cells; intestine; single-cell analysis
    DOI:  https://doi.org/10.1016/j.devcel.2023.11.013
  22. Cancers (Basel). 2023 Dec 06. pii: 5727. [Epub ahead of print]15(24):
    Inhibition of DHODH Enhances Replication-Associated Genomic Instability and Promotes Sensitivity in Endometrial Cancer.
    Shengyuan Zhao, Aaliyah Francois, Dawit Kidane.
      Endometrial carcinoma (EC) is the most common gynecological malignancy in the United States. De novo pyrimidine synthesis pathways generate nucleotides that are required for DNA synthesis. Approximately 38% of human endometrial tumors present with an overexpression of human dihydroorotate dehydrogenase (DHODH). However, the role of DHODH in cancer cell DNA replication and its impact on modulating a treatment response is currently unknown. Here, we report that endometrial tumors with overexpression of DHODH are associated with a high mutation count and chromosomal instability. Furthermore, tumors with an overexpression of DHODH show significant co-occurrence with mutations in DNA replication polymerases, which result in a histologically high-grade endometrial tumor. An in vitro experiment demonstrated that the inhibition of DHODH in endometrial cancer cell lines significantly induced replication-associated DNA damage and hindered replication fork progression. Furthermore, endometrial cancer cells were sensitive to the DHODH inhibitor either alone or in combination with the Poly (ADP-ribose) polymerase 1 inhibitor. Our findings may have important clinical implications for utilizing DHODH as a potential target to enhance cytotoxicity in high-grade endometrial tumors.
    Keywords:  DNA damage; DNA repair; de novo nucleotide biosynthesis; endometrial cancer
    DOI:  https://doi.org/10.3390/cancers15245727
  23. Cells. 2023 Dec 18. pii: 2859. [Epub ahead of print]12(24):
    Repurposing Metabolic Inhibitors in the Treatment of Colon Adenocarcinoma Patient-Derived Models.
    Bora Lee, ChuHee Lee, Hae-Min Moon, Se-Young Jo, Se Jin Jang, Young-Ah Suh.
      The effect of agonists on AMP-activated protein kinase (AMPK), mainly metformin and phenformin, has been appreciated in the treatment of multiple types of tumors. Specifically, the antitumor activity of phenformin has been demonstrated in melanomas containing the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) activating mutation. In this report, we elucidated the synergistic antitumor effects of biguanides with metabolism inhibitors on colon tumors. Phenformin with 2-deoxy-D-glucose (2DG) inhibited tumor cell growth in cancer cell lines, including HT29 cells harboring BRAF- and p53-mutations. Biochemical analyses showed that two chemotherapeutics exerted cooperative effects to reduce tumor growth through cell cycle arrest, apoptosis, and autophagy. The drugs demonstrated activity against phosphorylated ERK and the gain-of-function p53 mutant protein. To demonstrate tumor regressive effects in vivo, we established patient-derived models, including xenograft (PDX) and organoids (PDO). Co-treatment of biguanides with chemotherapeutics efficiently reduced the growth of patient-derived colon models in comparison to treatment with a single agent. These results strongly suggest that significant therapeutic advantages would be achieved by combining AMPK activators such as phenformin and cancer metabolic inhibitors such as 2DG.
    Keywords:  biguanide; cancer metabolism; colon tumor; patient-derived xenograft; tumor organoid
    DOI:  https://doi.org/10.3390/cells12242859
  24. Elife. 2023 Dec 21. pii: RP87894. [Epub ahead of print]12
    Identifying metabolic features of colorectal cancer liability using Mendelian randomization.
    Caroline Bull, Emma Hazelwood, Joshua A Bell, Vanessa Tan, Andrei-Emil Constantinescu, Carolina Borges, Danny Legge, Kimberley Burrows, Jeroen R Huyghe, Hermann Brenner, Sergi Castellvi-Bel, Andrew T Chan, Sun-Seog Kweon, Loic Le Marchand, Li Li, Iona Cheng, Rish K Pai, Jane C Figueiredo, Neil Murphy, Marc J Gunter, Nicholas J Timpson, Emma E Vincent.
      Background: Recognizing the early signs of cancer risk is vital for informing prevention, early detection, and survival.Methods: To investigate whether changes in circulating metabolites characterize the early stages of colorectal cancer (CRC) development, we examined the associations between a genetic risk score (GRS) associated with CRC liability (72 single-nucleotide polymorphisms) and 231 circulating metabolites measured by nuclear magnetic resonance spectroscopy in the Avon Longitudinal Study of Parents and Children (N = 6221). Linear regression models were applied to examine the associations between genetic liability to CRC and circulating metabolites measured in the same individuals at age 8 y, 16 y, 18 y, and 25 y.
    Results: The GRS for CRC was associated with up to 28% of the circulating metabolites at FDR-P < 0.05 across all time points, particularly with higher fatty acids and very-low- and low-density lipoprotein subclass lipids. Two-sample reverse Mendelian randomization (MR) analyses investigating CRC liability (52,775 cases, 45,940 controls) and metabolites measured in a random subset of UK Biobank participants (N = 118,466, median age 58 y) revealed broadly consistent effect estimates with the GRS analysis. In conventional (forward) MR analyses, genetically predicted polyunsaturated fatty acid concentrations were most strongly associated with higher CRC risk.
    Conclusions: These analyses suggest that higher genetic liability to CRC can cause early alterations in systemic metabolism and suggest that fatty acids may play an important role in CRC development.
    Funding: This work was supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol, the Wellcome Trust, the Medical Research Council, Diabetes UK, the University of Bristol NIHR Biomedical Research Centre, and Cancer Research UK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work used the computational facilities of the Advanced Computing Research Centre, University of Bristol - http://www.bristol.ac.uk/acrc/.
    Keywords:  Mendelian randomization; cancer biology; colorectal cancer; epidemiology; global health; human; metabolomics; obesity
    DOI:  https://doi.org/10.7554/eLife.87894
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