bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2023‒01‒01
twenty-one papers selected by
Kelsey Fisher-Wellman, East Carolina University
  1. How does density of the inner mitochondrial membrane influence mitochondrial performance?
  2. Multi-substrate metabolic tracing reveals marked heterogeneity and dependency on fatty acid metabolism in human prostate cancer.
  3. The membrane domain of respiratory complex I accumulates during muscle aging in Drosophila melanogaster.
  4. Hindering NAT8L expression in hepatocellular carcinoma increases cytosolic aspartate delivery that fosters pentose phosphate pathway and purine biosynthesis promoting cell proliferation.
  5. Ultrasensitive Small-Molecule Fluorescent Thermometer Reveals Hot Mitochondria in Surgically Resected Human Tumors.
  6. Age-associated alterations of brain mitochondria energetics.
  7. Mitochondria directly sense osmotic stress to trigger rapid metabolic remodeling via regulation of pyruvate dehydrogenase (PDH) phosphorylation.
  8. Mitochondria-localized lncRNA HITT inhibits fusion by attenuating formation of mitofusin-2 homo- or heterotypic complexes.
  9. Tumor Cell-Intrinsic CD96 Mediates Chemoresistance and Cancer Stemness by Regulating Mitochondrial Fatty Acid β-Oxidation.
  10. The role of mitochondria in pharmacological ascorbate-induced toxicity.
  11. Fluorinated triphenylphosphonium analogs improve cell selectivity and in vivo detection of mito-metformin.
  12. High-frequency and functional mitochondrial DNA mutations at the single-cell level.
  13. The lipid flippase SLC47A1 blocks metabolic vulnerability to ferroptosis.
  14. DNA-protein cross-links between abasic DNA damage and mitochondrial transcription factor A (TFAM).
  15. Proteogenomic analysis of acute myeloid leukemia associates relapsed disease with reprogrammed energy metabolism both in adults and children.
  16. Obesity triggers tumoral senescence and renders poorly immunogenic malignancies amenable to senolysis.
  17. Decoding the coupled decision-making of the epithelial-mesenchymal transition and metabolic reprogramming in cancer.
  18. Bisphenols S and F drive ovarian granulosa cell tumor invasion via a metabolic switch.
  19. Regulation and function of the mammalian tricarboxylic acid cycle.
  20. Effects of metabolic cancer therapy on tumor microenvironment.
  21. Lack of evidence for increased transcriptional noise in aged tissues.
  1. Am J Physiol Regul Integr Comp Physiol. 2022 Dec 26.
    How does density of the inner mitochondrial membrane influence mitochondrial performance?
    Kyle B Heine, Hailey A Parry, Wendy R Hood.
      Our current understanding of variation in mitochondrial performance is incomplete. The production of ATP via oxidative phosphorylation is dependent, in part, upon the structure of the inner mitochondrial membrane. Morphology of the inner membrane is crucial for the formation of the proton gradient across the inner membrane and, therefore, ATP synthesis. The inner mitochondrial membrane is dynamic, changing shape and surface area. These changes alter density (amount per volume) of the inner mitochondrial membrane within the confined space of the mitochondrion. Because the number of electron transport system proteins within the inner mitochondrial membrane changes with inner mitochondrial membrane area, a change in the amount of inner membrane alters the capacity for ATP production within the organelle. This review outlines the evidence that the association between ATP synthases, inner mitochondrial membrane density, and mitochondrial density (number of mitochondria per cell), impact ATP production by mitochondria. Further, we consider possible constraints on the capacity of mitochondria to produce ATP by increasing inner mitochondrial membrane density.
    Keywords:  ATP synthase; cristae; inter-membrane space; matrix; oxidative phosphorylation
    DOI:  https://doi.org/10.1152/ajpregu.00254.2022
  2. Mol Cancer Res. 2022 Dec 27. pii: MCR-22-0796. [Epub ahead of print]
    Multi-substrate metabolic tracing reveals marked heterogeneity and dependency on fatty acid metabolism in human prostate cancer.
    Gio Fidelito, David P De Souza, Birunthi Niranjan, William de Nardo, Shivakumar Keerthikumar, Kristin Brown, Renea A Taylor, Matthew J Watt.
      Cancer cells undergo metabolic reprogramming to meet increased bioenergetic demands. Studies in cells and mice have highlighted the importance of oxidative metabolism and lipogenesis in prostate cancer, however, the metabolic landscape of human prostate cancer remains unclear. To address this knowledge gap, we performed radiometric (14C) and stable (13C) isotope tracing assays in precision-cut slices of patient-derived xenografts (PDXs). Glucose, glutamine, and fatty acid oxidation was variably upregulated in malignant PDXs compared to benign PDXs. De novo lipogenesis (DNL) and storage of free fatty acids into phospholipids and triacylglycerols were increased in malignant PDXs. There was no difference in substrate utilization between localized and metastatic PDXs and hierarchical clustering revealed marked metabolic heterogeneity across all PDXs. Mechanistically, glucose utilization was mediated by acetyl-CoA production rather than carboxylation of pyruvate, while glutamine entered the TCA cycle through transaminase reactions before being utilized via oxidative or reductive pathways. Blocking fatty acid uptake or fatty acid oxidation with pharmacological inhibitors was sufficient to reduce cell viability in PDX-derived organoids (PDXOs), whereas blockade of DNL, or glucose or glutamine oxidation induced variable and limited therapeutic efficacy. These findings demonstrate that human prostate cancer, irrespective of disease stage, can effectively utilize all metabolic substrates, albeit with marked heterogeneity across tumors. We also confirm that fatty acid uptake and oxidation are targetable metabolic dependencies in human prostate cancer. Implications: Prostate cancer utilizes multiple substrates to fuel energy requirements, yet pharmacological targeting of fatty acid uptake and oxidation reveals metabolic dependencies in localised and metastatic tumors.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-22-0796
  3. Sci Rep. 2022 Dec 27. 12(1): 22433
    The membrane domain of respiratory complex I accumulates during muscle aging in Drosophila melanogaster.
    Kaniz Fatima Binte Hossain, Anjaneyulu Murari, Bibhuti Mishra, Edward Owusu-Ansah.
      The boot-shaped respiratory complex I (CI) consists of a mitochondrial matrix and membrane domain organized into N-, Q- and P-modules. The N-module is the most distal part of the matrix domain, whereas the Q-module is situated between the N-module and the membrane domain. The proton-pumping P-module is situated in the membrane domain. We explored the effect of aging on the disintegration of CI and its constituent subcomplexes and modules in Drosophila flight muscles. We find that the fully-assembled complex remains largely intact in aged flies. And while the effect of aging on the stability of many Q- and N-module subunits in subcomplexes was stochastic, NDUFS3 was consistently down-regulated in subcomplexes with age. This was associated with an accumulation of many P-module subunits in subcomplexes. The potential significance of these studies is that genetic manipulations aimed at boosting, perhaps, a few CI subunits may suffice to restore the whole CI biosynthesis pathway during muscle aging.
    DOI:  https://doi.org/10.1038/s41598-022-26414-5
  4. Redox Biol. 2022 Dec 24. pii: S2213-2317(22)00357-3. [Epub ahead of print]59 102585
    Hindering NAT8L expression in hepatocellular carcinoma increases cytosolic aspartate delivery that fosters pentose phosphate pathway and purine biosynthesis promoting cell proliferation.
    Pamela De Falco, Giacomo Lazzarino, Federica Felice, Enrico Desideri, Serena Castelli, Illari Salvatori, Fabio Ciccarone, Maria Rosa Ciriolo.
      N-acetylaspartate (NAA) is synthesized by the mitochondrial enzyme NAT8L, which uses acetyl-CoA and aspartate as substrates. These metabolites are fundamental for bioenergetics and anabolic requirements of highly proliferating cells, thus, NAT8L modulation may impinge on the metabolic reprogramming of cancer cells. Specifically, aspartate represents a limiting amino acid for nucleotide synthesis in cancer. Here, the expression of the NAT8L enzyme was modulated to verify how it impacts the metabolic adaptations and proliferative capacity of hepatocellular carcinoma. We demonstrated that NAT8L downregulation is associated with increased proliferation of hepatocellular carcinoma cells and immortalized hepatocytes. The overexpression of NAT8L instead decreased cell growth. The pro-tumoral effect of NAT8L silencing depended on glutamine oxidation and the rewiring of glucose metabolism. Mechanistically, NAT8L downregulation triggers aspartate outflow from mitochondria via the exporter SLC25A13 to promote glucose flux into the pentose phosphate pathway, boosting purine biosynthesis. These results were corroborated by the analyses of human and mouse hepatocellular carcinoma samples revealing a decrease in NAT8L expression compared to adjacent non-tumoral tissues. Overall, this work demonstrates that NAT8L expression in liver cells limits the cytosolic availability of aspartate necessary for enhancing the pentose phosphate pathway and purine biosynthesis, counteracting cell proliferation.
    Keywords:  Aspartate; Mitochondria; NAA; Nucleotides; Pentose phosphate pathway
    DOI:  https://doi.org/10.1016/j.redox.2022.102585
  5. ACS Sens. 2022 Dec 27.
    Ultrasensitive Small-Molecule Fluorescent Thermometer Reveals Hot Mitochondria in Surgically Resected Human Tumors.
    Qing Zhu, Yue Sun, Manlin Fu, Mianli Bian, Xiaomei Zhu, Kai Wang, Haoxing Geng, Wei Zeng, Wei Shen, Yi Hu.
      The Warburg effect suggests that upregulated glycolysis arising from high glucose uptake in cancer cells might be accompanied with suppressed mitochondrial respiration. However, recent studies have shown that the mitochondrial temperature in cancer cells could be relatively higher than that in normal cells, suggesting hyperactive mitochondrial respiration in cancer cells. However, hot mitochondria have not been reported in patients with cancer. Here, near-infrared small-molecule fluorescent probes TRNs are rationally designed with two ethyl amino groups as the temperature-sensitive moiety. Afterward, a mitochondrial targeting group is installed via ether bonds on TRN-8 to build MTN. To the best of our knowledge, MTN is the near-infrared probe with the highest sensitivity for mitochondrial temperature. Moreover, it also displays high photostability, wide linearity, and high specificity. Using MTN, we can monitor the ups and downs of mitochondrial temperature in cancer cells upon the perturbations of mitochondrial respiration. Furthermore, we demonstrate that the mitochondrial temperature in surgically resected human tumors is relatively higher than that in paracancerous tissues. Our results indicate that relatively hot mitochondria may exist in tumors from patients. We envisage that our study provides critical evidence for revisiting the Warburg effect and cancer metabolism.
    Keywords:  NIR; diethyl amino group; mitochondria; temperature-sensitive probe; tumor
    DOI:  https://doi.org/10.1021/acssensors.2c01563
  6. Biochem Biophys Res Commun. 2022 Dec 23. pii: S0006-291X(22)01741-7. [Epub ahead of print]643 1-7
    Age-associated alterations of brain mitochondria energetics.
    Timur Gainutdinov, Zemfira Gizatullina, Grazyna Debska-Vielhaber, Stefan Vielhaber, Robert Feldmann, Zulfiya Orynbayeva, Frank Norbert Gellerich.
      The study aimed to explore the role of age-associated elevated cytosolic Ca2+ in changes of brain mitochondria energetic processes. Two groups of rats, young adults (4 months) and advanced old (24 months), were evaluated for potential alterations of mitochondrial parameters, the oxidative phosphorylation (OxPhos), membrane potential, calcium retention capacity, activity of glutamate/aspartate carrier (aralar), and ROS formation. We demonstrated that the brain mitochondria of older animals have a lower resistance to Ca2+ stress with resulting consequences. The suppressed complex I OxPhos and decreased membrane potential were accompanied by reduction of the Ca2+ threshold required for induction of mPTP. The Ca2+ binding sites of mitochondrial aralar mediated a lower activity of old brain mitochondria. The altered interaction between aralar and mPTP may underlie mitochondrial dysregulation leading to energetic depression during aging. At the advanced stages of aging, the declined metabolism is accompanied by the diminished oxidative background.
    Keywords:  Aging; Aralar; Brain mitochondria; Ca(2+); OxPhos; ROS
    DOI:  https://doi.org/10.1016/j.bbrc.2022.12.070
  7. J Biol Chem. 2022 Dec 26. pii: S0021-9258(22)01280-7. [Epub ahead of print] 102837
    Mitochondria directly sense osmotic stress to trigger rapid metabolic remodeling via regulation of pyruvate dehydrogenase (PDH) phosphorylation.
    Takeshi Ikizawa, Kazutaka Ikeda, Makoto Arita, Shojiro Kitajima, Tomoyoshi Soga, Hidenori Ichijo, Isao Naguro.
      A high-salt diet significantly impacts various diseases, including cancer and immune diseases. Recent studies suggest that the high-salt/hyperosmotic environment in the body may alter the chronic properties of cancer and immune cells in the disease context. However, little is known about the acute metabolic changes in hyperosmotic stress. Here, we found that hyperosmotic stress for a few minutes induces Warburg-like metabolic remodeling in HeLa and Raw264.7 cells and suppresses fatty acid oxidation. Regarding Warburg-like remodeling, we determined that the pyruvate dehydrogenase (PDH) phosphorylation status was altered bidirectionally (high in hyperosmolarity and low in hypoosmolarity) to osmotic stress in isolated mitochondria, suggesting that mitochondria themselves have an acute osmo-sensing mechanism. Additionally, we demonstrate that Warburg-like remodeling is required for HeLa cells to maintain ATP levels and survive under hyperosmotic conditions. Collectively, our findings suggest that cells exhibit acute metabolic remodeling under osmotic stress via the regulation of PDH phosphorylation by direct osmosensing within mitochondria.
    Keywords:  Acyl-carnitine; Metabolic remodeling; Mitochondria; Osmotic stress; Pyruvate dehydrogenase
    DOI:  https://doi.org/10.1016/j.jbc.2022.102837
  8. J Biol Chem. 2022 Dec 22. pii: S0021-9258(22)01268-6. [Epub ahead of print] 102825
    Mitochondria-localized lncRNA HITT inhibits fusion by attenuating formation of mitofusin-2 homo- or heterotypic complexes.
    Xingwen Wang, Yi Zhang, Qingyu Lin, Kunming Zhao, Dantong Zhu, Ying Hu.
      Long non-coding RNAs (lncRNAs) are emerging as essential players in multiple biological processes. Mitochondrial dynamics, comprising the continuous cycle of fission and fusion, are required for healthy mitochondria that function properly. Despite long-term recognition of its significance in cell-fate control, the mechanism underlying mitochondrial fusion is not completely understood, particularly regarding the involvement of lncRNAs. Here, we show that the lncRNA HITT (HIF-1α inhibitor at translation level), can specifically localize in mitochondria. Cells expressing higher levels of HITT contain fragmented mitochondria. Conversely, we show that HITT knockdown cells have more tubular mitochondria than is present in control cells. Mechanistically, we demonstrate HITT directly binds mitofusin-2 (MFN2), a core component that mediates mitochondrial outer membrane fusion, by the in vitro RNA pull-down and UV-cross-linking RNA-IP (CLIP) assays. In doing so, we found HITT disturbs MFN2 homo- or heterotypic complex formation, attenuating mitochondrial fusion. Under stress conditions, such as ultraviolet radiation, we in addition show HITT stability increases as a consequence of MiR-205 downregulation, inhibiting MFN2-mediated fusion and leading to apoptosis. Overall, our data provide significant insights into the roles of organelle (mitochondria)-specific resident lncRNAs in regulating mitochondrial fusion, and also reveal how such a mechanism controls cellular sensitivity to UV radiation-induced apoptosis.
    Keywords:  LINC00637; MFN2; apoptosis; mitochondrial dynamics; mitochondrial fusion
    DOI:  https://doi.org/10.1016/j.jbc.2022.102825
  9. Adv Sci (Weinh). 2022 Dec 29. e2202956
    Tumor Cell-Intrinsic CD96 Mediates Chemoresistance and Cancer Stemness by Regulating Mitochondrial Fatty Acid β-Oxidation.
    Jiang Li, Qidong Xia, Can Di, Chunni Li, Hang Si, Boxuan Zhou, Shubin Yu, Yihong Li, Jingying Huang, Yiwen Lu, Min Huang, Huixin Liang, Xinwei Liu, Qiyi Zhao.
      Targeting CD96 that originates in immune cells has shown potential for cancer therapy. However, the role of intrinsic CD96 in solid tumor cells remains unknown. Here, it is found that CD96 is frequently expressed in tumor cells from clinical breast cancer samples and is correlated with poor long-term prognosis in these patients. The CD96+ cancer cell subpopulations exhibit features of both breast cancer stem cells and chemoresistance. In vivo inhibition of cancer cell-intrinsic CD96 enhances the chemotherapeutic response in a patient-derived tumor xenograft model. Mechanistically, CD96 enhances mitochondrial fatty acid β-oxidation via the CD155-CD96-Src-Stat3-Opa1 pathway, which subsequently promotes chemoresistance in breast cancer stem cells. A previously unknown role is identified for tumor cell-intrinsic CD96 and an attractive target in improving the chemotherapeutic response.
    Keywords:  CD96; cancer stem cells; chemoresistance; fatty acid β-oxidation; mitochondrial remodeling
    DOI:  https://doi.org/10.1002/advs.202202956
  10. Sci Rep. 2022 Dec 29. 12(1): 22521
    The role of mitochondria in pharmacological ascorbate-induced toxicity.
    Juan Du, Amanda N Pope, Brianne R O'Leary, Brett A Wagner, Prabhat C Goswami, Garry R Buettner, Joseph J Cullen.
      At pharmacological levels, ascorbate (P-AscH-) acts as a pro-oxidant by generating H2O2, depleting ATP in sensitive cells leading to cell death. The aim of this study was to determine the role of ATP production by oxidative phosphorylation or glycolysis in mechanisms of resistance to P-AscH-induced cell death. Pancreatic cancer cells were used to generate ρ0 cells by mitochondrial overexpression of the Y147A mutant uracil-N-glycosylase or Herpes Simplex Virus protein. The ρ0 phenotype was confirmed by probing for mitochondrial DNA, mitochondrial DNA-encoded cytochrome c oxidase subunit 2, and monitoring the rate of oxygen consumption. In ρ0 cells, glycolysis accounted for 100% of ATP production as there was no mitochondrial oxygen consumption. Even though the activities of H2O2-removing antioxidant enzymes were similar in both the parental and ρ0 clones, P-AscH- -induced clonogenic cell death in ρ0 cells showed more resistance than the parental cell line. In addition, P-AscH- induced more DNA damage and more consumption of NAD+ and greater decreases in the production of ATP in the parental cell line compared to the ρ0 cells. Thus, cancer cells that largely use oxidative phosphorylation to generate ATP may be more sensitive to P-AscH- compared with cells that are glycolysis-dependent.
    DOI:  https://doi.org/10.1038/s41598-022-27185-9
  11. iScience. 2022 Dec 22. 25(12): 105670
    Fluorinated triphenylphosphonium analogs improve cell selectivity and in vivo detection of mito-metformin.
    Mahmoud AbuEid, Robert F Keyes, Donna McAllister, Francis Peterson, Ishaque Pulikkal Kadamberi, Daniel J Sprague, Pradeep Chaluvally-Raghavan, Brian C Smith, Michael B Dwinell.
      Triphenylphosphonium (TPP+) conjugated compounds selectively target cancer cells by exploiting their hyperpolarized mitochondrial membrane potential. To date, studies have focused on modifying either the linker or the cargo of TPP+-conjugated compounds. Here, we investigated the biological effects of direct modification to TPP+ to improve the efficacy and detection of mito-metformin (MMe), a TPP+-conjugated probe we have shown to have promising preclinical efficacy against solid cancer cells. We designed, synthesized, and tested trifluoromethyl and methoxy MMe analogs (pCF3-MMe, mCF3-MMe, and pMeO-MMe) against multiple distinct human cancer cells. pCF3-MMe showed enhanced selectivity toward cancer cells compared to MMe, while retaining the same signaling mechanism. Importantly, pCF3-MMe allowed quantitative monitoring of cellular accumulation via 19F-NMR in vitro and in vivo. Furthermore, adding trifluoromethyl groups to TPP+ reduced toxicity in vivo while retaining anti-tumor efficacy, opening an avenue to de-risk these next-generation TPP+-conjugated compounds.
    Keywords:  Pharmaceutical science; biochemistry; biological sciences; chemistry
    DOI:  https://doi.org/10.1016/j.isci.2022.105670
  12. Proc Natl Acad Sci U S A. 2023 Jan 03. 120(1): e2201518120
    High-frequency and functional mitochondrial DNA mutations at the single-cell level.
    Xiaoxian Guo, Weilin Xu, Weiping Zhang, Cuiping Pan, Anna E Thalacker-Mercer, Hongxiang Zheng, Zhenglong Gu.
      Decline in mitochondrial function underlies aging and age-related diseases, but the role of mitochondrial DNA (mtDNA) mutations in these processes remains elusive. To investigate patterns of mtDNA mutations, it is particularly important to quantify mtDNA mutations and their associated pathogenic effects at the single-cell level. However, existing single-cell mtDNA sequencing approaches remain inefficient due to high cost and low mtDNA on-target rates. In this study, we developed a cost-effective mtDNA targeted-sequencing protocol called single-cell sequencing by targeted amplification of multiplex probes (scSTAMP) and experimentally validated its reliability. We then applied our method to assess single-cell mtDNA mutations in 768 B lymphocytes and 768 monocytes from a 76-y-old female. Across 632 B lymphocyte and 617 monocytes with medium mtDNA coverage over >100×, our results indicated that over 50% of cells carried at least one mtDNA mutation with variant allele frequencies (VAFs) over 20%, and that cells carried an average of 0.658 and 0.712 such mutation for B lymphocytes and monocytes, respectively. Surprisingly, more than 20% of the observed mutations had VAFs of over 90% in either cell population. In addition, over 60% of the mutations were in protein-coding genes, of which over 70% were nonsynonymous, and more than 50% of the nonsynonymous mutations were predicted to be highly pathogenic. Interestingly, about 80% of the observed mutations were singletons in the respective cell populations. Our results revealed mtDNA mutations with functional significance might be prevalent at advanced age, calling further investigation on age-related mtDNA mutation dynamics at the single-cell level.
    Keywords:  aging; mitochondrial DNA; single cell
    DOI:  https://doi.org/10.1073/pnas.2201518120
  13. Nat Commun. 2022 Dec 27. 13(1): 7965
    The lipid flippase SLC47A1 blocks metabolic vulnerability to ferroptosis.
    Zhi Lin, Jiao Liu, Fei Long, Rui Kang, Guido Kroemer, Daolin Tang, Minghua Yang.
      Ferroptosis is a type of regulated necrosis caused by unrestricted lipid peroxidation and subsequent plasma membrane rupture. However, the lipid remodeling mechanism that determines sensitivity to ferroptosis remains poorly understood. Here, we report a previously unrecognized role for the lipid flippase solute carrier family 47 member 1 (SLC47A1) as a regulator of lipid remodeling and survival during ferroptosis. Among 49 phospholipid scramblases, flippases, and floppases we analyzed, only SLC47A1 had mRNA that was selectively upregulated in multiple cancer cells exposed to ferroptotic inducers. Large-scale lipidomics and functional analyses revealed that the silencing of SLC47A1 increased RSL3- or erastin-induced ferroptosis by favoring ACSL4-SOAT1-mediated production of polyunsaturated fatty acid cholesterol esters. We identified peroxisome proliferator activated receptor alpha (PPARA) as a transcription factor that transactivates SLC47A1. The depletion of PPARA and SLC47A1 similarly sensitized cells to ferroptosis induction, whereas transfection-enforced re-expression of SLC47A1 restored resistance to ferroptosis in PPARA-deficient cells. Pharmacological or genetic blockade of the PPARA-SLC47A1 pathway increased the anticancer activity of a ferroptosis inducer in mice. These findings establish a direct molecular link between ferroptosis and lipid transporters, which may provide metabolic targets for overcoming drug resistance.
    DOI:  https://doi.org/10.1038/s41467-022-35707-2
  14. Nucleic Acids Res. 2022 Dec 30. pii: gkac1214. [Epub ahead of print]
    DNA-protein cross-links between abasic DNA damage and mitochondrial transcription factor A (TFAM).
    Wenyan Xu, Jin Tang, Linlin Zhao.
      In higher eukaryotic cells, mitochondria are essential organelles for energy production, metabolism, and signaling. Mitochondrial DNA (mtDNA) encodes 13 protein subunits for oxidative phosphorylation and a set of tRNAs and rRNAs. mtDNA damage, sourced from endogenous chemicals and environmental factors, contributes to mitochondrial genomic instability, which has been associated with various mitochondrial diseases. DNA-protein cross-links (DPCs) are deleterious DNA lesions that threaten genomic integrity. Although much has been learned about the formation and repair of DPCs in the nucleus, little is known about DPCs in mitochondria. Here, we present in vitro and in cellulo data to demonstrate the formation of DPCs between a prevalent abasic (AP) DNA lesion and a DNA-packaging protein, mitochondrial transcription factor A (TFAM). TFAM cleaves AP-DNA and forms DPCs and single-strand breaks (SSB). Lys residues of TFAM are critical for the formation of TFAM-DPC and a reactive 3'-phospho-α,β-unsaturated aldehyde (3'pUA) residue on SSB. The 3'pUA residue reacts with two Cys of TFAM and contributes to the stable TFAM-DPC formation. Glutathione reacts with 3'pUA and competes with TFAM-DPC formation, corroborating our cellular experiments showing the accumulation of TFAM-DPCs under limiting glutathione. Our data point to the involvement of TFAM in AP-DNA turnover and fill a knowledge gap regarding the protein factors in processing damaged mtDNA.
    DOI:  https://doi.org/10.1093/nar/gkac1214
  15. Leukemia. 2022 Dec 26.
    Proteogenomic analysis of acute myeloid leukemia associates relapsed disease with reprogrammed energy metabolism both in adults and children.
    Svea Stratmann, Mattias Vesterlund, Husen M Umer, Saeed Eshtad, Aron Skaftason, Morten Krogh Herlin, Christer Sundström, Anna Eriksson, Martin Höglund, Josefine Palle, Jonas Abrahamsson, Kirsi Jahnukainen, Monica Cheng Munthe-Kaas, Bernward Zeller, Katja Pokrovskaja Tamm, Cecilia Lindskog, Lucia Cavelier, Janne Lehtiö, Linda Holmfeldt.
      Despite improvement of current treatment strategies and novel targeted drugs, relapse and treatment resistance largely determine the outcome for acute myeloid leukemia (AML) patients. To identify the underlying molecular characteristics, numerous studies have been aimed to decipher the genomic- and transcriptomic landscape of AML. Nevertheless, further molecular changes allowing malignant cells to escape treatment remain to be elucidated. Mass spectrometry is a powerful tool enabling detailed insights into proteomic changes that could explain AML relapse and resistance. Here, we investigated AML samples from 47 adult and 22 pediatric patients at serial time-points during disease progression using mass spectrometry-based in-depth proteomics. We show that the proteomic profile at relapse is enriched for mitochondrial ribosomal proteins and subunits of the respiratory chain complex, indicative of reprogrammed energy metabolism from diagnosis to relapse. Further, higher levels of granzymes and lower levels of the anti-inflammatory protein CR1/CD35 suggest an inflammatory signature promoting disease progression. Finally, through a proteogenomic approach, we detected novel peptides, which present a promising repertoire in the search for biomarkers and tumor-specific druggable targets. Altogether, this study highlights the importance of proteomic studies in holistic approaches to improve treatment and survival of AML patients.
    DOI:  https://doi.org/10.1038/s41375-022-01796-7
  16. Proc Natl Acad Sci U S A. 2023 Jan 03. 120(1): e2209973120
    Obesity triggers tumoral senescence and renders poorly immunogenic malignancies amenable to senolysis.
    Frédérik Fournier, Roberto Diaz-Marin, Frédérique Pilon, Mathieu Neault, Rachel Juneau, Gabrielle Girouard, Ariel M Wilson, Bruno Larrivée, Frédérick A Mallette, Sergio Crespo-Garcia, Przemyslaw Sapieha.
      Obesity is a major risk factor for cancer. Conventional thought suggests that elevated adiposity predisposes to heightened inflammatory stress and potentiates tumor growth, yet underlying mechanisms remain ill-defined. Here, we show that tumors from patients with a body mass index >35 carry a high burden of senescent cells. In mouse syngeneic tumor models, we correlated a pronounced accretion of senescent cancer cells with poorly immunogenic tumors when mice were subjected to diet-induced obesity (DIO). Highly immunogenic tumors showed lesser senescence burden suggesting immune-mediated elimination of senescent cancer cells, likely targeted as a consequence of their senescence-associated secretory phenotype. Treatment with the senolytic BH3 mimetic small molecule inhibitor ABT-263 selectively stalled tumor growth in mice with DIO to rates comparable to regular diet-fed mice. Thus, consideration of body adiposity in the selection of cancer therapy may be a critical determinant for disease outcome in poorly immunogenic malignancies.
    Keywords:  cancer; immunogenicity; obesity; senescence
    DOI:  https://doi.org/10.1073/pnas.2209973120
  17. iScience. 2023 Jan 20. 26(1): 105719
    Decoding the coupled decision-making of the epithelial-mesenchymal transition and metabolic reprogramming in cancer.
    Madeline Galbraith, Herbert Levine, José N Onuchic, Dongya Jia.
      Cancer metastasis relies on an orchestration of traits driven by different interacting functional modules, including metabolism and epithelial-mesenchymal transition (EMT). During metastasis, cancer cells can acquire a hybrid metabolic phenotype (W/O) by increasing oxidative phosphorylation without compromising glycolysis and they can acquire a hybrid epithelial/mesenchymal (E/M) phenotype by engaging EMT. Both the W/O and E/M states are associated with high metastatic potentials, and many regulatory links coupling metabolism and EMT have been identified. Here, we investigate the coupled decision-making networks of metabolism and EMT. Their crosstalk can exhibit synergistic or antagonistic effects on the acquisition and stability of different coupled metabolism-EMT states. Strikingly, the aggressive E/M-W/O state can be enabled and stabilized by the crosstalk irrespective of these hybrid states' availability in individual metabolism or EMT modules. Our work emphasizes the mutual activation between metabolism and EMT, providing an important step toward understanding the multifaceted nature of cancer metastasis.
    Keywords:  Cancer systems biology; Metabolic flux analysis
    DOI:  https://doi.org/10.1016/j.isci.2022.105719
  18. Toxicol Lett. 2022 Dec 27. pii: S0378-4274(22)01823-9. [Epub ahead of print]
    Bisphenols S and F drive ovarian granulosa cell tumor invasion via a metabolic switch.
    Justyna Gogola-Mruk, Kinga Krawczyk, Weronika Marynowicz, Magdalena Rokita, Samantha Nimpsz, Anna Ptak.
      Alterations in the metabolism of cancer cells are crucial for tumor growth and progression. However, the mechanism whereby environmental pollutants such as bisphenols F (BPF) and S (BPS) affect glucose metabolism through the glycolytic pathway, and therefore influence tumor progression, are unclear. Both bisphenols are endocrine-disrupting molecules that are used in plastics. As a consequence of their widespread use, these compounds have been detected in various human body fluids. Thus, hormone-sensitive cancers, such as ovarian cancers, are exposed to these compounds. In the present study, we aimed to determine the effects of the concentrations of BPS and BPF found in body fluids on the cell viability, glucose uptake, glycolysis, oxygen consumption, and invasion by the adult ovarian granulosa cell tumor (AGCT) cell line. We found that BPS and BPF increased the glucose uptake, hexokinase activity, proliferation, and invasion of the cells at environmentally relevant concentrations. Furthermore, we identified an inhibition of glycolysis in parallel with an increase in oxygen consumption, suggesting a BPS/BPF-induced switch from aerobic glycolysis to mitochondrial respiration. In summary, these findings demonstrate a new mechanism through which BPS and BPF promote ovarian granulosa cell tumor progression by increasing energy production through mitochondrial respiration. Thus, both bisphenols induced a metabolic switch that appears to be a stimulus for AGCT progression.
    Keywords:  Bisphenol S and F; glucose uptake; glycolysis; granulosa cell tumor; spheroid invasion
    DOI:  https://doi.org/10.1016/j.toxlet.2022.12.011
  19. J Biol Chem. 2022 Dec 26. pii: S0021-9258(22)01281-9. [Epub ahead of print] 102838
    Regulation and function of the mammalian tricarboxylic acid cycle.
    Paige K Arnold, Lydia W S Finley.
      The tricarboxylic acid (TCA) cycle, otherwise known as the Krebs cycle, is a central metabolic pathway that performs the essential function of oxidizing nutrients to support cellular bioenergetics. More recently, it has become evident that TCA cycle behavior is dynamic and products of the TCA cycle can be co-opted in cancer and other pathologic states. In this review, we revisit the TCA cycle, including its potential origins and the history of its discovery. We provide a detailed accounting of the requirements for sustained TCA cycle function and the critical regulatory nodes that can stimulate or constrain TCA cycle activity. We also discuss recent advances in our understanding of the flexibility of TCA cycle wiring and the increasingly appreciated heterogeneity in TCA cycle activity exhibited by mammalian cells. Deeper insight into how the TCA cycle can be differentially regulated and, consequently, configured in different contexts will shed light on how this pathway is primed to meet the requirements of distinct mammalian cell states.
    DOI:  https://doi.org/10.1016/j.jbc.2022.102838
  20. Front Oncol. 2022 ;12 1046630
    Effects of metabolic cancer therapy on tumor microenvironment.
    Petra Hyroššová, Mirko Milošević, Josef Škoda, Jiří Vachtenheim, Jakub Rohlena, Kateřina Rohlenová.
      Targeting tumor metabolism for cancer therapy is an old strategy. In fact, historically the first effective cancer therapeutics were directed at nucleotide metabolism. The spectrum of metabolic drugs considered in cancer increases rapidly - clinical trials are in progress for agents directed at glycolysis, oxidative phosphorylation, glutaminolysis and several others. These pathways are essential for cancer cell proliferation and redox homeostasis, but are also required, to various degrees, in other cell types present in the tumor microenvironment, including immune cells, endothelial cells and fibroblasts. How metabolism-targeted treatments impact these tumor-associated cell types is not fully understood, even though their response may co-determine the overall effectivity of therapy. Indeed, the metabolic dependencies of stromal cells have been overlooked for a long time. Therefore, it is important that metabolic therapy is considered in the context of tumor microenvironment, as understanding the metabolic vulnerabilities of both cancer and stromal cells can guide new treatment concepts and help better understand treatment resistance. In this review we discuss recent findings covering the impact of metabolic interventions on cellular components of the tumor microenvironment and their implications for metabolic cancer therapy.
    Keywords:  cancer; endothelial cells; fatty acid metabolism; glycolysis; metabolism; nucleotide metabolism; oxidative phoshorylation; tumor micro environment (TME)
    DOI:  https://doi.org/10.3389/fonc.2022.1046630
  21. Elife. 2022 Dec 28. pii: e80380. [Epub ahead of print]11
    Lack of evidence for increased transcriptional noise in aged tissues.
    Olga Ibañez-Solé, Alex M Ascensión, Marcos J Araúzo-Bravo, Ander Izeta.
      Aging is often associated with a loss of cell type identity that results in an increase in transcriptional noise in aged tissues. If this phenomenon reflects a fundamental property of aging remains an open question. Transcriptional changes at the cellular level are best detected by single-cell RNA sequencing (scRNAseq). However, the diverse computational methods used for the quantification of age-related loss of cellular identity have prevented reaching meaningful conclusions by direct comparison of existing scRNAseq datasets. To address these issues we created Decibel, a Python toolkit that implements side-to-side four commonly used methods for the quantification of age-related transcriptional noise in scRNAseq data. Additionally, we developed Scallop, a novel computational method for the quantification of membership of single cells to their assigned cell type cluster. Cells with a greater Scallop membership score are transcriptionally more stable. Application of these computational tools to seven aging datasets showed large variability between tissues and datasets, suggesting that increased transcriptional noise is not a universal hallmark of aging. To understand the source of apparent loss of cell type identity associated with aging, we analyzed cell type-specific changes in transcriptional noise and the changes in cell type composition of the mammalian lung. No robust pattern of cell type-specific transcriptional noise alteration was found across aging lung datasets. In contrast, age-associated changes in cell type composition of the lung were consistently found, particularly of immune cells. These results suggest that claims of increased transcriptional noise of aged tissues should be reformulated.
    Keywords:  computational biology; human; mouse; systems biology
    DOI:  https://doi.org/10.7554/eLife.80380
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