bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2024‒01‒28
25 papers selected by
Kelsey Fisher-Wellman, East Carolina University
  1. Forward Genetic Screens Identify Mechanisms of Resistance to Small-Molecule Lactate Dehydrogenase Inhibitors.
  2. Phosphate starvation signaling increases mitochondrial membrane potential through respiration-independent mechanisms.
  3. Mitochondrial choline import regulates purine nucleotide pools via SLC25A48.
  4. PI3Kγ maintains the self-renewal of acute myeloid leukemia stem cells by regulating the pentose phosphate pathway.
  5. IDH1-Mutant Preleukemic Hematopoietic Stem Cells Can Be Eliminated by Inhibition of Oxidative Phosphorylation.
  6. The imipridone ONC213 targets α-ketoglutarate dehydrogenase to induce mitochondrial stress and suppress oxidative phosphorylation in acute myeloid leukemia.
  7. AKT1 phosphorylation of cytoplasmic ME2 induces a metabolic switch to glycolysis for tumorigenesis.
  8. Mitochondrial complex I inhibition triggers NAD+-independent glucose oxidation via successive NADPH formation, "futile" fatty acid cycling, and FADH2 oxidation.
  9. Mitochondrial membrane potential regulates nuclear DNA methylation and gene expression through phospholipid remodeling.
  10. Oxygen and Iron Availability Shapes Metabolic Adaptations of Cancer Cells.
  11. The gastrointestinal tract is a major source of the acute metformin-stimulated rise in GDF15.
  12. The redox requirement and regulation during cell proliferation.
  13. Metabolic heterogeneity in cancer.
  14. Deciphering cell states and genealogies of human hematopoiesis.
  15. Shared structural features of Miro binding control mitochondrial homeostasis.
  16. Mitochondrial reverse electron transport in myeloid cells perpetuates neuroinflammation.
  17. Lithium carbonate revitalizes tumor-reactive CD8+ T cells by shunting lactic acid into mitochondria.
  18. Human papillomavirus-associated head and neck squamous cell carcinoma cells rely on glycolysis and display reduced oxidative phosphorylation.
  19. Oncogenic fatty acid metabolism rewires energy supply chain in gastric carcinogenesis.
  20. Revisiting sensitivity of senescent cells to BH3 mimetics.
  21. Mitochondrial genomes revisited: why do different lineages retain different genes?
  22. Glutaredoxin 2 Protein (Grx2) as an Independent Prognostic Factor Associated with the Survival of Colon Adenocarcinoma Patients.
  23. Azacitidine, Venetoclax, and Gilteritinib in Newly Diagnosed and Relapsed or Refractory FLT3-Mutated AML.
  24. A mouse model to study glutathione limitation in vivo.
  25. A comprehensive landscape of the zinc-regulated human proteome.
  1. ACS Chem Biol. 2024 Jan 25.
    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 anticancer 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/10.1021/acschembio.3c00663
  2. Elife. 2024 Jan 22. pii: e84282. [Epub ahead of print]13
    Phosphate starvation signaling increases mitochondrial membrane potential through respiration-independent mechanisms.
    Yeyun Ouyang, Mi-Young Jeong, Corey N Cunningham, Jordan A Berg, Ashish G Toshniwal, Casey E Hughes, Kristina Seiler, Jonathan G Van Vranken, Ahmad A Cluntun, Geanette Lam, Jacob M Winter, Emel Akdoǧan, Katja K Dove, Sara M Nowinski, Matthew West, Greg Odorizzi, Steven P Gygi, Cory D Dunn, Dennis R Winge, Jared Rutter.
      Mitochondrial membrane potential directly powers many critical functions of mitochondria, including ATP production, mitochondrial protein import, and metabolite transport. Its loss is a cardinal feature of aging and mitochondrial diseases, and cells closely monitor membrane potential as an indicator of mitochondrial health. Given its central importance, it is logical that cells would modulate mitochondrial membrane potential in response to demand and environmental cues, but there has been little exploration of this question. We report that loss of the Sit4 protein phosphatase in yeast increases mitochondrial membrane potential, both through inducing the electron transport chain and the phosphate starvation response. Indeed, a similarly elevated mitochondrial membrane potential is also elicited simply by phosphate starvation or by abrogation of the Pho85-dependent phosphate sensing pathway. This enhanced membrane potential is primarily driven by an unexpected activity of the ADP/ATP carrier. We also demonstrate that this connection between phosphate limitation and enhancement of mitochondrial membrane potential is observed in primary and immortalized mammalian cells as well as in Drosophila. These data suggest that mitochondrial membrane potential is subject to environmental stimuli and intracellular signaling regulation and raise the possibility for therapeutic enhancement of mitochondrial function even in defective mitochondria.
    Keywords:  D. melanogaster; S. cerevisiae; cell biology; human
    DOI:  https://doi.org/10.7554/eLife.84282
  3. bioRxiv. 2024 Jan 01. pii: 2023.12.31.573776. [Epub ahead of print]
    Mitochondrial choline import regulates purine nucleotide pools via SLC25A48.
    Anthony R P Verkerke, Xu Shi, Ichitaro Abe, Robert E Gerszten, Shingo Kajimura.
      Choline is an essential nutrient for cellular metabolism, including the biosynthesis of phospholipids, neurotransmitters, and one-carbon metabolism. A critical step of choline catabolism is the mitochondrial import and synthesis of chorine-derived methyl donors, such as betaine. However, the underlying mechanisms and the biological significance of mitochondrial choline catabolism remain insufficiently understood. Here, we report that a mitochondrial inner-membrane protein SLC25A48 controls mitochondrial choline transport and catabolism in vivo . We demonstrate that SLC25A48 is highly expressed in brown adipose tissue and required for whole-body cold tolerance, thermogenesis, and mitochondrial respiration. Mechanistically, choline uptake into the mitochondrial matrix via SLC25A48 facilitates betaine synthesis and one-carbon metabolism. Importantly, cells lacking SLC25A48 exhibited reduced synthesis of purine nucleotides and failed to initiate the G1-to-S phase transition, thereby leading to cell death. Taken together, the present study identified SLC25A48 as a mitochondrial carrier that mediates choline import and plays a critical role in mitochondrial respiratory capacity, purine nucleotide synthesis, and cell survival.Key points: SLC25A48 is required for mitochondrial choline uptake.Mitochondrial choline uptake regulates one-carbon contribution to purine nucleotide synthesis.Brown fat thermogenesis requires mitochondrial choline catabolism for respiratory capacity.Cancer cells require mitochondrial choline uptake for cell survival.
    DOI:  https://doi.org/10.1101/2023.12.31.573776
  4. Blood. 2024 Jan 25. pii: blood.2023022202. [Epub ahead of print]
    PI3Kγ maintains the self-renewal of acute myeloid leukemia stem cells by regulating the pentose phosphate pathway.
    Hao Gu, Chiqi Chen, Zhi-Shuai Hou, Xia-Di He, Shaozhen Xie, Jing Ni, Changli Qian, Xin Cheng, Tao Jiang, Ce Yang, Thomas M Roberts, Junke Zheng, Judith A Varner, Scott A Armstrong, Jean J Zhao.
      Acute myeloid leukemia (AML) is an aggressive hematological malignancy originating from transformed hematopoietic stem/progenitor cells. AML prognosis remains poor, due to resistance and relapse driven by leukemia stem cells (LSCs). Targeting molecules essential for LSC function is a promising therapeutic approach. The PI3K/AKT pathway is often dysregulated in AML. We found while that PI3Kγ is highly enriched in LSCs and critical for self-renewal, it was dispensable for normal hematopoietic stem cells. Mechanistically, PI3Kγ-AKT signaling promotes NRF2 nuclear accumulation, which induces PGD and the pentose phosphate pathway, thereby maintaining LSC stemness. Importantly, genetic or pharmacological inhibition of PI3Kγ impaired expansion and stemness of murine and human AML cells in vitro and in vivo. Together, our findings reveal a key role for PI3Kγ in selectively maintaining LSC function by regulating AKT-NRF2-PGD metabolic pathway. Targeting the PI3Kγ pathway may therefore eliminate LSCs without damaging normal hematopoiesis, providing a promising therapeutic strategy for AML.
    DOI:  https://doi.org/10.1182/blood.2023022202
  5. Blood Cancer Discov. 2024 Jan 23. OF1-OF18
    IDH1-Mutant Preleukemic Hematopoietic Stem Cells Can Be Eliminated by Inhibition of Oxidative Phosphorylation.
    Niklas Landberg, Thomas Köhnke, Yang Feng, Yusuke Nakauchi, Amy C Fan, Miles H Linde, Daiki Karigane, Kelly Lim, Rahul Sinha, Luca Malcovati, Daniel Thomas, Ravindra Majeti.
      Rare preleukemic hematopoietic stem cells (pHSC) harboring only the initiating mutations can be detected at the time of acute myeloid leukemia (AML) diagnosis. pHSCs are the origin of leukemia and a potential reservoir for relapse. Using primary human samples and gene editing to model isocitrate dehydrogenase 1 (IDH1) mutant pHSCs, we show epigenetic, transcriptional, and metabolic differences between pHSCs and healthy hematopoietic stem cells (HSC). We confirm that IDH1-driven clonal hematopoiesis is associated with cytopenia, suggesting an inherent defect to fully reconstitute hematopoiesis. Despite giving rise to multilineage engraftment, IDH1-mutant pHSCs exhibited reduced proliferation, blocked differentiation, downregulation of MHC class II genes, and reprogramming of oxidative phosphorylation metabolism. Critically, inhibition of oxidative phosphorylation resulted in the complete eradication of IDH1-mutant pHSCs but not IDH2-mutant pHSCs or wild-type HSCs. Our results indicate that IDH1-mutant preleukemic clones can be targeted with complex I inhibitors, offering a potential strategy to prevent the development and relapse of leukemia.SIGNIFICANCE: A high burden of pHSCs is associated with worse overall survival in AML. Using single-cell sequencing, metabolic assessment, and gene-edited human models, we find human pHSCs with IDH1 mutations to be metabolically vulnerable and sensitive to eradication by complex I inhibition. See related commentary by Steensma.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-23-0195
  6. Cancer Res. 2024 Jan 24.
    The imipridone ONC213 targets α-ketoglutarate dehydrogenase to induce mitochondrial stress and suppress oxidative phosphorylation in acute myeloid leukemia.
    Yongwei Su, Jenna L Carter, Xinyu Li, Yu Fukuda, Ashley Gray, John Lynch, Holly Edwards, Jun Ma, Patrick Schreiner, Lisa Polin, Juiwanna Kushner, Sijana H Dzinic, Steven A Buck, Shondra M Pruett-Miller, Katie Hege Hurrish, Camenzind Robinson, Xinan Qiao, Shuang Liu, Shuangshuang Wu, Guan Wang, Jing Li, Joshua E Allen, Varun V Prabhu, Aaron D Schimmer, Dhananjay Joshi, Shiva Kalhor-Monfared, Iain D G Watson, Richard Marcellus, Methvin B Isaac, Rima Al-Awar, Jeffrey W Taub, Hai Lin, John D Schuetz, Yubin Ge.
      Eradication of acute myeloid leukemia (AML) is therapeutically challenging; many patients succumb to AML despite initially responding to conventional treatments. Here, we showed that the imipridone ONC213 elicits potent antileukemia activity in a subset of AML cell lines and primary patient samples, particularly in leukemia stem cells, while producing negligible toxicity in normal hematopoietic cells. ONC213 suppressed mitochondrial respiration and elevated alpha-ketoglutarate by suppressing alpha-ketoglutarate dehydrogenase (α-KGDH) activity. Deletion of OGDH, which encodes α-KGDH, suppressed AML fitness and impaired oxidative phosphorylation, highlighting the key role for α-KGDH inhibition in ONC213-induced death. ONC213 treatment induced a unique mitochondrial stress response and suppressed de novo protein synthesis in AML cells. Additionally, ONC213 reduced translation of MCL-1, which contributed to ONC213-induced apoptosis. Importantly, a patient-derived xenograft from a relapsed AML patient was sensitivity to ONC213 in vivo. Collectively these findings support further development of ONC213 for treating AML.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-2659
  7. Nat Commun. 2024 Jan 23. 15(1): 686
    AKT1 phosphorylation of cytoplasmic ME2 induces a metabolic switch to glycolysis for tumorigenesis.
    Taiqi Chen, Siyi Xie, Jie Cheng, Qiao Zhao, Hong Wu, Peng Jiang, Wenjing Du.
      Many types of tumors feature aerobic glycolysis for meeting their increased energetic and biosynthetic demands. However, it remains still unclear how this glycolytic phenomenon is achieved and coordinated with other metabolic pathways in tumor cells in response to growth stimuli. Here we report that activation of AKT1 induces a metabolic switch to glycolysis from the mitochondrial metabolism via phosphorylation of cytoplasmic malic enzyme 2 (ME2), named ME2fl (fl means full length), favoring an enhanced glycolytic phenotype. Mechanistically, in the cytoplasm, AKT1 phosphorylates ME2fl at serine 9 in the mitochondrial localization signal peptide at the N-terminus, preventing its mitochondrial translocation. Unlike mitochondrial ME2, which accounts for adjusting the tricarboxylic acid (TCA) cycle, ME2fl functions as a scaffold that brings together the key glycolytic enzymes phosphofructokinase (PFKL), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and pyruvate kinase M2 (PKM2), as well as Lactate dehydrogenase A (LDHA), to promote glycolysis in the cytosol. Thus, through phosphorylation of ME2fl, AKT1 enhances the glycolytic capacity of tumor cells in vitro and in vivo, revealing an unexpected role for subcellular translocation switching of ME2 mediated by AKT1 in the metabolic adaptation of tumor cells to growth stimuli.
    DOI:  https://doi.org/10.1038/s41467-024-44772-8
  8. Geroscience. 2024 Jan 25.
    Mitochondrial complex I inhibition triggers NAD+-independent glucose oxidation via successive NADPH formation, "futile" fatty acid cycling, and FADH2 oxidation.
    Roman Abrosimov, Marius W Baeken, Samuel Hauf, Ilka Wittig, Parvana Hajieva, Carmen E Perrone, Bernd Moosmann.
      Inhibition of mitochondrial complex I (NADH dehydrogenase) is the primary mechanism of the antidiabetic drug metformin and various unrelated natural toxins. Complex I inhibition can also be induced by antidiabetic PPAR agonists, and it is elicited by methionine restriction, a nutritional intervention causing resistance to diabetes and obesity. Still, a comprehensible explanation to why complex I inhibition exerts antidiabetic properties and engenders metabolic inefficiency is missing. To evaluate this issue, we have systematically reanalyzed published transcriptomic datasets from MPP-treated neurons, metformin-treated hepatocytes, and methionine-restricted rats. We found that pathways leading to NADPH formation were widely induced, together with anabolic fatty acid biosynthesis, the latter appearing highly paradoxical in a state of mitochondrial impairment. However, concomitant induction of catabolic fatty acid oxidation indicated that complex I inhibition created a "futile" cycle of fatty acid synthesis and degradation, which was anatomically distributed between adipose tissue and liver in vivo. Cofactor balance analysis unveiled that such cycling would indeed be energetically futile (-3 ATP per acetyl-CoA), though it would not be redox-futile, as it would convert NADPH into respirable FADH2 without any net production of NADH. We conclude that inhibition of NADH dehydrogenase leads to a metabolic shift from glycolysis and the citric acid cycle (both generating NADH) towards the pentose phosphate pathway, whose product NADPH is translated 1:1 into FADH2 by fatty acid cycling. The diabetes-resistant phenotype following hepatic and intestinal complex I inhibition is attributed to FGF21- and GDF15-dependent fat hunger signaling, which remodels adipose tissue into a glucose-metabolizing organ.
    Keywords:  Diabetes; FGF21; Metformin; Methionine restriction; NADH dehydrogenase; Peroxisome proliferator-activated receptor
    DOI:  https://doi.org/10.1007/s11357-023-01059-y
  9. bioRxiv. 2024 Jan 13. pii: 2024.01.12.575075. [Epub ahead of print]
    Mitochondrial membrane potential regulates nuclear DNA methylation and gene expression through phospholipid remodeling.
    Mateus Prates Mori, Oswaldo Lozoya, Ashley M Brooks, Dagoberto Grenet, Cristina A Nadalutti, Birgitta Ryback, Kai Ting Huang, Prottoy Hasan, Gyӧrgy Hajnóczky, Janine H Santos.
      Maintenance of the mitochondrial inner membrane potential (ΔΨM) is critical for many aspects of mitochondrial function, including mitochondrial protein import and ion homeostasis. While ΔΨM loss and its consequences are well studied, little is known about the effects of increased ΔΨM. In this study, we used cells deleted of ATPIF1 , a natural inhibitor of the hydrolytic activity of the ATP synthase, as a genetic model of mitochondrial hyperpolarization. Our data show that chronic ΔΨM increase leads to nuclear DNA hypermethylation, regulating transcription of mitochondria, carbohydrate and lipid metabolism genes. Surprisingly, remodeling of phospholipids, but not metabolites or redox changes, mechanistically links the ΔΨM to the epigenome. These changes were also observed upon chemical exposures and reversed by decreasing the ΔΨM, highlighting them as hallmark adaptations to chronic mitochondrial hyperpolarization. Our results reveal the ΔΨM as the upstream signal conveying the mitochondrial status to the epigenome to regulate cellular biology, providing a new framework for how mitochondria can influence health outcomes in the absence of canonical dysfunction.Highlights: Mitochondria hyperpolarization leads to nuclear DNA hypermethylationDNA methylation regulates expression of mitochondrial and lipid metabolism genesPhospholipid remodeling mediates the epigenetic effects of mitochondrial hyperpolarization.
    DOI:  https://doi.org/10.1101/2024.01.12.575075
  10. World J Oncol. 2024 Feb;15(1): 28-37
    Oxygen and Iron Availability Shapes Metabolic Adaptations of Cancer Cells.
    Rui Wang, Aashiq Hussain, Quan Quan Guo, Xiao Wei Jin, Miao Miao Wang.
      The dynamic changes between glycolysis and oxidative phosphorylation (OXPHOS) for adenosine triphosphate (ATP) output, along with glucose, glutamine, and fatty acid utilization, etc., lead to the maintenance and selection of growth advantageous to tumor cell subgroups in an environment of iron starvation and hypoxia. Iron plays an important role in the three major biochemical reactions in nature: photosynthesis, nitrogen fixation, and oxidative respiration, which all require the participation of iron-sulfur proteins, such as ferredoxin, cytochrome b, and the complex I, II, III in the electron transport chain, respectively. Abnormal iron-sulfur cluster synthesis process or hypoxia will directly affect the function of mitochondrial electron transfer and mitochondrial OXPHOS. More research results have indicated that iron metabolism, oxygen availability and hypoxia-inducible factor mutually regulate the shift between glycolysis and OXPHOS. In this article, we make a perspective review to provide novel opinions of the regulation of glycolysis and OXPHOS in tumor cells.
    Keywords:  Glycolysis; Iron; Metabolism; OXPHOS; Oxygen; Tumor
    DOI:  https://doi.org/10.14740/wjon1739
  11. Sci Rep. 2024 01 22. 14(1): 1899
    The gastrointestinal tract is a major source of the acute metformin-stimulated rise in GDF15.
    John W R Kincaid, Debra Rimmington, John A Tadross, Irene Cimino, Ilona Zvetkova, Arthur Kaser, Paul Richards, Satish Patel, Stephen O'Rahilly, Anthony P Coll.
      The hormone GDF15 is secreted in response to cellular stressors. Metformin elevates circulating levels of GDF15, an action important for the drug's beneficial effects on body weight. Metformin can also inhibit mammalian respiratory complex I, leading to decreases in ATP:AMP ratio, activation of AMP Kinase (AMPK), and increased GDF15 production. We undertook studies using a range of mice with tissue-specific loss of Gdf15 (namely gut, liver and global deletion) to determine the relative contributions of two classical metformin target tissues, the gut and liver, to the elevation of GDF15 seen with metformin. In addition, we performed comparative studies with another pharmacological agent, the AMP kinase pan-activator, MK-8722. Deletion of Gdf15 from the intestinal epithelium significantly reduced the circulating GDF15 response to oral metformin, whereas deletion of Gdf15 from the liver had no effect. In contrast, deletion of Gdf15 from the liver, but not the gut, markedly reduced circulating GDF15 responses to MK-8722. Further, our data show that, while GDF15 restricts high-fat diet-induced weight gain, the intestinal production of GDF15 is not necessary for this effect. These findings add to the body of evidence implicating the intestinal epithelium in key aspects of the pharmacology of metformin action.
    DOI:  https://doi.org/10.1038/s41598-024-51866-2
  12. Trends Endocrinol Metab. 2024 Jan 22. pii: S1043-2760(23)00278-3. [Epub ahead of print]
    The redox requirement and regulation during cell proliferation.
    Zhuoran Zhen, Jiankun Ren, Jiajun Zhu.
      The intracellular metabolic network comprises a variety of reduction-oxidation (redox) reactions that occur in a temporally and spatially distinct manner. In order to coordinate these redox processes, mammalian cells utilize a collection of electron-carrying molecules common to many redox reactions, including NAD, NADP, coenzyme Q (CoQ), and glutathione (GSH). This review considers the metabolic basis of redox regulation in the context of cell proliferation by analyzing how cells acquire and utilize electron carriers to maintain directional carbon flux, sustain reductive biosynthesis, and support antioxidant defense. Elucidating the redox requirement during cell proliferation can advance the understanding of human diseases such as cancer, and reveal effective therapeutic opportunities in the clinic.
    Keywords:  CoQ; GSH; NAD; NADP; cancer; cell proliferation; metabolism; redox
    DOI:  https://doi.org/10.1016/j.tem.2023.12.010
  13. Nat Metab. 2024 Jan 24.
    Metabolic heterogeneity in cancer.
    Margherita Demicco, Xiao-Zheng Liu, Katharina Leithner, Sarah-Maria Fendt.
      Cancer cells rewire their metabolism to survive during cancer progression. In this context, tumour metabolic heterogeneity arises and develops in response to diverse environmental factors. This metabolic heterogeneity contributes to cancer aggressiveness and impacts therapeutic opportunities. In recent years, technical advances allowed direct characterisation of metabolic heterogeneity in tumours. In addition to the metabolic heterogeneity observed in primary tumours, metabolic heterogeneity temporally evolves along with tumour progression. In this Review, we summarize the mechanisms of environment-induced metabolic heterogeneity. In addition, we discuss how cancer metabolism and the key metabolites and enzymes temporally and functionally evolve during the metastatic cascade and treatment.
    DOI:  https://doi.org/10.1038/s42255-023-00963-z
  14. Nature. 2024 Jan 22.
    Deciphering cell states and genealogies of human hematopoiesis.
    Chen Weng, Fulong Yu, Dian Yang, Michael Poeschla, L Alexander Liggett, Matthew G Jones, Xiaojie Qiu, Lara Wahlster, Alexis Caulier, Jeffrey A Hussmann, Alexandra Schnell, Kathryn E Yost, Luke Koblan, Jorge D Martin-Rufino, Joseph Min, Alessandro Hammond, Daniel Ssozi, Raphael Bueno, Hari Mallidi, Antonia Kreso, Javier Escabi, William M Rideout, Tyler Jacks, Sahand Hormoz, Peter van Galen, Jonathan S Weissman, Vijay G Sankaran.
      The human blood system is maintained through the differentiation and massive amplification of a limited number of long-lived hematopoietic stem cells (HSCs)1. Perturbations to this process underlie diverse diseases, but the clonal contributions to human hematopoiesis and how this changes with age remain incompletely understood. While recent insights have emerged from barcoding studies in model systems4,5,16,17, simultaneous detection of cell states and phylogenies from natural barcodes in humans has been challenging. Here, we introduce an improved single-cell lineage tracing system based on deep detection of naturally-occurring mitochondrial DNA (mtDNA) mutations with simultaneous readout of transcriptional states and chromatin accessibility. We use this system to define the clonal architecture of HSCs and map the physiological state and output of clones. We uncover functional heterogeneity in HSC clones, which is stable over months and manifests as differences in total HSC output as well as biases toward the production of different mature cell types. We also find that the diversity of HSC clones decreases dramatically with age leading to an oligoclonal structure with multiple distinct clonal expansions. Our study thus provides the first clonally-resolved and cell-state aware atlas of human hematopoiesis at single-cell resolution revealing an unappreciated functional diversity of human HSC clones and more broadly paves the way for refined studies of clonal dynamics across a range of tissues in human health and disease.
    DOI:  https://doi.org/10.1038/s41586-024-07066-z
  15. EMBO J. 2024 Jan 24.
    Shared structural features of Miro binding control mitochondrial homeostasis.
    Christian Covill-Cooke, Brian Kwizera, Guillermo López-Doménech, Caleb Od Thompson, Ngaam J Cheung, Ema Cerezo, Martin Peterka, Josef T Kittler, Benoît Kornmann.
      Miro proteins are universally conserved mitochondrial calcium-binding GTPases that regulate a multitude of mitochondrial processes, including transport, clearance, and lipid trafficking. The exact role of Miro in these functions is unclear but involves binding to a variety of client proteins. How this binding is operated at the molecular level and whether and how it is important for mitochondrial health, however, remains unknown. Here, we show that known Miro interactors-namely, CENPF, Trak, and MYO19-all use a similar short motif to bind the same structural element: a highly conserved hydrophobic pocket in the first calcium-binding domain of Miro. Using these Miro-binding motifs, we identified direct interactors de novo, including MTFR1/2/1L, the lipid transporters Mdm34 and VPS13D, and the ubiquitin E3-ligase Parkin. Given the shared binding mechanism of these functionally diverse clients and its conservation across eukaryotes, we propose that Miro is a universal mitochondrial adaptor coordinating mitochondrial health.
    Keywords:  AlphaFold; ERMES; Lipid Transport; Mitophagy; Organelle Transport
    DOI:  https://doi.org/10.1038/s44318-024-00028-1
  16. bioRxiv. 2024 Jan 04. pii: 2024.01.03.574059. [Epub ahead of print]
    Mitochondrial reverse electron transport in myeloid cells perpetuates neuroinflammation.
    L Peruzzotti-Jametti, C M Willis, R Hamel, G Krzak, J A Reisz, H A Prag, V Wu, Y Xiang, A M R van den Bosch, A M Nicaise, L Roth, G R Bates, H Huang, A E Vincent, C Frezza, C Viscomi, J C Marioni, A D'Alessandro, Z Takats, M P Murphy, S Pluchino.
      Sustained smouldering, or low grade, activation of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis (MS) 1 . Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells 2 . However, how these metabolic features act to perpetuate neuroinflammation is currently unknown. Using a multiomics approach, we identified a new molecular signature that perpetuates the activation of myeloid cells through mitochondrial complex II (CII) and I (CI) activity driving reverse electron transport (RET) and the production of reactive oxygen species (ROS). Blocking RET in pro-inflammatory myeloid cells protected the central nervous system (CNS) against neurotoxic damage and improved functional outcomes in animal disease models in vivo . Our data show that RET in myeloid cells is a potential new therapeutic target to foster neuroprotection in smouldering inflammatory CNS disorders 3 .
    DOI:  https://doi.org/10.1101/2024.01.03.574059
  17. Nat Immunol. 2024 Jan 23.
    Lithium carbonate revitalizes tumor-reactive CD8+ T cells by shunting lactic acid into mitochondria.
    Jingwei Ma, Liang Tang, Yaoyao Tan, Jingxuan Xiao, Keke Wei, Xin Zhang, Yuan Ma, Shuai Tong, Jie Chen, Nannan Zhou, Li Yang, Zhang Lei, Yonggang Li, Jiadi Lv, Junwei Liu, Huafeng Zhang, Ke Tang, Yi Zhang, Bo Huang.
      The steady flow of lactic acid (LA) from tumor cells to the extracellular space via the monocarboxylate transporter symport system suppresses antitumor T cell immunity. However, LA is a natural energy metabolite that can be oxidized in the mitochondria and could potentially stimulate T cells. Here we show that the lactate-lowering mood stabilizer lithium carbonate (LC) can inhibit LA-mediated CD8+ T cell immunosuppression. Cytoplasmic LA increased the pumping of protons into lysosomes. LC interfered with vacuolar ATPase to block lysosomal acidification and rescue lysosomal diacylglycerol-PKCθ signaling to facilitate monocarboxylate transporter 1 localization to mitochondrial membranes, thus transporting LA into the mitochondria as an energy source for CD8+ T cells. These findings indicate that targeting LA metabolism using LC could support cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41590-023-01738-0
  18. Front Oncol. 2023 ;13 1304106
    Human papillomavirus-associated head and neck squamous cell carcinoma cells rely on glycolysis and display reduced oxidative phosphorylation.
    Nora Li, Imen Chamkha, Gaurav Verma, Sabine Swoboda, Malin Lindstedt, Lennart Greiff, Eskil Elmér, Johannes Ehinger.
      Introduction: Head and neck squamous cell carcinoma (HNSCC) constitutes a heterogeneous group of cancers. Human papilloma virus (HPV) is associated with a subtype of HNSCC with a better response to treatment and more favorable prognosis. Mitochondrial function and metabolism vary depending on cancer type and can be related to tumor aggressiveness. This study aims to characterize the metabolism of HPV-positive and HPV-negative HNSCC cell lines.Methods: Oxidative phosphorylation (OXPHOS) and glycolysis were assessed in intact cells, in four HNSCC cell lines using Seahorse XF Analyzer. OXPHOS was further studied in permeabilized cells using high-resolution respirometry in an Oroboros O2K. Metabolomic analysis was performed using mass spectroscopy.
    Results: The HPV-negative cell lines were found to display a higher OXPHOS capacity and were also able to upregulate glycolysis when needed. The HPV-positive cell line had a higher basal glycolytic rate but lower spare OXPHOS capacity. These cells were also unable to increase respiration in response to succinate, unlike the HPV-negative cells. In the metabolomic analysis, the HPV-positive cells showed a higher kynurenine/tryptophan ratio.
    Discussion: HPV-positive HNSCC preferred glycolysis to compensate for lower OXPHOS reserves, while the HPV-negative HNSCC displayed a more versatile metabolism, which might be related to increased tumor aggressiveness. The higher kynurenine/tryptophan ratio of HPV-positive HNSCC might be related to increased indoleamine 2,3-dioxygenase activity due to the carcinoma's viral origin. This study highlights important metabolic differences between HPV-positive and HPV-negative cancers and suggests that future metabolic targets for cancer treatment should be individualized based on specific tumor metabolism.
    Keywords:  glycolysis; head and neck squamous cell carcinomas; human papillomavirus; metabolomics; mitochondria
    DOI:  https://doi.org/10.3389/fonc.2023.1304106
  19. Gastroenterology. 2024 Jan 23. pii: S0016-5085(24)00064-7. [Epub ahead of print]
    Oncogenic fatty acid metabolism rewires energy supply chain in gastric carcinogenesis.
    Yoonkyung Won, Bogun Jang, Su-Hyung Lee, Michelle L Reyzer, Kimberly S Presentation, Hyesung Kim, Brianna Caldwell, Changqing Zhang, Hye Seung Lee, Cheol Lee, Vincent Q Trinh, Marcus C B Tan, Kwangho Kim, Richard M Caprioli, Eunyoung Choi.
      BACKGROUND & AIMS: Gastric carcinogenesis develops within a sequential carcinogenic cascade from pre-cancerous metaplasia to dysplasia and adenocarcinoma, and oncogenic gene activation can drive the process. Metabolic reprogramming is considered a key mechanism for cancer cell growth and proliferation. However, it remains unclear how metabolic changes contribute to the progression of metaplasia to dysplasia. We have examined metabolic dynamics during gastric carcinogenesis using a novel mouse model that induces Kras activation in zymogen-secreting chief cells.METHODS: We generated a Gif-rtTA;TetO-Cre;KrasG12D (GCK) mouse model which continuously induces active Kras expression in chief cells following doxycycline treatment. Histological examination and imaging mass spectrometry were performed in the GCK mouse stomachs at 2 to 14 weeks after doxycycline treatment. Mouse and human gastric organoids were used for metabolic enzyme inhibitor treatment. The GCK mice were treated with a stearoyl-CoA desaturase (SCD) inhibitor to inhibit the fatty acid desaturation. Tissue microarrays were used to assess the SCD expression in human gastrointestinal cancers.
    RESULTS: The GCK mice developed metaplasia and high-grade dysplasia within 4 months. Metabolic reprogramming from glycolysis to fatty acid metabolism occurred during metaplasia progression to dysplasia. Altered fatty acid desaturation through SCD produces a novel Eicosenoic acid, which fuels dysplastic cell hyperproliferation and survival. The SCD inhibitor killed both mouse and human dysplastic organoids and selectively targeted dysplastic cells in vivo. SCD was upregulated during carcinogenesis in human gastrointestinal cancers.
    CONCLUSIONS: Active Kras expression only in gastric chief cells drives the full spectrum of gastric carcinogenesis. Also, oncogenic metabolic rewiring is an essential adaptation for high energy demand in dysplastic cells.
    Keywords:  Carcinogenesis; Fatty acid metabolism; Imaging mass spectrometry; Kras; Stearoyl-CoA desaturase
    DOI:  https://doi.org/10.1053/j.gastro.2024.01.027
  20. Trends Pharmacol Sci. 2024 Jan 19. pii: S0165-6147(24)00002-6. [Epub ahead of print]
    Revisiting sensitivity of senescent cells to BH3 mimetics.
    Nadine Martin, Anda Huna, Athanasios Tsalikis, David Bernard.
      B cell leukemia/lymphoma 2 (BCL2) homology domain 3 (BH3) mimetics were reported to selectively kill senescent cells and improve age-related diseases. Defining why these cells show increased sensitivity to these molecules will help to identify new pharmacological compounds with senolytic activity. Here, we discuss how recent research findings provide new clues to understand this vulnerability.
    Keywords:  BCL2; MOMP; aging; cellular senescence; senolytics
    DOI:  https://doi.org/10.1016/j.tips.2024.01.002
  21. BMC Biol. 2024 Jan 25. 22(1): 15
    Mitochondrial genomes revisited: why do different lineages retain different genes?
    Anzhelika Butenko, Julius Lukeš, Dave Speijer, Jeremy G Wideman.
      The mitochondria contain their own genome derived from an alphaproteobacterial endosymbiont. From thousands of protein-coding genes originally encoded by their ancestor, only between 1 and about 70 are encoded on extant mitochondrial genomes (mitogenomes). Thanks to a dramatically increasing number of sequenced and annotated mitogenomes a coherent picture of why some genes were lost, or relocated to the nucleus, is emerging. In this review, we describe the characteristics of mitochondria-to-nucleus gene transfer and the resulting varied content of mitogenomes across eukaryotes. We introduce a 'burst-upon-drift' model to best explain nuclear-mitochondrial population genetics with flares of transfer due to genetic drift.
    Keywords:  CoRR hypothesis; Endosymbiont gene transfer; Evolutionary cell biology; Mitochondrial DNA; Mitochondrial evolution; Mitochondrial mutation rates
    DOI:  https://doi.org/10.1186/s12915-024-01824-1
  22. Int J Mol Sci. 2024 Jan 15. pii: 1060. [Epub ahead of print]25(2):
    Glutaredoxin 2 Protein (Grx2) as an Independent Prognostic Factor Associated with the Survival of Colon Adenocarcinoma Patients.
    Marlena Brzozowa-Zasada, Adam Piecuch, Karolina Bajdak-Rusinek, Karolina Gołąbek, Marek Michalski, Kamil Janelt, Natalia Matysiak.
      Glutaredoxin 2 (Grx2; Glrx2) is a glutathione-dependent oxidoreductase located in mitochondria, which is central to the regulation of glutathione homeostasis and mitochondrial redox, and plays a crucial role in highly metabolic tissues. In response to mitochondrial redox signals and oxidative stress, Grx2 can catalyze the oxidation and S-glutathionylation of membrane-bound thiol proteins in mitochondria. Therefore, it can have a significant impact on cancer development. To investigate this further, we performed an immunohistochemical analysis of Grx2 protein expression in colon adenocarcinoma samples collected from patients with primary colon adenocarcinoma (stage I and II) and patients with metastasis to regional lymph nodes (stage III). The results of our study revealed a significant relationship between the immunohistochemical expression of Grx2 and tumor histological grade, depth of invasion, regional lymph node involvement, angioinvasion, staging, and PCNA immunohistochemical expression. It was found that 87% of patients with stage I had high levels of Grx2 expression. In contrast, only 33% of patients with stage II and 1% of patients with stage III had high levels of Grx2 expression. Moreover, the multivariate analysis revealed that the immunohistochemical expression of Grx2 protein apart from the grade of tumor differentiation was an independent prognostic factors for the survival of patients with colon adenocarcinoma. Studies analyzing Grx2 levels in patients' blood confirmed that the highest levels of serum Grx2 protein was also found in stage I patients, which was reflected in the survival curves. A higher level of Grx2 in the serum has been associated with a more favorable outcome. These results were supported by in vitro analysis conducted on colorectal cancer cell lines that corresponded to stages I, II, and III of colorectal cancer, using qRT-PCR and Western Blot.
    Keywords:  ELISA; Grx2; S-gluathionylation; colon adenocarcinoma; glutaredoxins; glutathione (GSH); oxidative stress; prognostic factor; redox balance
    DOI:  https://doi.org/10.3390/ijms25021060
  23. J Clin Oncol. 2024 Jan 26. JCO2301911
    Azacitidine, Venetoclax, and Gilteritinib in Newly Diagnosed and Relapsed or Refractory FLT3-Mutated AML.
    Nicholas J Short, Naval Daver, Courtney D Dinardo, Tapan Kadia, Lewis F Nasr, Walid Macaron, Musa Yilmaz, Gautam Borthakur, Guillermo Montalban-Bravo, Guillermo Garcia-Manero, Ghayas C Issa, Kelly S Chien, Elias Jabbour, Cedric Nasnas, Xuelin Huang, Wei Qiao, Jairo Matthews, Christopher J Stojanik, Keyur P Patel, Regina Abramova, Jennifer Thankachan, Marina Konopleva, Hagop Kantarjian, Farhad Ravandi.
      PURPOSE: Azacitidine plus venetoclax is a standard of care for patients with newly diagnosed AML who are unfit for intensive chemotherapy. However, FLT3 mutations are a common mechanism of resistance to this regimen. The addition of gilteritinib, an oral FLT3 inhibitor, to azacitidine and venetoclax may improve outcomes in patients with FLT3-mutated AML.METHODS: This phase I/II study evaluated azacitidine, venetoclax, and gilteritinib in two cohorts: patients with (1) newly diagnosed FLT3-mutated AML who were unfit for intensive chemotherapy or (2) relapsed/refractory FLT3-mutated AML (ClinicalTrials.gov identifier: NCT04140487). The primary end points were the maximum tolerated dose of gilteritinib (phase I) and the combined complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate (phase II).
    RESULTS: Fifty-two patients were enrolled (frontline [n = 30]; relapsed/refractory [n = 22]). The recommended phase II dose was gilteritinib 80 mg once daily in combination with azacitidine and venetoclax. In the frontline cohort, the median age was 71 years and 73% of patients had an FLT3-internal tandem duplication (ITD) mutation. The CR/CRi rate was 96% (CR, 90%; CRi, 6%). Sixty-five percent of evaluable patients achieved FLT3-ITD measurable residual disease <5 × 10-5 within four cycles. With a median follow-up of 19.3 months, the median relapse-free survival (RFS) and overall survival (OS) have not been reached and the 18-month RFS and OS rates are 71% and 72%, respectively. In the relapsed/refractory cohort, the CR/CRi rate was 27%; nine additional patients (41%) achieved a morphologic leukemia-free state. The most common grade 3 or higher nonhematologic adverse events were infection (62%) and febrile neutropenia (38%), which were more frequent in the relapsed/refractory cohort.
    CONCLUSION: The combination of azacitidine, venetoclax, and gilteritinib resulted in high rates of CR/CRi, deep FLT3 molecular responses, and encouraging survival in newly diagnosed FLT3-mutated AML. Myelosuppression was manageable with mitigative dosing strategies.
    DOI:  https://doi.org/10.1200/JCO.23.01911
  24. bioRxiv. 2024 Jan 09. pii: 2024.01.08.574722. [Epub ahead of print]
    A mouse model to study glutathione limitation in vivo.
    Rebecca C Timson, Artem Khan, Beste Uygur, Marwa Saad, Hsi-Wen Yeh, Nicole DelGaudio, Ross Weber, Hanan Alwaseem, Jing Gao, Chingwen Yang, Kıvanç Birsoy.
      Glutathione (GSH) is a highly abundant tripeptide thiol that performs diverse protective and biosynthetic functions in cells. While changes in GSH availability are linked to many diseases, including cancer and neurodegenerative disorders, determining the function of GSH in physiology and disease has been challenging due to its tight regulation. To address this, we generated cell and mouse models that express a bifunctional glutathione-synthesizing enzyme from Streptococcus Thermophilus (GshF). GshF expression allows efficient production of GSH in the cytosol and mitochondria and prevents cell death in response to GSH depletion, but not ferroptosis, indicating that GSH is not a limiting factor under lipid peroxidation. CRISPR screens using engineered enzymes revealed metabolic liabilities under compartmentalized GSH depletion. Finally, GshF expression in mice is embryonically lethal but sustains postnatal viability when restricted to adulthood. Overall, our work identifies a conditional mouse model to investigate the role of GSH availability in physiology and disease.
    DOI:  https://doi.org/10.1101/2024.01.08.574722
  25. bioRxiv. 2024 Jan 05. pii: 2024.01.04.574225. [Epub ahead of print]
    A comprehensive landscape of the zinc-regulated human proteome.
    Nils Burger, Melanie J Mittenbühler, Haopeng Xiao, Sanghee Shin, Luiz H M Bozi, Shelley Wei, Hans-Georg Sprenger, Yizhi Sun, Yingde Zhu, Narek Darabedian, Jonathan J Petrocelli, Pedro Latorre- Muro, Jianwei Che, Edward T Chouchani.
      Zinc is an essential micronutrient that regulates a wide range of physiological processes, principally through Zn 2+ binding to protein cysteine residues. Despite being critical for modulation of protein function, for the vast majority of the human proteome the cysteine sites subject to regulation by Zn 2+ binding remain undefined. Here we develop ZnCPT, a comprehensive and quantitative mapping of the zinc-regulated cysteine proteome. We define 4807 zinc-regulated protein cysteines, uncovering protein families across major domains of biology that are subject to either constitutive or inducible modification by zinc. ZnCPT enables systematic discovery of zinc-regulated structural, enzymatic, and allosteric functional domains. On this basis, we identify 52 cancer genetic dependencies subject to zinc regulation, and nominate malignancies sensitive to zinc-induced cytotoxicity. In doing so, we discover a mechanism of zinc regulation over Glutathione Reductase (GSR) that drives cell death in GSR-dependent lung cancers. We provide ZnCPT as a resource for understanding mechanisms of zinc regulation over protein function.
    DOI:  https://doi.org/10.1101/2024.01.04.574225
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