bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2023–12–24
forty-four papers selected by
Christian Frezza, Universität zu Köln



  1. Cell Metab. 2023 Dec 12. pii: S1550-4131(23)00460-6. [Epub ahead of print]
      Cells in multicellular organisms experience diverse neighbors, signals, and evolving physical environments that drive functional and metabolic demands. To maintain proper development and homeostasis while avoiding inappropriate cell proliferation or death, individual cells interact with their neighbors via "social" cues to share and partition available nutrients. Metabolic signals also contribute to cell fate by providing biochemical links between cell-extrinsic signals and available resources. In addition to metabolic checkpoints that sense nutrients and directly supply molecular intermediates for biosynthetic pathways, many metabolites directly signal or provide the basis for post-translational modifications of target proteins and chromatin. In this review, we survey the landscape of T cell nutrient sensing and metabolic signaling that supports proper immunity while avoiding immunodeficiency or autoimmunity. The integration of cell-extrinsic microenvironmental cues with cell-intrinsic metabolic signaling provides a social metabolic control model to integrate cell signaling, metabolism, and fate.
    Keywords:  T cells; epigenetics; immunometabolism; metabolic signaling; social control model
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.009
  2. Nature. 2023 Dec 20.
      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
  3. Nat Cell Biol. 2023 Dec 21.
      The structures and functions of organelles in cells depend on each other but have not been systematically explored. We established stable knockout cell lines of peroxisomal, Golgi and endoplasmic reticulum genes identified in a whole-genome CRISPR knockout screen for inducers of mitochondrial biogenesis stress, showing that defects in peroxisome, Golgi and endoplasmic reticulum metabolism disrupt mitochondrial structure and function. Our quantitative total-organelle profiling approach for focussed ion beam scanning electron microscopy revealed in unprecedented detail that specific organelle dysfunctions precipitate multi-organelle biogenesis defects, impair mitochondrial morphology and reduce respiration. Multi-omics profiling showed a unified proteome response and global shifts in lipid and glycoprotein homeostasis that are elicited when organelle biogenesis is compromised, and that the resulting mitochondrial dysfunction can be rescued with precursors for ether-glycerophospholipid metabolic pathways. This work defines metabolic and morphological interactions between organelles and how their perturbation can cause disease.
    DOI:  https://doi.org/10.1038/s41556-023-01297-4
  4. Nat Commun. 2023 Dec 18. 14(1): 8405
      Precise coupling between cellular physiology and metabolism is emerging as a vital relationship underpinning tissue health and longevity. Nevertheless, functional-metabolic coupling within heterogenous microenvironments in vivo remains poorly understood due to tissue complexity and metabolic plasticity. Here, we establish the Drosophila renal system as a paradigm for linking mechanistic analysis of metabolism, at single-cell resolution, to organ-wide physiology. Kidneys are amongst the most energetically-demanding organs, yet exactly how individual cell types fine-tune metabolism to meet their diverse, unique physiologies over the life-course remains unclear. Integrating live-imaging of metabolite and organelle dynamics with spatio-temporal genetic perturbation within intact functional tissue, we uncover distinct cellular metabolic signatures essential to support renal physiology and healthy ageing. Cell type-specific programming of glucose handling, PPP-mediated glutathione regeneration and FA β-oxidation via dynamic lipid-peroxisomal networks, downstream of differential ERR receptor activity, precisely match cellular energetic demands whilst limiting damage and premature senescence; however, their dramatic dysregulation may underlie age-related renal dysfunction.
    DOI:  https://doi.org/10.1038/s41467-023-44098-x
  5. Cell Metab. 2023 Dec 14. pii: S1550-4131(23)00449-7. [Epub ahead of print]
      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
  6. J Biol Chem. 2023 Nov 22. pii: S0021-9258(23)02498-5. [Epub ahead of print]300(1): 105470
      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
  7. Mol Cell Oncol. 2023 ;10(1): 2014734
      Our recent study revealed that APOBEC3B is upregulated during the preinvasive stages of non-small cell lung cancer and breast cancer. In addition to its role in mediating single nucleotide variants, we propose that APOBEC3 promotes copy number intratumor heterogeneity prior to invasion, providing a substrate for cancer evolution.
    Keywords:  APOBEC; breast cancer; chromosomal instability; intratumor heterogeneity; non-small cell lung cancer
    DOI:  https://doi.org/10.1080/23723556.2021.2014734
  8. Cell Metab. 2023 Dec 08. pii: S1550-4131(23)00421-7. [Epub ahead of print]
      Common genetic variants in glucokinase regulator (GCKR), which encodes GKRP, a regulator of hepatic glucokinase (GCK), influence multiple metabolic traits in genome-wide association studies (GWASs), making GCKR one of the most pleiotropic GWAS loci in the genome. It is unclear why. Prior work has demonstrated that GCKR influences the hepatic cytosolic NADH/NAD+ ratio, also referred to as reductive stress. Here, we demonstrate that reductive stress is sufficient to activate the transcription factor ChREBP and necessary for its activation by the GKRP-GCK interaction, glucose, and ethanol. We show that hepatic reductive stress induces GCKR GWAS traits such as increased hepatic fat, circulating FGF21, and circulating acylglycerol species, which are also influenced by ChREBP. We define the transcriptional signature of hepatic reductive stress and show its upregulation in fatty liver disease and downregulation after bariatric surgery in humans. These findings highlight how a GCKR-reductive stress-ChREBP axis influences multiple human metabolic traits.
    Keywords:  ChREBP; FGF21; GCK; GCKR; MLIXPL; NAD(+); NADH; fatty liver disease; gastric bypass surgery; metabolism; reductive stress; trigylcerides
    DOI:  https://doi.org/10.1016/j.cmet.2023.11.010
  9. Nature. 2024 Jan;625(7993): 35-36
      
    Keywords:  Cell biology; Immunology; Physiology
    DOI:  https://doi.org/10.1038/d41586-023-03972-w
  10. Biochem Biophys Res Commun. 2023 Dec 17. pii: S0006-291X(23)01476-6. [Epub ahead of print]694 149382
      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
  11. Biochem Soc Trans. 2023 Dec 20. 51(6): 1989-2004
      SLC25A51 is the primary mitochondrial NAD+ transporter in humans and controls many local reactions by mediating the influx of oxidized NAD+. Intriguingly, SLC25A51 lacks several key features compared with other members in the mitochondrial carrier family, thus its molecular mechanism has been unclear. A deeper understanding would shed light on the control of cellular respiration, the citric acid cycle, and free NAD+ concentrations in mammalian mitochondria. This review discusses recent insights into the transport mechanism of SLC25A51, and in the process highlights a multitiered regulation that governs NAD+ transport. The aspects regulating SLC25A51 import activity can be categorized as contributions from (1) structural characteristics of the transporter itself, (2) its microenvironment, and (3) distinctive properties of the transported ligand. These unique mechanisms further evoke compelling new ideas for modulating the activity of this transporter, as well as new mechanistic models for the mitochondrial carrier family.
    Keywords:  MCART1; NAD; SLC25A51; mitochondrial carrier family; mitochondrial transport
    DOI:  https://doi.org/10.1042/BST20220318
  12. Nat Commun. 2023 Dec 20. 14(1): 8464
      The mechanistic target of rapamycin complex 1 (mTORC1) is a crucial regulator of cell growth. It senses nutrient signals and adjusts cellular metabolism accordingly. Deregulation of mTORC1 has been associated with metabolic diseases, cancer, and aging. Amino acid signals are transduced to mTORC1 through sensor proteins and two protein complexes named GATOR1 and GATOR2. In this study, we identify VWCE (von Willebrand factor C and EGF domains) as a negative regulator of amino acid-dependent mTORC1 signaling. Knockdown of VWCE promotes mTORC1 activity even in the absence of amino acids. VWCE interacts with the KICSTOR complex to facilitate the recruitment of GATOR1 to the lysosomes. Bioinformatic analysis reveals that expression of VWCE is reduced in prostate cancer. More importantly, overexpression of VWCE inhibits the development of prostate cancer. Therefore, VWCE may serve as a potential therapeutic target for the treatment of prostate cancers.
    DOI:  https://doi.org/10.1038/s41467-023-44241-8
  13. Cancer Immunol Res. 2023 Dec 21. OF1-OF5
      Immune cells in the tumor niche robustly influence disease progression. Remarkably, in cancer, developmental pathways are reenacted. Many parallels between immune regulation of embryonic development and immune regulation of tumor progression can be drawn, with evidence clearly supporting an immune-suppressive microenvironment in both situations. In these ecosystems, metabolic and bioenergetic circuits guide and regulate immune cell differentiation, plasticity, and functional properties of suppressive and inflammatory immune subsets. As such, there is an emerging pattern of intersection across the dynamic process of ontogeny and the ever-evolving tumor neighborhood. In this article, we focus on the convergence of immune programming during ontogeny and in the tumor microenvironment. Exemplifying dysregulation of Hedgehog (Hh) activity, a key player during ontogeny, we highlight a critical convergence of these fields and the metabolic axis of the nutrient sensing hexosamine biosynthetic pathway (HBP) that integrates glucose, glutamine, amino acids, acetyl CoA, and uridine-5'-triphosphate (UTP), culminating in the synthesis of UDP-GlcNAc, a metabolite that functions as a metabolic and bioenergetic sensor. We discuss an emerging pattern of immune regulation, orchestrated by O-GlcNAcylation of key transcriptional regulators, spurring suppressive activity of dysfunctional immune cells in the tumor microenvironment.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-23-0433
  14. Trends Endocrinol Metab. 2023 Dec 15. pii: S1043-2760(23)00243-6. [Epub ahead of print]
      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
  15. Metabolites. 2023 Dec 12. pii: 1196. [Epub ahead of print]13(12):
      NAD synthetase 1 (encoded by the gene NADSYN1) is a cytosolic enzyme that catalyzes the final step in the biosynthesis of nicotinamide adenine dinucleotide (NAD+) from tryptophan and nicotinic acid. NADSYN1 deficiency has recently been added to the spectrum of congenital NAD+ deficiency disorders. To gain insight into the metabolic consequences of NADSYN1 deficiency, the encoding gene was disrupted in A549 and HEK293T cells, and the metabolome was profiled in the presence of different NAD+ precursors, including tryptophan, nicotinamide and nicotinic acid. We demonstrate that when precursors of the NAD+ salvage pathway in the form of nicotinamide become limiting, NADSYN1 deficiency results in a decline in intracellular NAD+ levels even in the presence of other potential NAD+ sources such as tryptophan and nicotinic acid. As a consequence, alterations in 122 and 69 metabolites are observed in NADSYN1-deficient A549 and HEK293T cells compared to the wild-type cell line (FC > 2 and p < 0.05). We thus show that NADSYN1 deficiency results in a metabolic phenotype characterized by alterations in glycolysis, the TCA cycle, the pentose phosphate pathway, and the polyol pathway.
    Keywords:  NAD+ deficiency; NAD+ salvage pathway; NADSYN1; Preiss–Handler pathway; de novo NAD+ synthesis pathway; glycolysis; metabolomics; pentose phosphate pathway; polyol pathway
    DOI:  https://doi.org/10.3390/metabo13121196
  16. Nat Commun. 2023 Dec 20. 14(1): 8474
      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
  17. Cell Metab. 2023 Dec 14. pii: S1550-4131(23)00445-X. [Epub ahead of print]
      Glioblastoma (GBM) is a malignancy dominated by the infiltration of tumor-associated myeloid cells (TAMCs). Examination of TAMC metabolic phenotypes in mouse models and patients with GBM identified the de novo creatine metabolic pathway as a hallmark of TAMCs. Multi-omics analyses revealed that TAMCs surround the hypoxic peri-necrotic regions of GBM and express the creatine metabolic enzyme glycine amidinotransferase (GATM). Conversely, GBM cells located within these same regions are uniquely specific in expressing the creatine transporter (SLC6A8). We hypothesized that TAMCs provide creatine to tumors, promoting GBM progression. Isotopic tracing demonstrated that TAMC-secreted creatine is taken up by tumor cells. Creatine supplementation protected tumors from hypoxia-induced stress, which was abrogated with genetic ablation or pharmacologic inhibition of SLC6A8. Lastly, inhibition of creatine transport using the clinically relevant compound, RGX-202-01, blunted tumor growth and enhanced radiation therapy in vivo. This work highlights that myeloid-to-tumor transfer of creatine promotes tumor growth in the hypoxic niche.
    Keywords:  creatine metabolism; glioblastoma; myeloid cells; pseudopalisading necrosis
    DOI:  https://doi.org/10.1016/j.cmet.2023.11.013
  18. Curr Biol. 2023 Dec 18. pii: S0960-9822(23)01489-6. [Epub ahead of print]33(24): R1289-R1291
      Lysosomes are highly dynamic organelles that rapidly respond to changes in cellular nutrient status. A new study identifies a phosphoinositide switch that dictates lysosome function during nutrient starvation.
    DOI:  https://doi.org/10.1016/j.cub.2023.10.066
  19. Nat Metab. 2023 Dec;5(12): 2094-2110
      The thyroid functions as an apex endocrine organ that controls growth, differentiation and metabolism1, and thyroid diseases comprise the most common endocrine disorders2. Nevertheless, high-resolution views of the cellular composition and signals that govern the thyroid have been lacking3,4. Here, we show that Notch signalling controls homeostasis and thermoregulation in adult mammals through a mitochondria-based mechanism in a subset of thyrocytes. We discover two thyrocyte subtypes in mouse and human thyroids, identified in single-cell analyses by different levels of metabolic activity and Notch signalling. Therapeutic antibody blockade of Notch in adult mice inhibits a thyrocyte-specific transcriptional program and induces thyrocyte defects due to decreased mitochondrial activity and ROS production. Thus, disrupting Notch signalling in adult mice causes hypothyroidism, characterized by reduced levels of circulating thyroid hormone and dysregulation of whole-body thermoregulation. Inducible genetic deletion of Notch1 and 2 in thyrocytes phenocopies this antibody-induced hypothyroidism, establishing a direct role for Notch in adult murine thyrocytes. We confirm that hypothyroidism is enriched in children with Alagille syndrome, a genetic disorder marked by Notch mutations, suggesting that these findings translate to humans.
    DOI:  https://doi.org/10.1038/s42255-023-00937-1
  20. Nat Commun. 2023 Dec 20. 14(1): 8480
      Succinic acid (SA) is an important C4-dicarboxylic acid. Microbial production of SA at low pH results in low purification costs and hence good overall process economics. However, redox imbalances limited SA biosynthesis from glucose via the reductive tricarboxylic acid (TCA) cycle in yeast. Here, we engineer the strictly aerobic yeast Yarrowia lipolytica for efficient SA production without pH control. Introduction of the reductive TCA cycle into the cytosol of a succinate dehydrogenase-disrupted yeast strain causes arrested cell growth. Although adaptive laboratory evolution restores cell growth, limited NADH supply restricts SA production. Reconfiguration of the reductive SA biosynthesis pathway in the mitochondria through coupling the oxidative and reductive TCA cycle for NADH regeneration results in improved SA production. In pilot-scale fermentation, the engineered strain produces 111.9 g/L SA with a yield of 0.79 g/g glucose within 62 h. This study paves the way for industrial production of biobased SA.
    DOI:  https://doi.org/10.1038/s41467-023-44245-4
  21. Trends Cancer. 2023 Dec 22. pii: S2405-8033(23)00238-8. [Epub ahead of print]
      The tumor microenvironment (TME) contains a complex cellular ecosystem where cancer, stromal, vascular, and immune cells interact. Macrophages and regulatory T cells (Tregs) are critical not only for maintaining immunological homeostasis and tumor growth but also for monitoring the functional states of other immune cells. Emerging evidence reveals that metabolic changes in macrophages and Tregs significantly influence their pro-/antitumor functions through the regulation of signaling cascades and epigenetic reprogramming. Hence, they are increasingly recognized as therapeutic targets in cancer immunotherapy. Specific metabolites in the TME may also affect their pro-/antitumor functions by intervening with the metabolic machinery. We discuss how metabolites influence the immunosuppressive phenotypes of tumor-associated macrophages (TAMs) and Tregs. We then describe how TAMs and Tregs, independently or collaboratively, utilize metabolic mechanisms to suppress the activity of CD8+ T cells. Finally, we highlight promising metabolic interventions that can improve the outcome of current cancer therapies.
    Keywords:  cancer immunotherapy; immunometabolism; immunosuppression; macrophage; regulatory T cell; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2023.11.007
  22. J Biol Chem. 2023 Dec 13. pii: S0021-9258(23)02591-7. [Epub ahead of print] 105563
      Intermediary metabolites and flux through various pathways have emerged as key determinants of post-translational modifications. Independently, dynamic fluctuations in their concentrations are known to drive cellular energetics in a bi-directional manner. Notably, intracellular fatty acid pools that drastically change during fed and fasted states act as precursors for both ATP production and fatty acylation of proteins. Protein fatty acylation is well regarded for its role in regulating structure and functions of diverse proteins, however the effect of intracellular concentrations of fatty acids on protein modification is less understood. In this regard, we unequivocally demonstrate that metabolic contexts, viz. fed and fasted states, dictate the extent of global fatty acylation. Moreover, we show that presence or absence of glucose, that influences cellular and mitochondrial uptake/utilization of fatty acids, affects palmitoylation and oleoylation, which is consistent with their intracellular abundance in fed and fasted states. Employing complementary approaches including click-chemistry, lipidomics and imaging, we show the top-down control of cellular metabolic state. Importantly, our results establish the crucial role of mitochondria and retrograde signaling components like SIRT4, AMPK and mTOR in orchestrating protein fatty acylation at a whole cell level. Specifically, pharmacogenetic perturbations that alter either mitochondrial functions and/or retrograde signaling affect protein fatty acylation. Besides illustrating the cross-talk between carbohydrate and lipid metabolism in mediating bulk post-translational modification, our findings also highlight the involvement of mitochondrial energetics.
    Keywords:  Acylation; acyl exchange; free fatty acids; oleate; palmitate; sirtuins
    DOI:  https://doi.org/10.1016/j.jbc.2023.105563
  23. Cell Rep. 2023 Dec 13. pii: S2211-1247(23)01576-0. [Epub ahead of print]42(12): 113564
      Triple-negative breast cancer (TNBC) is a heterogeneous disease with limited treatment options. To characterize TNBC heterogeneity, we defined transcriptional, epigenetic, and metabolic subtypes and subtype-driving super-enhancers and transcription factors by combining functional and molecular profiling with computational analyses. Single-cell RNA sequencing revealed relative homogeneity of the major transcriptional subtypes (luminal, basal, and mesenchymal) within samples. We found that mesenchymal TNBCs share features with mesenchymal neuroblastoma and rhabdoid tumors and that the PRRX1 transcription factor is a key driver of these tumors. PRRX1 is sufficient for inducing mesenchymal features in basal but not in luminal TNBC cells via reprogramming super-enhancer landscapes, but it is not required for mesenchymal state maintenance or for cellular viability. Our comprehensive, large-scale, multiplatform, multiomics study of both experimental and clinical TNBC is an important resource for the scientific and clinical research communities and opens venues for future investigation.
    Keywords:  CP: Cancer; triple-negative breast cancer; tumor heterogeneity
    DOI:  https://doi.org/10.1016/j.celrep.2023.113564
  24. Proc Natl Acad Sci U S A. 2023 Dec 26. 120(52): e2313693120
      Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) expression correlates with poor prognosis in many cancers, and we previously discovered that ENPP1 is the dominant hydrolase of extracellular cGAMP: a cancer-cell-produced immunotransmitter that activates the anticancer stimulator of interferon genes (STING) pathway. However, ENPP1 has other catalytic activities and the molecular and cellular mechanisms contributing to its tumorigenic effects remain unclear. Here, using single-cell RNA-seq, we show that ENPP1 in both cancer and normal tissues drives primary breast tumor growth and metastasis by dampening extracellular 2'3'-cyclic-GMP-AMP (cGAMP)-STING-mediated antitumoral immunity. ENPP1 loss-of-function in both cancer cells and normal tissues slowed primary tumor growth and abolished metastasis. Selectively abolishing the cGAMP hydrolysis activity of ENPP1 phenocopied ENPP1 knockout in a STING-dependent manner, demonstrating that restoration of paracrine cGAMP-STING signaling is the dominant anti-cancer mechanism of ENPP1 inhibition. Finally, ENPP1 expression in breast tumors deterministically predicated whether patients would remain free of distant metastasis after pembrolizumab (anti-PD-1) treatment followed by surgery. Altogether, ENPP1 blockade represents a strategy to exploit cancer-produced extracellular cGAMP for controlled local activation of STING and is therefore a promising therapeutic approach against breast cancer.
    Keywords:  ENPP1; STING; breast cancer metastasis; extracellular cGAMP; immune checkpoint
    DOI:  https://doi.org/10.1073/pnas.2313693120
  25. J Plant Physiol. 2023 Dec 13. pii: S0176-1617(23)00256-0. [Epub ahead of print]292 154162
      Plant central carbon metabolism comprises several important metabolic pathways acting together to support plant growth and yield establishment. Despite the emergence of 13C-based dynamic approaches, the regulation of metabolic fluxes between light and dark conditions has not yet received sufficient attention for agronomically relevant plants. Here, we investigated the impact of light/dark conditions on carbon allocation processes within central carbon metabolism of Brassica napus after U-13C-glucose incorporation into leaf discs. Leaf gas-exchanges and metabolite contents were weakly impacted by the leaf disc method and the incorporation of glucose. 13C-analysis by GC-MS showed that U-13C-glucose was converted to fructose for de novo biosynthesis of sucrose at similar rates in both light and dark conditions. However, light conditions led to a reduced commitment of glycolytic carbons towards respiratory substrates (pyruvate, alanine, malate) and TCA cycle intermediates compared to dark conditions. Analysis of 13C-enrichment at the isotopologue level and metabolic pathway isotopic tracing reconstructions identified the contribution of multiple pathways to serine biosynthesis in light and dark conditions. However, the direct contribution of the glucose-6-phosphate shunt to serine biosynthesis was not observed. Our results also provided isotopic evidences for an active metabolic connection between the TCA cycle, glycolysis and photorespiration in light conditions through a rapid reallocation of TCA cycle decarboxylations back to the TCA cycle through photorespiration and glycolysis. Altogether, these results suggest the active coordination of core metabolic pathways across multiple compartments to reorganize C-flux modes.
    Keywords:  Brassica napus; Carbon isotopologue distribution; Dark; Glycolysis; Isotope; Light; Serine; Tricarboxylic acid cycle
    DOI:  https://doi.org/10.1016/j.jplph.2023.154162
  26. Biochim Biophys Acta Rev Cancer. 2023 Dec 13. pii: S0304-419X(23)00200-7. [Epub ahead of print] 189051
      This review delves into the most recent research on the metabolic adaptability of cancer cells and examines how their metabolic functions can impact their progression into metastatic forms. We emphasize the growing significance of lipid metabolism and dietary lipids within the tumor microenvironment, underscoring their influence on tumor progression. Additionally, we present an outline of the interplay between metabolic processes and the epigenome of cancer cells, underscoring the importance regarding the metastatic process. Lastly, we examine the potential of targeting metabolism as a therapeutic approach in combating cancer progression, shedding light on innovative drugs/targets currently undergoing preclinical evaluation.
    Keywords:  Epigenetics; Lipid metabolism; Metastasis; Microenvironment; Therapies
    DOI:  https://doi.org/10.1016/j.bbcan.2023.189051
  27. Aging Cell. 2023 Dec 22. e14058
      Several premature aging mouse models have been developed to study aging and identify interventions that can delay age-related diseases. Yet, it is still unclear whether these models truly recapitulate natural aging. Here, we analyzed DNA methylation in multiple tissues of four previously reported mouse models of premature aging (Ercc1, LAKI, Polg, and Xpg). We estimated DNA methylation (DNAm) age of these samples using the Horvath clock. The most pronounced increase in DNAm age could be observed in Ercc1 mice, a strain which exhibits a deficit in DNA nucleotide excision repair. Similarly, we detected an increase in epigenetic age in fibroblasts isolated from patients with progeroid syndromes associated with mutations in DNA excision repair genes. These findings highlight that mouse models with deficiencies in DNA repair, unlike other premature aging models, display accelerated epigenetic age, suggesting a strong connection between DNA damage and epigenetic dysregulation during aging.
    Keywords:  DNA damage; accelerated aging; epigenetic clock; methylation; progeria
    DOI:  https://doi.org/10.1111/acel.14058
  28. Cell. 2023 Dec 21. pii: S0092-8674(23)01312-0. [Epub ahead of print]186(26): 5876-5891.e20
      Harmonizing cell types across the single-cell community and assembling them into a common framework is central to building a standardized Human Cell Atlas. Here, we present CellHint, a predictive clustering tree-based tool to resolve cell-type differences in annotation resolution and technical biases across datasets. CellHint accurately quantifies cell-cell transcriptomic similarities and places cell types into a relationship graph that hierarchically defines shared and unique cell subtypes. Application to multiple immune datasets recapitulates expert-curated annotations. CellHint also reveals underexplored relationships between healthy and diseased lung cell states in eight diseases. Furthermore, we present a workflow for fast cross-dataset integration guided by harmonized cell types and cell hierarchy, which uncovers underappreciated cell types in adult human hippocampus. Finally, we apply CellHint to 12 tissues from 38 datasets, providing a deeply curated cross-tissue database with ∼3.7 million cells and various machine learning models for automatic cell annotation across human tissues.
    Keywords:  Human Cell Atlas; cell hierarchy; cell-type harmonization; data integration; harmonization graph; machine learning; organ atlas; predictive clustering tree; single cell
    DOI:  https://doi.org/10.1016/j.cell.2023.11.026
  29. Mol Cell. 2023 Dec 11. pii: S1097-2765(23)00968-1. [Epub ahead of print]
      Autophagy, an important quality control and recycling process vital for cellular homeostasis, is tightly regulated. The mTORC1 signaling pathway regulates autophagy under conditions of nutrient availability and scarcity. However, how mTORC1 activity is fine-tuned during nutrient availability to allow basal autophagy is unclear. Here, we report that the WD-domain repeat protein MORG1 facilitates basal constitutive autophagy by inhibiting mTORC1 signaling through Rag GTPases. Mechanistically, MORG1 interacts with active Rag GTPase complex inhibiting the Rag GTPase-mediated recruitment of mTORC1 to the lysosome. MORG1 depletion in HeLa cells increases mTORC1 activity and decreases autophagy. The autophagy receptor p62/SQSTM1 binds to MORG1, but MORG1 is not an autophagy substrate. However, p62/SQSTM1 binding to MORG1 upon re-addition of amino acids following amino acid's depletion precludes MORG1 from inhibiting the Rag GTPases, allowing mTORC1 activation. MORG1 depletion increases cell proliferation and migration. Low expression of MORG1 correlates with poor survival in several important cancers.
    Keywords:  MORG1; Rag GTPases; WD-domain repeat protein; autophagy; mTORC1; p62/SQSTM1
    DOI:  https://doi.org/10.1016/j.molcel.2023.11.023
  30. Nat Commun. 2023 Dec 16. 14(1): 8381
      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
  31. Proc Natl Acad Sci U S A. 2023 Dec 26. 120(52): e2309387120
      Our planet is a self-sustaining ecosystem powered by light energy from the sun, but roughly closed to matter. Many ecosystems on Earth are also approximately closed to matter and recycle nutrients by self-organizing stable nutrient cycles, e.g., microbial mats, lakes, open ocean gyres. However, existing ecological models do not exhibit the self-organization and dynamical stability widely observed in such planetary-scale ecosystems. Here, we advance a conceptual model that explains the self-organization, stability, and emergent features of closed microbial ecosystems. Our model incorporates the bioenergetics of metabolism into an ecological framework. By studying this model, we uncover a crucial thermodynamic feedback loop that enables metabolically diverse communities to almost always stabilize nutrient cycles. Surprisingly, highly diverse communities self-organize to extract [Formula: see text]10[Formula: see text] of the maximum extractable energy, or [Formula: see text]100 fold more than randomized communities. Further, with increasing diversity, distinct ecosystems show strongly correlated fluxes through nutrient cycles. However, as the driving force from light increases, the fluxes of nutrient cycles become more variable and species-dependent. Our results highlight that self-organization promotes the efficiency and stability of complex ecosystems at extracting energy from the environment, even in the absence of any centralized coordination.
    Keywords:  adaptation; biogeochemical cycles; ecosystems; redox metabolism; self-organization
    DOI:  https://doi.org/10.1073/pnas.2309387120
  32. Curr Opin Biotechnol. 2023 Dec 15. pii: S0958-1669(23)00161-1. [Epub ahead of print]85 103051
      N-acetyl-L-aspartic acid (NAA) is a prominent amino acid derivative primarily associated with vertebrate brain metabolism. This review delineates the critical role of NAA across various cell types and its significance in pathophysiological contexts, including Canavan disease and cancer metabolism. Although traditionally linked with myelination and aspartoacylase-driven carbon donation, its significance as a carbon source for myelination remains debated. Evidence suggests that intact NAA might substantially impact cellular signaling, particularly processes such as histone acetylation. Beyond the brain, NAA metabolism's relevance is evident in diverse tissues, such as adipocytes, immune cells, and notably, cancer cells. In several cancer types, there is an observed upregulation of NAA synthesis accompanied by a simultaneous downregulation of its degradation. This pattern highlights the potential signaling role of intact NAA in disease.
    DOI:  https://doi.org/10.1016/j.copbio.2023.103051
  33. Cell. 2023 Dec 13. pii: S0092-8674(23)01317-X. [Epub ahead of print]
      Deciphering the cell-state transitions underlying immune adaptation across time is fundamental for advancing biology. Empirical in vivo genomic technologies that capture cellular dynamics are currently lacking. We present Zman-seq, a single-cell technology recording transcriptomic dynamics across time by introducing time stamps into circulating immune cells, tracking them in tissues for days. Applying Zman-seq resolved cell-state and molecular trajectories of the dysfunctional immune microenvironment in glioblastoma. Within 24 hours of tumor infiltration, cytotoxic natural killer cells transitioned to a dysfunctional program regulated by TGFB1 signaling. Infiltrating monocytes differentiated into immunosuppressive macrophages, characterized by the upregulation of suppressive myeloid checkpoints Trem2, Il18bp, and Arg1, over 36 to 48 hours. Treatment with an antagonistic anti-TREM2 antibody reshaped the tumor microenvironment by redirecting the monocyte trajectory toward pro-inflammatory macrophages. Zman-seq is a broadly applicable technology, enabling empirical measurements of differentiation trajectories, which can enhance the development of more efficacious immunotherapies.
    Keywords:  cancer; computational biology; dynamics; glioblastoma; immunology; immunotherapy; single-cell biology; systems immunology; temporal transcriptomics; tumor-associated-macrophages
    DOI:  https://doi.org/10.1016/j.cell.2023.11.032
  34. Cell Rep. 2023 Dec 20. pii: S2211-1247(23)01611-X. [Epub ahead of print]43(1): 113599
      Target of rapamycin complex 1 (TORC1) is a master regulator that monitors the availability of various amino acids to promote cell growth in Saccharomyces cerevisiae. It is activated via two distinct upstream pathways: the Gtr pathway, which corresponds to mammalian Rag, and the Pib2 pathway. This study shows that Ser3 was phosphorylated exclusively in a Pib2-dependent manner. Using Ser3 as an indicator of TORC1 activity, together with the established TORC1 substrate Sch9, we investigated which pathways were employed by individual amino acids. Different amino acids exhibited different dependencies on the Gtr and Pib2 pathways. Cysteine was most dependent on the Pib2 pathway and increased the interaction between TORC1 and Pib2 in vivo and in vitro. Moreover, cysteine directly bound to Pib2 via W632 and F635, two critical residues in the T(ail) motif that are necessary to activate TORC1. These results indicate that Pib2 functions as a sensor for cysteine in TORC1 regulation.
    Keywords:  CP: Molecular biology; Cysteine; Pib2; TORC1; mTORC1
    DOI:  https://doi.org/10.1016/j.celrep.2023.113599
  35. Cell Rep. 2023 Dec 14. pii: S2211-1247(23)01589-9. [Epub ahead of print]42(12): 113577
      Neurodegenerative disorders, such as Alzheimer's disease (AD) or Huntington's disease (HD), are linked to protein aggregate neurotoxicity. According to the "cholinergic hypothesis," loss of acetylcholine (ACh) signaling contributes to the AD pathology, and therapeutic restoration of ACh signaling is a common treatment strategy. How disease causation and the effect of ACh are linked to protein aggregation and neurotoxicity remains incompletely understood, thus limiting the development of more effective therapies. Here, we show that BAZ-2, the Caenorhabditis elegans ortholog of human BAZ2B, limits ACh signaling. baz-2 mutations reverse aggregation and toxicity of amyloid-beta as well as polyglutamine peptides, thereby restoring health and lifespan in nematode models of AD and HD, respectively. The neuroprotective effect of Δbaz-2 is mediated by choline acetyltransferase, phenocopied by ACh-esterase depletion, and dependent on ACh receptors. baz-2 reduction or ectopic ACh treatment augments proteostasis via induction of the endoplasmic reticulum unfolded protein response and the ubiquitin proteasome system.
    Keywords:  Alzheimer's disease; CP: Metabolism; CP: Neuroscience; acetylcholine; amyloid-beta; baz-2; neurodegenerative disorders; non-cell-autonomous signaling; proteostasis regulation; ubiquitin proteasome system; unfolded protein response in the endoplasmic reticulum
    DOI:  https://doi.org/10.1016/j.celrep.2023.113577
  36. Nat Commun. 2023 Dec 21. 14(1): 8508
      Enzyme evolution is characterized by constant alterations of the intramolecular residue networks supporting their functions. The rewiring of these network interactions can give rise to epistasis. As mutations accumulate, the epistasis observed across diverse genotypes may appear idiosyncratic, that is, exhibit unique effects in different genetic backgrounds. Here, we unveil a quantitative picture of the prevalence and patterns of epistasis in enzyme evolution by analyzing 41 fitness landscapes generated from seven enzymes. We show that >94% of all mutational and epistatic effects appear highly idiosyncratic, which greatly distorted the functional prediction of the evolved enzymes. By examining seemingly idiosyncratic changes in epistasis along adaptive trajectories, we expose several instances of higher-order, intramolecular rewiring. Using complementary structural data, we outline putative molecular mechanisms explaining higher-order epistasis along two enzyme trajectories. Our work emphasizes the prevalence of epistasis and provides an approach to exploring this phenomenon through a molecular lens.
    DOI:  https://doi.org/10.1038/s41467-023-44333-5
  37. Trends Endocrinol Metab. 2023 Dec 21. pii: S1043-2760(23)00246-1. [Epub ahead of print]
      Exaggerated blood excursions of nutrients and endogenous molecules in response to food intake may have health consequences if they repeatedly exceed the capacity of homeostatic mechanisms. Here, I discuss the significance of abnormally high postprandial metabolic fluctuations, the role of some influencing factors, and suggest ways to avoid them.
    Keywords:  food consumption; genetics; gut microbiota; homeostatic limits; metabolic health; postprandial metabolism
    DOI:  https://doi.org/10.1016/j.tem.2023.12.001
  38. Cancers (Basel). 2023 Dec 18. pii: 5897. [Epub ahead of print]15(24):
      Clear cell renal cell carcinoma (CCRCC) is an aggressive form of cancer and a paradigmatic example of intratumor heterogeneity (ITH). The hawk-dove game is a mathematical tool designed to analyze competition in biological systems. Using this game, the study reported here analyzes the early phase of CCRCC development, comparing clonal fitness in homogeneous (linear evolutionary) and highly heterogeneous (branching evolutionary) models. Fitness in the analysis is a measure of tumor aggressiveness. The results show that the fittest clone in a heterogeneous environment is fitter than the clone in a homogeneous context in the early phases of tumor evolution. Early and late periods of tumor evolution in CCRCC are also compared. The study shows the convergence of mathematical, histological, and genomics studies with respect to clonal aggressiveness in different periods of the natural history of CCRCC. Such convergence highlights the importance of multidisciplinary approaches for obtaining a better understanding of the intricacies of cancer.
    Keywords:  cancer evolution; clear cell renal cell carcinoma; game theory; intratumor heterogeneity
    DOI:  https://doi.org/10.3390/cancers15245897
  39. Proc Natl Acad Sci U S A. 2023 Dec 26. 120(52): e2313282120
      An organism's phenotype has been shaped by evolution but the specific processes have to be indirectly inferred for most species. For example, correlations among traits imply the historical action of correlated selection and, more generally, the expression and distribution of traits is expected to be reflective of the adaptive landscapes that have shaped a population. However, our expectations about how quantitative traits-like most behaviors, physiological processes, and life-history traits-should be distributed under different evolutionary processes are not clear. Here, we show that genetic variation in quantitative traits is not distributed as would be expected under dominant evolutionary models. Instead, we found that genetic variation in quantitative traits across six phyla and 60 species (including both Plantae and Animalia) is consistent with evolution across high-dimensional "holey landscapes." This suggests that the leading conceptualizations and modeling of the evolution of trait integration fail to capture how phenotypes are shaped and that traits are integrated in a manner contrary to predictions of dominant evolutionary theory. Our results demonstrate that our understanding of how evolution has shaped phenotypes remains incomplete and these results provide a starting point for reassessing the relevance of existing evolutionary models.
    Keywords:  G matrix; evolutionary constraints; fitness landscapes
    DOI:  https://doi.org/10.1073/pnas.2313282120