bims-celmim 2024-03-10 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2024–03–10
29 papers selected by
Marc Segarra Mondejar, University of Cologne

The interplay between mitochondrial dynamics and autophagy: From a key homeostatic mechanism to a driver of pathology.
An unexpected journey for BNIP3.
Metabolism-regulated ferroptosis in cancer progression and therapy.
Detection of nitric oxide-mediated metabolic effects using real-time extracellular flux analysis.
Metabolic remodeling in cancer and senescence and its therapeutic implications.
ISGylation of DRP1 closely balances other post-translational modifications to mediate mitochondrial fission.
Exploring the diverse role of pyruvate kinase M2 in cancer: Navigating beyond glycolysis and the Warburg effect.
Activity-dependent compartmentalization of dendritic mitochondria morphology through local regulation of fusion-fission balance in neurons in vivo.
Metabolomics analysis reveals novel serum metabolite alterations in cancer cachexia.
Real-time resolution studies of the regulation of lactate production by hexokinases binding to mitochondria in single cells.
Mitochondrial ATP generation is more proteome efficient than glycolysis.
How and When to Measure Mitochondrial Inner Membrane Potentials.
The metabolic domestication syndrome of budding yeast.
Pink1 balances reticulophagy and mitophagy by regulating distinct E3 ubiquitin ligases.
Two ancient membrane pores mediate mitochondrial-nucleus membrane contact sites.
Autophagy sustains mitochondrial respiration and determines resistance to BRAFV600E inhibition in thyroid carcinoma cells.
Metabolism of asparagine in the physiological state and cancer.
MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors.
A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate.
Regulation of urea cycle by reversible high-stoichiometry lysine succinylation.
Lipid droplets and cellular lipid flux.
Supercharging cancer-fighting T cells with lithium carbonate.
Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing.
Modulation of nucleotide metabolism by picornaviruses.
Futile lipid cycling: from biochemistry to physiology.
Metabolic regulation of mRNA splicing.
A glutamine tug-of-war between cancer and immune cells: recent advances in unraveling the ongoing battle.
Aerobic glycolysis comes with an enzyme cost but robustness gain.
Hepatic malonyl-CoA synthesis restrains gluconeogenesis by suppressing fat oxidation, pyruvate carboxylation, and amino acid availability.

Semin Cell Dev Biol. 2024 Mar 01. pii: S1084-9521(24)00022-3. [Epub ahead of print]161-162 1-19

The interplay between mitochondrial dynamics and autophagy: From a key homeostatic mechanism to a driver of pathology.

Alice Lacombe, Luca Scorrano.

  The complex relationship between mitochondrial dynamics and autophagy illustrates how two cellular housekeeping processes are intimately linked, illuminating fundamental principles of cellular homeostasis and shedding light on disparate pathological conditions including several neurodegenerative disorders. Here we review the basic tenets of mitochondrial dynamics i.e., the concerted balance between fusion and fission of the organelle, and its interplay with macroautophagy and selective mitochondrial autophagy, also dubbed mitophagy, in the maintenance of mitochondrial quality control and ultimately in cell viability. We illustrate how conditions of altered mitochondrial dynamics reverberate on autophagy and vice versa. Finally, we illustrate how altered interplay between these two key cellular processes participates in the pathogenesis of human disorders affecting multiple organs and systems.

Keywords:  Mitochondria; autophagy; diseases; fusion-fission; mitophagy

DOI:  https://doi.org/10.1016/j.semcdb.2024.02.001
Autophagy. 2024 Mar 06. 1-2

An unexpected journey for BNIP3.

José M Delgado, Christopher J Shoemaker.

  Mitophagy is a cellular process that enables the selective degradation of damaged, dysfunctional, or superfluous mitochondria. During mitophagy, specific proteins recognize and tag mitochondria for degradation. These tagged mitochondria are engulfed by specialized structures called phagophores that then mature into autophagosomes/mitophagosomes. Mitophagosomes subsequently transport their mitochondrial cargo to lysosomes, where the mitochondria are broken down and recycled. While the PINK1-PRKN-dependent mitophagy pathway is well understood, mitophagy can also occur independently of this pathway. BNIP3 and BNIP3L/NIX, paralogous membrane proteins on the outer mitochondrial membrane (OMM), serve as ubiquitin-independent mitophagy receptors. Historically, BNIP3 regulation was thought to be primarily transcriptional through HIF1A (hypoxia inducible factor 1 subunit alpha). However, recent work has revealed a significant post-translational dimension, highlighting the strong role of the ubiquitin-proteasome system (UPS) in BNIP3 regulation. With these emerging concepts in mind, we aimed to develop a unified understanding of how steady-state levels of BNIP3 are established and maintained and how this regulation governs underlying cell physiology.

Keywords:  BNIP3; EMC; ER membrane protein complex; NIX; membrane trafficking; mitophagy

DOI:  https://doi.org/10.1080/15548627.2024.2312038
Cell Death Dis. 2024 Mar 08. 15(3): 196

Metabolism-regulated ferroptosis in cancer progression and therapy.

Lvlan Ye, Xiangqiong Wen, Jiale Qin, Xiang Zhang, Youpeng Wang, Ziyang Wang, Ti Zhou, Yuqin Di, Weiling He.

Cancer metabolism mainly includes carbohydrate, amino acid and lipid metabolism, each of which can be reprogrammed. These processes interact with each other to adapt to the complicated microenvironment. Ferroptosis is a regulated cell death induced by iron-dependent lipid peroxidation, which is morphologically different from apoptosis, necrosis, necroptosis, pyroptosis, autophagy-dependent cell death and cuprotosis. Cancer metabolism plays opposite roles in ferroptosis. On the one hand, carbohydrate metabolism can produce NADPH to maintain GPX4 and FSP1 function, and amino acid metabolism can provide substrates for synthesizing GPX4; on the other hand, lipid metabolism might synthesize PUFAs to trigger ferroptosis. The mechanisms through which cancer metabolism affects ferroptosis have been investigated extensively for a long time; however, some mechanisms have not yet been elucidated. In this review, we summarize the interaction between cancer metabolism and ferroptosis. Importantly, we were most concerned with how these targets can be utilized in cancer therapy.

DOI: https://doi.org/10.1038/s41419-024-06584-y
PLoS One. 2024 ;19(3): e0299294

Detection of nitric oxide-mediated metabolic effects using real-time extracellular flux analysis.

Bay Vagher, Eyal Amiel.

Dendritic cell (DC) activation is marked by key events including: (I) rapid induction and shifting of metabolism favoring glycolysis for generation of biosynthetic metabolic intermediates and (II) large scale changes in gene expression including the upregulation of the antimicrobial enzyme inducible nitric oxide synthase (iNOS) which produces the toxic gas nitric oxide (NO). Historically, acute metabolic reprogramming and NO-mediated effects on cellular metabolism have been studied at specific timepoints during the DC activation process, namely at times before and after NO production. However, no formal method of real time detection of NO-mediated effects on DC metabolism have been fully described. Here, using Real-Time Extracellular Flux Analysis, we experimentally establish the phenomenon of an NO-dependent mitochondrial respiration threshold, which shows how titration of an activating stimulus is inextricably linked to suppression of mitochondrial respiration in an NO-dependent manner. As part of this work, we explore the efficacy of two different iNOS inhibitors in blocking the iNOS reaction kinetically in real time and explore/discuss parameters and considerations for application using Real Time Extracellular Flux Analysis technology. In addition, we show, the temporal relationship between acute metabolic reprogramming and NO-mediated sustained metabolic reprogramming kinetically in single real-time assay. These findings provide a method for detection of NO-mediated metabolic effects in DCs and offer novel insight into the timing of the DC activation process with its associated key metabolic events, revealing a better understanding of the nuances of immune cell biology.

DOI: https://doi.org/10.1371/journal.pone.0299294
Trends Endocrinol Metab. 2024 Mar 06. pii: S1043-2760(24)00037-7. [Epub ahead of print]

Metabolic remodeling in cancer and senescence and its therapeutic implications.

Yeonju Kim, Yeji Jang, Mi-Sung Kim, Chanhee Kang.

  Cellular metabolism is a flexible and plastic network that often dictates physiological and pathological states of the cell, including differentiation, cancer, and aging. Recent advances in cancer metabolism represent a tremendous opportunity to treat cancer by targeting its altered metabolism. Interestingly, despite their stable growth arrest, senescent cells - a critical component of the aging process - undergo metabolic changes similar to cancer metabolism. A deeper understanding of the similarities and differences between these disparate pathological conditions will help identify which metabolic reprogramming is most relevant to the therapeutic liabilities of senescence. Here, we compare and contrast cancer and senescence metabolism and discuss how metabolic therapies can be established as a new modality of senotherapy for healthy aging.

Keywords:  aging; cancer; metabolism; senescence; senotherapy

DOI:  https://doi.org/10.1016/j.tem.2024.02.008
Cell Death Dis. 2024 Mar 02. 15(3): 184

ISGylation of DRP1 closely balances other post-translational modifications to mediate mitochondrial fission.

Palamou Das, Oishee Chakrabarti.

Dynamin related protein 1 (DRP1), a pivotal mitochondrial fission protein, is post-translationally modified by multiple mechanisms. Here we identify a new post-translational modification of DRP1 by the ubiquitin-like protein, interferon-stimulated gene 15 (ISG15). DRP1 ISGylation is mediated by ISG15 E3 ligase, HERC5; this promotes mitochondrial fission. DeISGylation of DRP1 however leads to hyperfusion. Heterologous expression of SARS-CoV2 PLpro, a deISGylating enzyme, results in similar mitochondrial filamentation, significant decrease in total DRP1 protein levels and efflux of mtDNA. We report that deISGylated DRP1 gets ubiquitylated and degraded by TRIM25, instead of PARKIN and MITOL. While the cytosolic pool of DRP1 is primarily ISGylated, both mitochondrial and cytosolic fractions may be ubiquitylated. It is known that phosphorylation of DRP1 at S616 residue regulates its mitochondrial localisation; we show that ISGylation of phospho-DRP1 (S616) renders fission competence at mitochondria. This is significant because DRP1 ISGylation affects its functionality and mitochondrial dynamics in Alzheimer's disease pathophysiology.

DOI: https://doi.org/10.1038/s41419-024-06543-7
Biochim Biophys Acta Rev Cancer. 2024 Mar 06. pii: S0304-419X(24)00020-9. [Epub ahead of print] 189089

Exploring the diverse role of pyruvate kinase M2 in cancer: Navigating beyond glycolysis and the Warburg effect.

Saurabh Upadhyay, Shumayila Khan, Md Imtaiyaz Hassan.

  Pyruvate Kinase M2, a key enzyme in glycolysis, has garnered significant attention in cancer research due to its pivotal role in the metabolic reprogramming of cancer cells. Originally identified for its association with the Warburg effect, PKM2 has emerged as a multifaceted player in cancer biology. The functioning of PKM2 is intricately regulated at multiple levels, including controlling the gene expression via various transcription factors and non-coding RNAs, as well as adding post-translational modifications that confer distinct functions to the protein. Here, we explore the diverse functions of PKM2, encompassing newly emerging roles in non-glycolytic metabolic regulation, immunomodulation, inflammation, DNA repair and mRNA processing, beyond its canonical role in glycolysis. The ever-expanding list of its functions has recently grown to include roles in subcellular compartments such as the mitochondria and extracellular milieu as well, all of which make PKM2 an attractive drug target in the pursuit of therapeutics for cancer.

Keywords:  Cancer therapeutics; Inflammation; Metabolic reprogramming; Pyruvate Kinase Muscle Isoform 2 (PKM2); Tumorigenesis; Warburg effect

DOI:  https://doi.org/10.1016/j.bbcan.2024.189089
Nat Commun. 2024 Mar 08. 15(1): 2142

Activity-dependent compartmentalization of dendritic mitochondria morphology through local regulation of fusion-fission balance in neurons in vivo.

Daniel M Virga, Stevie Hamilton, Bertha Osei, Abigail Morgan, Parker Kneis, Emiliano Zamponi, Natalie J Park, Victoria L Hewitt, David Zhang, Kevin C Gonzalez, Fiona M Russell, D Grahame Hardie, Julien Prudent, Erik Bloss, Attila Losonczy, Franck Polleux, Tommy L Lewis.

Neuronal mitochondria play important roles beyond ATP generation, including Ca2+ uptake, and therefore have instructive roles in synaptic function and neuronal response properties. Mitochondrial morphology differs significantly between the axon and dendrites of a given neuronal subtype, but in CA1 pyramidal neurons (PNs) of the hippocampus, mitochondria within the dendritic arbor also display a remarkable degree of subcellular, layer-specific compartmentalization. In the dendrites of these neurons, mitochondria morphology ranges from highly fused and elongated in the apical tuft, to more fragmented in the apical oblique and basal dendritic compartments, and thus occupy a smaller fraction of dendritic volume than in the apical tuft. However, the molecular mechanisms underlying this striking degree of subcellular compartmentalization of mitochondria morphology are unknown, precluding the assessment of its impact on neuronal function. Here, we demonstrate that this compartment-specific morphology of dendritic mitochondria requires activity-dependent, Ca2+ and Camkk2-dependent activation of AMPK and its ability to phosphorylate two direct effectors: the pro-fission Drp1 receptor Mff and the recently identified anti-fusion, Opa1-inhibiting protein, Mtfr1l. Our study uncovers a signaling pathway underlying the subcellular compartmentalization of mitochondrial morphology in dendrites of neurons in vivo through spatially precise and activity-dependent regulation of mitochondria fission/fusion balance.

DOI: https://doi.org/10.1038/s41467-024-46463-w
Front Oncol. 2024 ;14 1286896

Metabolomics analysis reveals novel serum metabolite alterations in cancer cachexia.

Tushar H More, Karsten Hiller, Martin Seifert, Thomas Illig, Rudi Schmidt, Raphael Gronauer, Thomas von Hahn, Hauke Weilert, Axel Stang.

   Background: Cachexia is a body wasting syndrome that significantly affects well-being and prognosis of cancer patients, without effective treatment. Serum metabolites take part in pathophysiological processes of cancer cachexia, but apart from altered levels of select serum metabolites, little is known on the global changes of the overall serum metabolome, which represents a functional readout of the whole-body metabolic state. Here, we aimed to comprehensively characterize serum metabolite alterations and analyze associated pathways in cachectic cancer patients to gain new insights that could help instruct strategies for novel interventions of greater clinical benefit.
Methods: Serum was sampled from 120 metastatic cancer patients (stage UICC IV). Patients were grouped as cachectic or non-cachectic according to the criteria for cancer cachexia agreed upon international consensus (main criterium: weight loss adjusted to body mass index). Samples were pooled by cachexia phenotype and assayed using non-targeted gas chromatography-mass spectrometry (GC-MS). Normalized metabolite levels were compared using t-test (p < 0.05, adjusted for false discovery rate) and partial least squares discriminant analysis (PLS-DA). Machine-learning models were applied to identify metabolite signatures for separating cachexia states. Significant metabolites underwent MetaboAnalyst 5.0 pathway analysis.
Results: Comparative analyses included 78 cachectic and 42 non-cachectic patients. Cachectic patients exhibited 19 annotable, significantly elevated (including glucose and fructose) or decreased (mostly amino acids) metabolites associating with aminoacyl-tRNA, glutathione and amino acid metabolism pathways. PLS-DA showed distinct clusters (accuracy: 85.6%), and machine-learning models identified metabolic signatures for separating cachectic states (accuracy: 83.2%; area under ROC: 88.0%). We newly identified altered blood levels of erythronic acid and glucuronic acid in human cancer cachexia, potentially linked to pentose-phosphate and detoxification pathways.
Conclusion: We found both known and yet unknown serum metabolite and metabolic pathway alterations in cachectic cancer patients that collectively support a whole-body metabolic state with impaired detoxification capability, altered glucose and fructose metabolism, and substrate supply for increased and/or distinct metabolic needs of cachexia-associated tumors. These findings together imply vulnerabilities, dependencies and targets for novel interventions that have potential to make a significant impact on future research in an important field of cancer patient care.

Keywords:  GC-MS metabolomics; body metabolism; cancer cachexia; erythronic acid; glucuronic acid; metabolic pathways; serum metabolites

DOI:  https://doi.org/10.3389/fonc.2024.1286896
PLoS One. 2024 ;19(3): e0300150

Real-time resolution studies of the regulation of lactate production by hexokinases binding to mitochondria in single cells.

Scott John, Guillaume Calmettes, Shili Xu, Bernard Ribalet.

During hypoxia accumulation of lactate may be a key factor in acidosis-induced tissue damage. Binding of hexokinase (HK) to the outer membrane of mitochondria may have a protective effect under these conditions. We have investigated the regulation of lactate metabolism by hexokinases (HKs), using HEK293 cells in which the endogenous hexokinases have been knocked down to enable overexpression of wild type and mutant HKs. To assess the real-time changes in intracellular lactate levels the cells were also transfected with a lactate specific FRET probe. In the HKI/HKII double knockdown HEK cells, addition of extracellular pyruvate caused a large and sustained decrease in lactate. Upon inhibition of the mitochondrial electron transfer chain by NaCN this effect was reversed as a rapid increase in lactate developed which was followed by a slow and sustained increase in the continued presence of the inhibitor. Incubation of the HKI/HKII double knockdown HEK cells with the inhibitor of the malic enzyme, ME1*, blocked the delayed accumulation of lactate evoked by NaCN. With replacement by overexpression of HKI or HKII the accumulation of intracellular lactate evoked by NaCN was prevented. Blockage of the pentose phosphate pathway with the inhibitor 6-aminonicotinamide (6-AN) abolished the protective effect of HK expression, with NaCN causing again a sustained increase in lactate. The effect of HK was dependent on HK's catalytic activity and interaction with the mitochondrial outer membrane (MOM). Based on these data we propose that transformation of glucose into G6P by HK activates the pentose phosphate pathway which increases the production of NADPH, which then blocks the activity of the malic enzyme to transform malate into pyruvate and lactate.

DOI: https://doi.org/10.1371/journal.pone.0300150
Nat Chem Biol. 2024 Mar 06.

Mitochondrial ATP generation is more proteome efficient than glycolysis.

Yihui Shen, Hoang V Dinh, Edward R Cruz, Zihong Chen, Caroline R Bartman, Tianxia Xiao, Catherine M Call, Rolf-Peter Ryseck, Jimmy Pratas, Daniel Weilandt, Heide Baron, Arjuna Subramanian, Zia Fatma, Zong-Yen Wu, Sudharsan Dwaraknath, John I Hendry, Vinh G Tran, Lifeng Yang, Yasuo Yoshikuni, Huimin Zhao, Costas D Maranas, Martin Wühr, Joshua D Rabinowitz.

Metabolic efficiency profoundly influences organismal fitness. Nonphotosynthetic organisms, from yeast to mammals, derive usable energy primarily through glycolysis and respiration. Although respiration is more energy efficient, some cells favor glycolysis even when oxygen is available (aerobic glycolysis, Warburg effect). A leading explanation is that glycolysis is more efficient in terms of ATP production per unit mass of protein (that is, faster). Through quantitative flux analysis and proteomics, we find, however, that mitochondrial respiration is actually more proteome efficient than aerobic glycolysis. This is shown across yeast strains, T cells, cancer cells, and tissues and tumors in vivo. Instead of aerobic glycolysis being valuable for fast ATP production, it correlates with high glycolytic protein expression, which promotes hypoxic growth. Aerobic glycolytic yeasts do not excel at aerobic growth but outgrow respiratory cells during oxygen limitation. We accordingly propose that aerobic glycolysis emerges from cells maintaining a proteome conducive to both aerobic and hypoxic growth.

DOI: https://doi.org/10.1038/s41589-024-01571-y
Biophys J. 2024 Mar 06. pii: S0006-3495(24)00176-0. [Epub ahead of print]

How and When to Measure Mitochondrial Inner Membrane Potentials.

Alicia J Kowaltowski, Fernando Abdulkader.

The scientific literature on mitochondria has increased significantly over the years, due to findings that these organelles have widespread roles in the onset and progression of pathological conditions such as metabolic disorders, neurodegenerative and cardiovascular diseases, inflammation, and cancer. Researchers have extensively explored how mitochondrial properties and functions are modified in different models, often using fluorescent inner mitochondrial membrane potential (ΔΨm) probes to assess functional mitochondrial aspects such as protonmotive force and oxidative phosphorylation. This review provides an overview of existing techniques to measure ΔpH and ΔΨm, highlighting their advantages, limitations, and applications. It discusses drawbacks of ΔΨm probes, especially when used without calibration, and conditions where alternative methods should replace ΔΨm measurements for the benefit of the specific scientific objectives entailed. Studies investigating mitochondria and their vast biological roles would be significantly advanced by the understanding of the correct applications as well as limitations of protonmotive force measurements and use of fluorescent ΔΨm probes, adopting more precise, artifact-free, sensitive, and quantitative measurements of mitochondrial functionality.

DOI: https://doi.org/10.1016/j.bpj.2024.03.011
Proc Natl Acad Sci U S A. 2024 Mar 12. 121(11): e2313354121

The metabolic domestication syndrome of budding yeast.

Roland Tengölics, Balázs Szappanos, Michael Mülleder, Dorottya Kalapis, Gábor Grézal, Csilla Sajben, Federica Agostini, João Benhur Mokochinski, Balázs Bálint, László G Nagy, Markus Ralser, Balázs Papp.

  Cellular metabolism evolves through changes in the structure and quantitative states of metabolic networks. Here, we explore the evolutionary dynamics of metabolic states by focusing on the collection of metabolite levels, the metabolome, which captures key aspects of cellular physiology. Using a phylogenetic framework, we profiled metabolites in 27 populations of nine budding yeast species, providing a graduated view of metabolic variation across multiple evolutionary time scales. Metabolite levels evolve more rapidly and independently of changes in the metabolic network's structure, providing complementary information to enzyme repertoire. Although metabolome variation accumulates mainly gradually over time, it is profoundly affected by domestication. We found pervasive signatures of convergent evolution in the metabolomes of independently domesticated clades of Saccharomyces cerevisiae. Such recurring metabolite differences between wild and domesticated populations affect a substantial part of the metabolome, including rewiring of the TCA cycle and several amino acids that influence aroma production, likely reflecting adaptation to human niches. Overall, our work reveals previously unrecognized diversity in central metabolism and the pervasive influence of human-driven selection on metabolite levels in yeasts.

Keywords:  Saccharomyces cerevisiae; convergent evolution; domestication; metabolomics; phylogenetic comparative methods

DOI:  https://doi.org/10.1073/pnas.2313354121
Autophagy. 2024 Mar 08. 1-2

Pink1 balances reticulophagy and mitophagy by regulating distinct E3 ubiquitin ligases.

Zhangyuan Yin, Daniel J Klionsky.

  The selective clearance of unwanted, damaged or dangerous components by macroautophagy/autophagy is critical for maintaining cellular homeostasis in organisms from yeast to humans. In recent years, significant progress has been made in understanding how phagophores selectively sequester specific cargo. Nevertheless, a fundamental question remains: Can distinct selective autophagy programs simultaneously operate within the same cell? A recent study from the Baehrecke lab has unveiled a developmentally programmed Pink1-dependent reticulophagy process in the Drosophila intestine. Furthermore, this study demonstrated that autophagy differentially clears mitochondria and ER in the same cell under the regulation of Pink1 through different E3 ubiquitin ligases, highlighting the need for further exploration in understanding the complexity of autophagic substrate selection and crosstalk between diverse autophagy programs.

Keywords:  Autophagy receptor; Keap1; Pink1; mitophagy; selective autophagy

DOI:  https://doi.org/10.1080/15548627.2024.2323294
J Cell Biol. 2024 Apr 01. pii: e202304075. [Epub ahead of print]223(4):

Two ancient membrane pores mediate mitochondrial-nucleus membrane contact sites.

Jana Ovciarikova, Shikha Shikha, Alice Lacombe, Flavie Courjol, Rosalind McCrone, Wasim Hussain, Andrew Maclean, Leandro Lemgruber, Erica S Martins-Duarte, Mathieu Gissot, Lilach Sheiner.

Coordination between nucleus and mitochondria is essential for cell survival, and thus numerous communication routes have been established between these two organelles over eukaryotic cell evolution. One route for organelle communication is via membrane contact sites, functional appositions formed by molecular tethers. We describe a novel nuclear-mitochondrial membrane contact site in the protozoan Toxoplasma gondii. We have identified specific contacts occurring at the nuclear pore and demonstrated an interaction between components of the nuclear pore and the mitochondrial protein translocon, highlighting them as molecular tethers. Genetic disruption of the nuclear pore or the TOM translocon components, TgNup503 or TgTom40, respectively, result in contact site reduction, supporting their potential involvement in this tether. TgNup503 depletion further leads to specific mitochondrial morphology and functional defects, supporting a role for nuclear-mitochondrial contacts in mediating their communication. The discovery of a contact formed through interaction between two ancient mitochondrial and nuclear complexes sets the ground for better understanding of mitochondrial-nuclear crosstalk in eukaryotes.

DOI: https://doi.org/10.1083/jcb.202304075
Autophagy. 2024 Mar 04. 1-15

Autophagy sustains mitochondrial respiration and determines resistance to BRAFV600E inhibition in thyroid carcinoma cells.

Sergio Díaz-Gago, Javier Vicente-Gutiérrez, Jose Manuel Ruiz-Rodríguez, Josep Calafell, Alicia Álvarez-Álvarez, Marina Lasa, Antonio Chiloeches, Pablo Baquero.

  BRAFV600E is the most prevalent mutation in thyroid cancer and correlates with poor prognosis and therapy resistance. Although selective inhibitors of BRAFV600E have been developed, more advanced tumors such as anaplastic thyroid carcinomas show a poor response in clinical trials. Therefore, the study of alternative survival mechanisms is needed. Since metabolic changes have been related to malignant progression, in this work we explore metabolic dependencies of thyroid tumor cells to exploit them therapeutically. Our results show that respiration of thyroid carcinoma cells is highly dependent on fatty acid oxidation and, in turn, fatty acid mitochondrial availability is regulated through macroautophagy/autophagy. Furthermore, we show that both lysosomal inhibition and the knockout of the essential autophagy gene, ATG7, lead to enhanced lipolysis; although this effect is not essential for survival of thyroid carcinoma cells. We also demonstrate that following inhibition of either autophagy or fatty acid oxidation, thyroid tumor cells compensate oxidative phosphorylation deficiency with an increase in glycolysis. In contrast to lipolysis induction, upon autophagy inhibition, glycolytic boost in autophagy-deficient cells is essential for survival and, importantly, correlates with a higher sensitivity to the BRAFV600E selective inhibitor, vemurafenib. In agreement, downregulation of the glycolytic pathway results in enhanced mitochondrial respiration and vemurafenib resistance. Our work provides new insights into the role of autophagy in thyroid cancer metabolism and supports mitochondrial targeting in combination with vemurafenib to eliminate BRAFV600E-positive thyroid carcinoma cells.Abbreviations: AMP: adenosine monophosphate; ATC: anaplastic thyroid carcinoma; ATG: autophagy related; ATP: adenosine triphosphate; BRAF: B-Raf proto-oncogene, serine/threonine kinase; Cas9: CRISPR-associated protein; CREB: cAMP responsive element binding protein; CRISPR: clustered regularly interspaced short palindromic repeats; 2DG: 2-deoxyglucose; FA: fatty acid; FAO: fatty acid oxidation; FASN: fatty acid synthase; FCCP: trifluoromethoxy carbonyl cyanide phenylhydrazone; LAMP1: lysosomal associated membrane protein 1; LIPE/HSL: lipase E, hormone sensitive type; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; OCR: oxygen consumption rate; OXPHOS: oxidative phosphorylation; PRKA/PKA: protein kinase cAMP-activated; PTC: papillary thyroid carcinoma; SREBF1/SREBP1: sterol regulatory element binding transcription factor 1.

Keywords:  Cancer metabolism; fatty acid oxidation; glycolysis; oxidative phosphorylation; thyroid cancer; vemurafenib resistance

DOI:  https://doi.org/10.1080/15548627.2024.2312790
Cell Commun Signal. 2024 Mar 06. 22(1): 163

Metabolism of asparagine in the physiological state and cancer.

Qiong Yuan, Liyang Yin, Jun He, Qiting Zeng, Yuxin Liang, Yingying Shen, Xuyu Zu.

  Asparagine, an important amino acid in mammals, is produced in several organs and is widely used for the production of other nutrients such as glucose, proteins, lipids, and nucleotides. Asparagine has also been reported to play a vital role in the development of cancer cells. Although several types of cancer cells can synthesise asparagine alone, their synthesis levels are insufficient to meet their requirements. These cells must rely on the supply of exogenous asparagine, which is why asparagine is considered a semi-essential amino acid. Therefore, nutritional inhibition by targeting asparagine is often considered as an anti-cancer strategy and has shown success in the treatment of leukaemia. However, asparagine limitation alone does not achieve an ideal therapeutic effect because of stress responses that upregulate asparagine synthase (ASNS) to meet the requirements for asparagine in cancer cells. Various cancer cells initiate different reprogramming processes in response to the deficiency of asparagine. Therefore, it is necessary to comprehensively understand the asparagine metabolism in cancers. This review primarily discusses the physiological role of asparagine and the current progress in the field of cancer research.

Keywords:  Asparaginase synthase; Asparagine; Cancer; Metabolism; Stress response

DOI:  https://doi.org/10.1186/s12964-024-01540-x
iScience. 2024 Mar 15. 27(3): 109188

MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors.

HaEun Kim, Benjamin Lebeau, David Papadopoli, Predrag Jovanovic, Mariana Russo, Daina Avizonis, Masahiro Morita, Farzaneh Afzali, Josie Ursini-Siegel, Lynne-Marie Postovit, Michael Witcher, Ivan Topisirovic.

  Emerging data suggest a significant cross-talk between metabolic and epigenetic programs. However, the relationship between the mechanistic target of rapamycin (mTOR), which is a pivotal metabolic regulator, and epigenetic modifications remains poorly understood. Our results show that mTORC1 activation caused by the abrogation of its negative regulator tuberous sclerosis complex 2 (TSC2) coincides with increased levels of the histone modification H3K27me3 but not H3K4me3 or H3K9me3. This selective H3K27me3 induction was mediated via 4E-BP-dependent increase in EZH2 protein levels. Surprisingly, mTOR inhibition also selectively induced H3K27me3. This was independent of TSC2, and was paralleled by reduced EZH2 and increased EZH1 protein levels. Notably, the ability of mTOR inhibitors to induce H3K27me3 levels was positively correlated with their anti-proliferative effects. Collectively, our findings demonstrate that both activation and inhibition of mTOR selectively increase H3K27me3 by distinct mechanisms, whereby the induction of H3K27me3 may potentiate the anti-proliferative effects of mTOR inhibitors.

Keywords:  Epigenetics; Molecular biology; Molecular mechanism of gene regulation

DOI:  https://doi.org/10.1016/j.isci.2024.109188
Cell Stem Cell. 2024 Mar 07. pii: S1934-5909(24)00047-X. [Epub ahead of print]31(3): 359-377.e10

A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate.

Massimo Bonora, Claudia Morganti, Nick van Gastel, Kyoko Ito, Enrica Calura, Ilaria Zanolla, Letizia Ferroni, Yang Zhang, Yookyung Jung, Gabriele Sales, Paolo Martini, Takahisa Nakamura, Francesco Massimo Lasorsa, Toren Finkel, Charles P Lin, Barbara Zavan, Paolo Pinton, Irene Georgakoudi, Chiara Romualdi, David T Scadden, Keisuke Ito.

  Mitochondrial fatty acid oxidation (FAO) is essential for hematopoietic stem cell (HSC) self-renewal; however, the mechanism by which mitochondrial metabolism controls HSC fate remains unknown. Here, we show that within the hematopoietic lineage, HSCs have the largest mitochondrial NADPH pools, which are required for proper HSC cell fate and homeostasis. Bioinformatic analysis of the HSC transcriptome, biochemical assays, and genetic inactivation of FAO all indicate that FAO-generated NADPH fuels cholesterol synthesis in HSCs. Interference with FAO disturbs the segregation of mitochondrial NADPH toward corresponding daughter cells upon single HSC division. Importantly, we have found that the FAO-NADPH-cholesterol axis drives extracellular vesicle (EV) biogenesis and release in HSCs, while inhibition of EV signaling impairs HSC self-renewal. These data reveal the existence of a mitochondrial NADPH-cholesterol axis for EV biogenesis that is required for hematopoietic homeostasis and highlight the non-stochastic nature of HSC fate determination.

Keywords:  HSC self-renewal; NADPH; cholesterol; exosomes; extracellular vesicles; fate determination; fatty acid oxidation; hematopoietic stem cell; metabolism; mitochondria

DOI:  https://doi.org/10.1016/j.stem.2024.02.004
Nat Metab. 2024 Mar 06.

Regulation of urea cycle by reversible high-stoichiometry lysine succinylation.

Ran Zhang, Jingqi Fang, Xueshu Xie, Chris Carrico, Jesse G Meyer, Lei Wei, Joanna Bons, Jacob Rose, Rebeccah Riley, Ryan Kwok, Prasanna Vadhana Ashok Kumaar, Yini Zhang, Wenjuan He, Yuya Nishida, Xiaojing Liu, Jason W Locasale, Birgit Schilling, Eric Verdin.

The post-translational modification lysine succinylation is implicated in the regulation of various metabolic pathways. However, its biological relevance remains uncertain due to methodological difficulties in determining high-impact succinylation sites. Here, using stable isotope labelling and data-independent acquisition mass spectrometry, we quantified lysine succinylation stoichiometries in mouse livers. Despite the low overall stoichiometry of lysine succinylation, several high-stoichiometry sites were identified, especially upon deletion of the desuccinylase SIRT5. In particular, multiple high-stoichiometry lysine sites identified in argininosuccinate synthase (ASS1), a key enzyme in the urea cycle, are regulated by SIRT5. Mutation of the high-stoichiometry lysine in ASS1 to succinyl-mimetic glutamic acid significantly decreased its enzymatic activity. Metabolomics profiling confirms that SIRT5 deficiency decreases urea cycle activity in liver. Importantly, SIRT5 deficiency compromises ammonia tolerance, which can be reversed by the overexpression of wild-type, but not succinyl-mimetic, ASS1. Therefore, lysine succinylation is functionally important in ammonia metabolism.

DOI: https://doi.org/10.1038/s42255-024-01005-y
Nat Cell Biol. 2024 Mar 07.

Lipid droplets and cellular lipid flux.

Alyssa J Mathiowetz, James A Olzmann.

Lipid droplets are dynamic organelles that store neutral lipids, serve the metabolic needs of cells, and sequester lipids to prevent lipotoxicity and membrane damage. Here we review the current understanding of the mechanisms of lipid droplet biogenesis and turnover, the transfer of lipids and metabolites at membrane contact sites, and the role of lipid droplets in regulating fatty acid flux in lipotoxicity and cell death.

DOI: https://doi.org/10.1038/s41556-024-01364-4
Cell Metab. 2024 Mar 05. pii: S1550-4131(24)00052-4. [Epub ahead of print]36(3): 463-465

Supercharging cancer-fighting T cells with lithium carbonate.

Yue Xu, Kaili Ma, Lianjun Zhang, Guideng Li.

Lactate influences the behavior of various immune cell types. In a recent Nature Immunology study, Ma et al. revealed that lithium carbonate induces monocarboxylate transporter 1 translocation to mitochondria, enhancing cytoplasmic lactate transport into the mitochondria and increasing lactate mitochondrial metabolism, thereby promoting T cell effector function.

DOI: https://doi.org/10.1016/j.cmet.2024.02.006
Nat Commun. 2024 Mar 02. 15(1): 1931

Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing.

Martha M Zarou, Kevin M Rattigan, Daniele Sarnello, Engy Shokry, Amy Dawson, Angela Ianniciello, Karen Dunn, Mhairi Copland, David Sumpton, Alexei Vazquez, G Vignir Helgason.

Supporting cell proliferation through nucleotide biosynthesis is an essential requirement for cancer cells. Hence, inhibition of folate-mediated one carbon (1C) metabolism, which is required for nucleotide synthesis, has been successfully exploited in anti-cancer therapy. Here, we reveal that mitochondrial folate metabolism is upregulated in patient-derived leukaemic stem cells (LSCs). We demonstrate that inhibition of mitochondrial 1C metabolism through impairment of de novo purine synthesis has a cytostatic effect on chronic myeloid leukaemia (CML) cells. Consequently, changes in purine nucleotide levels lead to activation of AMPK signalling and suppression of mTORC1 activity. Notably, suppression of mitochondrial 1C metabolism increases expression of erythroid differentiation markers. Moreover, we find that increased differentiation occurs independently of AMPK signalling and can be reversed through reconstitution of purine levels and reactivation of mTORC1. Of clinical relevance, we identify that combination of 1C metabolism inhibition with imatinib, a frontline treatment for CML patients, decreases the number of therapy-resistant CML LSCs in a patient-derived xenograft model. Our results highlight a role for folate metabolism and purine sensing in stem cell fate decisions and leukaemogenesis.

DOI: https://doi.org/10.1038/s41467-024-46114-0
PLoS Pathog. 2024 Mar;20(3): e1012036

Modulation of nucleotide metabolism by picornaviruses.

Lonneke V Nouwen, Martijn Breeuwsma, Esther A Zaal, Chris H A van de Lest, Inge Buitendijk, Marleen Zwaagstra, Pascal Balić, Dmitri V Filippov, Celia R Berkers, Frank J M van Kuppeveld.

Viruses actively reprogram the metabolism of the host to ensure the availability of sufficient building blocks for virus replication and spreading. However, relatively little is known about how picornaviruses-a large family of small, non-enveloped positive-strand RNA viruses-modulate cellular metabolism for their own benefit. Here, we studied the modulation of host metabolism by coxsackievirus B3 (CVB3), a member of the enterovirus genus, and encephalomyocarditis virus (EMCV), a member of the cardiovirus genus, using steady-state as well as 13C-glucose tracing metabolomics. We demonstrate that both CVB3 and EMCV increase the levels of pyrimidine and purine metabolites and provide evidence that this increase is mediated through degradation of nucleic acids and nucleotide recycling, rather than upregulation of de novo synthesis. Finally, by integrating our metabolomics data with a previously acquired phosphoproteomics dataset of CVB3-infected cells, we identify alterations in phosphorylation status of key enzymes involved in nucleotide metabolism, providing insight into the regulation of nucleotide metabolism during infection.

DOI: https://doi.org/10.1371/journal.ppat.1012036
Nat Metab. 2024 Mar 08.

Futile lipid cycling: from biochemistry to physiology.

Anand Kumar Sharma, Radhika Khandelwal, Christian Wolfrum.

In the healthy state, the fat stored in our body isn't just inert. Rather, it is dynamically mobilized to maintain an adequate concentration of fatty acids (FAs) in our bloodstream. Our body tends to produce excess FAs to ensure that the FA availability is not limiting. The surplus FAs are actively re-esterified into glycerides, initiating a cycle of breakdown and resynthesis of glycerides. This cycle consumes energy without generating a new product and is commonly referred to as the 'futile lipid cycle' or the glyceride/FA cycle. Contrary to the notion that it's a wasteful process, it turns out this cycle is crucial for systemic metabolic homeostasis. It acts as a control point in intra-adipocyte and inter-organ cross-talk, a metabolic rheostat, an energy sensor and a lipid diversifying mechanism. In this Review, we discuss the metabolic regulation and physiological implications of the glyceride/FA cycle and its mechanistic underpinnings.

DOI: https://doi.org/10.1038/s42255-024-01003-0
Trends Cell Biol. 2024 Mar 01. pii: S0962-8924(24)00025-4. [Epub ahead of print]

Metabolic regulation of mRNA splicing.

Haissi Cui, Qingyu Shi, Colette Maya Macarios, Paul Schimmel.

  Alternative mRNA splicing enables the diversification of the proteome from a static genome and confers plasticity and adaptiveness on cells. Although this is often explored in development, where hard-wired programs drive the differentiation and specialization, alternative mRNA splicing also offers a way for cells to react to sudden changes in outside stimuli such as small-molecule metabolites. Fluctuations in metabolite levels and availability in particular convey crucial information to which cells react and adapt. We summarize and highlight findings surrounding the metabolic regulation of mRNA splicing. We discuss the principles underlying the biochemistry and biophysical properties of mRNA splicing, and propose how these could intersect with metabolite levels. Further, we present examples in which metabolites directly influence RNA-binding proteins and splicing factors. We also discuss the interplay between alternative mRNA splicing and metabolite-responsive signaling pathways. We hope to inspire future research to obtain a holistic picture of alternative mRNA splicing in response to metabolic cues.

Keywords:  RNA; amino acid; glucose; mRNA splicing; metabolite

DOI:  https://doi.org/10.1016/j.tcb.2024.02.002
J Exp Clin Cancer Res. 2024 Mar 08. 43(1): 74

A glutamine tug-of-war between cancer and immune cells: recent advances in unraveling the ongoing battle.

Bolin Wang, Jinli Pei, Shengnan Xu, Jie Liu, Jinming Yu.

  Glutamine metabolism plays a pivotal role in cancer progression, immune cell function, and the modulation of the tumor microenvironment. Dysregulated glutamine metabolism has been implicated in cancer development and immune responses, supported by mounting evidence. Cancer cells heavily rely on glutamine as a critical nutrient for survival and proliferation, while immune cells require glutamine for activation and proliferation during immune reactions. This metabolic competition creates a dynamic tug-of-war between cancer and immune cells. Targeting glutamine transporters and downstream enzymes involved in glutamine metabolism holds significant promise in enhancing anti-tumor immunity. A comprehensive understanding of the intricate molecular mechanisms underlying this interplay is crucial for developing innovative therapeutic approaches that improve anti-tumor immunity and patient outcomes. In this review, we provide a comprehensive overview of recent advances in unraveling the tug-of-war of glutamine metabolism between cancer and immune cells and explore potential applications of basic science discoveries in the clinical setting. Further investigations into the regulation of glutamine metabolism in cancer and immune cells are expected to yield valuable insights, paving the way for future therapeutic interventions.

Keywords:  Cancer; Glutamine metabolism; Immune cells; Therapeutic strategies; Tumor microenvironment

DOI:  https://doi.org/10.1186/s13046-024-02994-0
Nat Chem Biol. 2024 Mar 08.

Aerobic glycolysis comes with an enzyme cost but robustness gain.

DOI: https://doi.org/10.1038/s41589-024-01581-w
Cell Metab. 2024 Mar 01. pii: S1550-4131(24)00050-0. [Epub ahead of print]

Hepatic malonyl-CoA synthesis restrains gluconeogenesis by suppressing fat oxidation, pyruvate carboxylation, and amino acid availability.

Stanislaw Deja, Justin A Fletcher, Chai-Wan Kim, Blanka Kucejova, Xiaorong Fu, Monika Mizerska, Morgan Villegas, Natalia Pudelko-Malik, Nicholas Browder, Melissa Inigo-Vollmer, Cameron J Menezes, Prashant Mishra, Eric D Berglund, Jeffrey D Browning, John P Thyfault, Jamey D Young, Jay D Horton, Shawn C Burgess.

  Acetyl-CoA carboxylase (ACC) promotes prandial liver metabolism by producing malonyl-CoA, a substrate for de novo lipogenesis and an inhibitor of CPT-1-mediated fat oxidation. We report that inhibition of ACC also produces unexpected secondary effects on metabolism. Liver-specific double ACC1/2 knockout (LDKO) or pharmacologic inhibition of ACC increased anaplerosis, tricarboxylic acid (TCA) cycle intermediates, and gluconeogenesis by activating hepatic CPT-1 and pyruvate carboxylase flux in the fed state. Fasting should have marginalized the role of ACC, but LDKO mice maintained elevated TCA cycle intermediates and preserved glycemia during fasting. These effects were accompanied by a compensatory induction of proteolysis and increased amino acid supply for gluconeogenesis, which was offset by increased protein synthesis during feeding. Such adaptations may be related to Nrf2 activity, which was induced by ACC inhibition and correlated with fasting amino acids. The findings reveal unexpected roles for malonyl-CoA synthesis in liver and provide insight into the broader effects of pharmacologic ACC inhibition.

Keywords:  Nrf2; TCA cycle; acetyl-CoA carboxylase; anaplerosis; autophagy; gluconeogenesis; lipogenesis; malonyl-CoA; protein synthesis; proteolysis

DOI:  https://doi.org/10.1016/j.cmet.2024.02.004