bims-camemi 2023-04-23 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2023‒04‒23
48 papers selected by
Christian Frezza, Universität zu Köln

Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis.
Learning the metabolic language of cancer.
Uncoupled glycerol-3-phosphate shuttle in kidney cancer reveals that cytosolic GPD is essential to support lipid synthesis.
Mitochondrial GTP Metabolism Regulates Reproductive Aging.
Pyruvate-supported flux through medium-chain ketothiolase promotes mitochondrial lipid tolerance in cardiac and skeletal muscles.
Isocitrate dehydrogenase 1 sustains a hybrid cytoplasmic-mitochondrial tricarboxylic acid cycle that can be targeted for therapeutic purposes in prostate cancer.
Fructose-1,6-bisphosphatase is a nonenzymatic safety valve that curtails AKT activation to prevent insulin hyperresponsiveness.
Extracellular Domains of CAR Reprogram T-Cell Metabolism Without Antigen Stimulation.
Genetic perturbation of mitochondrial function reveals functional role for specific mitonuclear genes, metabolites, and pathways that regulate lifespan.
Autophagy supports mitochondrial metabolism through the regulation of iron homeostasis in pancreatic cancer.
An SPNS1-dependent lysosomal lipid transport pathway that enables cell survival under choline limitation.
Measuring Mitochondrial Uncoupling in Mouse Primary Brown Adipocytes Differentiated Ex Vivo.
A rapid microglial metabolic response controls metabolism and improves memory.
Are some mutations more equal than others?
ZFP36-mediated mRNA decay regulates metabolism.
Reduced methionine synthase expression results in uracil accumulation in mitochondrial DNA and impaired oxidative capacity.
NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency.
The mitochondrion of Plasmodium falciparum is required for cellular acetyl-CoA metabolism and protein acetylation.
Insufficient evidence for non-neutrality of synonymous mutations.
Low production of mitochondrial reactive oxygen species after anoxia and reoxygenation in turtle hearts.
Impact of context-dependent autophagy states on tumor progression.
Induction of lysosomal and mitochondrial biogenesis by AMPK phosphorylation of FNIP1.
The nutrient-sensing GCN2 signaling pathway is essential for circadian clock function by regulating histone acetylation under amino acid starvation.
FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity.
AMPK activation protects against prostate cancer by inducing a catabolic cellular state.
Copy number variation in tRNA isodecoder genes impairs mammalian development and balanced translation.
Modeling collective cell behavior in cancer: Perspectives from an interdisciplinary conversation.
Enzyme lights dual fires to promote cancer.
Li-Fraumeni Syndrome-Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death.
Assessment of Bioenergetics in BAT Mitochondria.
Mitochondrial Membrane Potential Instability on Reperfusion After Ischemia Does Not Depend on Mitochondrial Ca2+ Uptake.
Hepatocyte SREBP signaling mediates clock communication within the liver.
Cellular signals integrate cell cycle and metabolic control in cancer.
Nutrient-sensing AgRP neurons relay control of liver autophagy during energy deprivation.
DNMT1 mutant ants develop normally but have disrupted oogenesis.
Convergent genomic diversity and novel BCAA metabolism in intrahepatic cholangiocarcinoma.
Allosteric role of the citrate synthase homology domain of ATP citrate lyase.
Amino acids downregulate SIRT4 to detoxify ammonia through the urea cycle.
Thermogenic Phenotyping in Mice.
The metabolic cross-talk between cancer and T cells.
Integrated glycoproteomic characterization of clear cell renal cell carcinoma.
Dynamic fluctuations in a bacterial metabolic network.
PI3Kβ controls immune evasion in PTEN-deficient breast tumours.
The proteomic landscape of genome-wide genetic perturbations.
Succinate signalling regulates leptin production in adipocytes.
Characterization of methionine dependence in melanoma cells.
Mechanisms of division of labor in mammalian tissue.
Oncogenic CDK13 mutations impede nuclear RNA surveillance.

Nat Commun. 2023 04 17. 14(1): 2194

Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis.

Ziheng Chen, I-Lin Ho, Melinda Soeung, Er-Yen Yen, Jintan Liu, Liang Yan, Johnathon L Rose, Sanjana Srinivasan, Shan Jiang, Q Edward Chang, Ningping Feng, Jason P Gay, Qi Wang, Jing Wang, Philip L Lorenzi, Lucas J Veillon, Bo Wei, John N Weinstein, Angela K Deem, Sisi Gao, Giannicola Genovese, Andrea Viale, Wantong Yao, Costas A Lyssiotis, Joseph R Marszalek, Giulio F Draetta, Haoqiang Ying.

Mitochondria are hubs where bioenergetics, redox homeostasis, and anabolic metabolism pathways integrate through a tightly coordinated flux of metabolites. The contributions of mitochondrial metabolism to tumor growth and therapy resistance are evident, but drugs targeting mitochondrial metabolism have repeatedly failed in the clinic. Our study in pancreatic ductal adenocarcinoma (PDAC) finds that cellular and mitochondrial lipid composition influence cancer cell sensitivity to pharmacological inhibition of electron transport chain complex I. Profiling of patient-derived PDAC models revealed that monounsaturated fatty acids (MUFAs) and MUFA-linked ether phospholipids play a critical role in maintaining ROS homeostasis. We show that ether phospholipids support mitochondrial supercomplex assembly and ROS production; accordingly, blocking de novo ether phospholipid biosynthesis sensitized PDAC cells to complex I inhibition by inducing mitochondrial ROS and lipid peroxidation. These data identify ether phospholipids as a regulator of mitochondrial redox control that contributes to the sensitivity of PDAC cells to complex I inhibition.

DOI: https://doi.org/10.1038/s41467-023-37924-9
Nature. 2023 Apr;616(7958): 670-671

Learning the metabolic language of cancer.

Minervo Perez, Jordan L Meier.



Keywords:  Cancer; Cell biology; Metabolism

DOI:  https://doi.org/10.1038/d41586-023-01024-x
Mol Cell. 2023 Apr 20. pii: S1097-2765(23)00213-7. [Epub ahead of print]83(8): 1340-1349.e7

Uncoupled glycerol-3-phosphate shuttle in kidney cancer reveals that cytosolic GPD is essential to support lipid synthesis.

Cong-Hui Yao, Joon Seok Park, Kiran Kurmi, Song-Hua Hu, Giulia Notarangelo, Joseph Crowley, Heidi Jacobson, Sheng Hui, Arlene H Sharpe, Marcia C Haigis.

  The glycerol-3-phosphate shuttle (G3PS) is a major NADH shuttle that regenerates reducing equivalents in the cytosol and produces energy in the mitochondria. Here, we demonstrate that G3PS is uncoupled in kidney cancer cells where the cytosolic reaction is ∼4.5 times faster than the mitochondrial reaction. The high flux through cytosolic glycerol-3-phosphate dehydrogenase (GPD) is required to maintain redox balance and support lipid synthesis. Interestingly, inhibition of G3PS by knocking down mitochondrial GPD (GPD2) has no effect on mitochondrial respiration. Instead, loss of GPD2 upregulates cytosolic GPD on a transcriptional level and promotes cancer cell proliferation by increasing glycerol-3-phosphate supply. The proliferative advantage of GPD2 knockdown tumor can be abolished by pharmacologic inhibition of lipid synthesis. Taken together, our results suggest that G3PS is not required to run as an intact NADH shuttle but is instead truncated to support complex lipid synthesis in kidney cancer.

Keywords:  GPD; NAD; glycerol; glycerol-3-phosphate dehydrogenase; glycerol-3-phosphate shuttle; kidney cancer; lipids; metabolism; mitochondria

DOI:  https://doi.org/10.1016/j.molcel.2023.03.023
bioRxiv. 2023 Apr 03. pii: 2023.04.02.535296. [Epub ahead of print]

Mitochondrial GTP Metabolism Regulates Reproductive Aging.

Yi-Tang Lee, Marzia Savini, Tao Chen, Jin Yang, Qian Zhao, Lang Ding, Shihong Max Gao, Mumine Senturk, Jessica Sowa, Jue D Wang, Meng C Wang.

Healthy mitochondria are critical for reproduction. During aging, both reproductive fitness and mitochondrial homeostasis decline. Mitochondrial metabolism and dynamics are key factors in supporting mitochondrial homeostasis. However, how they are coupled to control reproductive health remains unclear. We report that mitochondrial GTP metabolism acts through mitochondrial dynamics factors to regulate reproductive aging. We discovered that germline-only inactivation of GTP- but not ATP-specific succinyl-CoA synthetase (SCS), promotes reproductive longevity in Caenorhabditis elegans. We further revealed an age-associated increase in mitochondrial clustering surrounding oocyte nuclei, which is attenuated by the GTP-specific SCS inactivation. Germline-only induction of mitochondrial fission factors sufficiently promotes mitochondrial dispersion and reproductive longevity. Moreover, we discovered that bacterial inputs affect mitochondrial GTP and dynamics factors to modulate reproductive aging. These results demonstrate the significance of mitochondrial GTP metabolism in regulating oocyte mitochondrial homeostasis and reproductive longevity and reveal mitochondrial fission induction as an effective strategy to improve reproductive health.

DOI: https://doi.org/10.1101/2023.04.02.535296
Cell Metab. 2023 Apr 11. pii: S1550-4131(23)00094-3. [Epub ahead of print]

Pyruvate-supported flux through medium-chain ketothiolase promotes mitochondrial lipid tolerance in cardiac and skeletal muscles.

Timothy R Koves, Guo-Fang Zhang, Michael T Davidson, Alec B Chaves, Scott B Crown, Jordan M Johnson, Dorothy H Slentz, Paul A Grimsrud, Deborah M Muoio.

  Even-chain acylcarnitine (AC) metabolites, most of which are generated as byproducts of incomplete fatty acid oxidation (FAO), are viewed as biomarkers of mitochondrial lipid stress attributable to one or more metabolic bottlenecks in the β-oxidation pathway. The origins and functional implications of FAO bottlenecks remain poorly understood. Here, we combined a sophisticated mitochondrial phenotyping platform with state-of-the-art molecular profiling tools and multiple two-state mouse models of respiratory function to uncover a mechanism that connects AC accumulation to lipid intolerance, metabolic inflexibility, and respiratory inefficiency in skeletal muscle mitochondria. These studies also identified a short-chain carbon circuit at the C4 node of FAO wherein reverse flux of glucose-derived acetyl CoA through medium-chain ketothiolase enhances lipid tolerance and redox stability in heart mitochondria by regenerating free CoA and NAD+. The findings help to explain why diminished FAO capacity, AC accumulation, and metabolic inflexibility are tightly linked to poor health outcomes.

Keywords:  acylcarnitines; bioenergetics; exercise; fatty acid oxidation; heart; ketothiolase; metabolic flexibility; mitochondria; pyruvate; skeletal muscle

DOI:  https://doi.org/10.1016/j.cmet.2023.03.016
Mol Oncol. 2023 Apr 22.

Isocitrate dehydrogenase 1 sustains a hybrid cytoplasmic-mitochondrial tricarboxylic acid cycle that can be targeted for therapeutic purposes in prostate cancer.

Kevin Gonthier, Cindy Weidmann, Line Berthiaume, Cynthia Jobin, Aurélie Lacouture, Camille Lafront, Mario Harvey, Bertrand Neveu, Jérémy Loehr, Alain Bergeron, Yves Fradet, Louis Lacombe, Julie Riopel, Éva Latulippe, Chantal Atallah, Michael Shum, Jean-Philippe Lambert, Frédéric Pouliot, Martin Pelletier, Étienne Audet-Walsh.

  The androgen receptor (AR) is an established orchestrator of cell metabolism in prostate cancer (PCa), notably by inducing an oxidative mitochondrial program. Intriguingly, AR regulates cytoplasmic isocitrate dehydrogenase 1 (IDH1) but not its mitochondrial counterparts IDH2 and IDH3. Here, we aimed to understand the functional role of IDH1 in PCa. Mouse models, in vitro human PCa cell lines, and human patient-derived organoids (PDOs) were used to study the expression and activity of IDH enzymes in the normal prostate and PCa. Genetic and pharmacological inhibition of IDH1 was then combined with extracellular flux analysis and gas chromatography-mass spectrometry for metabolomic analyses and cancer cell proliferation in vitro and in vivo. In PCa cells, more than 90% of the total IDH activity is mediated through IDH1 rather than its mitochondrial counterparts. This profile seems to originate from the specialized prostate metabolic program, as observed using mouse prostate and PDOs. Pharmacological and genetic inhibition of IDH1 impaired mitochondrial respiration, suggesting that this cytoplasmic enzyme contributes to the mitochondrial tricarboxylic acid cycle (TCA) in PCa. Mass spectrometry-based metabolomics confirmed this hypothesis, showing that inhibition of IDH1 impairs carbon flux into the TCA cycle. Consequently, inhibition of IDH1 decreased PCa cell proliferation in vitro and in vivo. These results demonstrate that PCa cells have a hybrid cytoplasmic-mitochondrial TCA cycle that depends on IDH1. This metabolic enzyme represents a metabolic vulnerability of PCa cells and a potential new therapeutic target.

Keywords:  IDH1; androgen receptor; castration-resistant prostate cancer; citric acid; mitochondria; nuclear receptor

DOI:  https://doi.org/10.1002/1878-0261.13441
Cell Metab. 2023 Apr 12. pii: S1550-4131(23)00126-2. [Epub ahead of print]

Fructose-1,6-bisphosphatase is a nonenzymatic safety valve that curtails AKT activation to prevent insulin hyperresponsiveness.

Li Gu, Yahui Zhu, Kosuke Watari, Maiya Lee, Junlai Liu, Sofia Perez, Melinda Thai, Joshua E Mayfield, Bichen Zhang, Karina Cunha E Rocha, Fuming Li, Laura C Kim, Alexander C Jones, Igor H Wierzbicki, Xiao Liu, Alexandra C Newton, Tatiana Kisseleva, Jun Hee Lee, Wei Ying, David J Gonzalez, Alan R Saltiel, M Celeste Simon, Michael Karin.

  Insulin inhibits gluconeogenesis and stimulates glucose conversion to glycogen and lipids. How these activities are coordinated to prevent hypoglycemia and hepatosteatosis is unclear. Fructose-1,6-bisphosphatase (FBP1) is rate controlling for gluconeogenesis. However, inborn human FBP1 deficiency does not cause hypoglycemia unless accompanied by fasting or starvation, which also trigger paradoxical hepatomegaly, hepatosteatosis, and hyperlipidemia. Hepatocyte FBP1-ablated mice exhibit identical fasting-conditional pathologies along with AKT hyperactivation, whose inhibition reversed hepatomegaly, hepatosteatosis, and hyperlipidemia but not hypoglycemia. Surprisingly, fasting-mediated AKT hyperactivation is insulin dependent. Independently of its catalytic activity, FBP1 prevents insulin hyperresponsiveness by forming a stable complex with AKT, PP2A-C, and aldolase B (ALDOB), which specifically accelerates AKT dephosphorylation. Enhanced by fasting and weakened by elevated insulin, FBP1:PP2A-C:ALDOB:AKT complex formation, which is disrupted by human FBP1 deficiency mutations or a C-terminal FBP1 truncation, prevents insulin-triggered liver pathologies and maintains lipid and glucose homeostasis. Conversely, an FBP1-derived complex disrupting peptide reverses diet-induced insulin resistance.

Keywords:  AKT; FBP1; hepatomegaly; hepatosteatosis

DOI:  https://doi.org/10.1016/j.cmet.2023.03.021
bioRxiv. 2023 Apr 04. pii: 2023.04.03.533021. [Epub ahead of print]

Extracellular Domains of CAR Reprogram T-Cell Metabolism Without Antigen Stimulation.

Aliya Lakhani, Ximin Chen, Laurence C Chen, Mobina Khericha, Yvonne Y Chen, Junyoung O Park.

Metabolism is an indispensable part of T-cell proliferation, activation, and exhaustion, yet the metabolism of chimeric antigen receptor (CAR)-T cells remains incompletely understood. CARs are comprised of extracellular domains that determine cancer specificity, often using single-chain variable fragments (scFvs), and intracellular domains that trigger signaling upon antigen binding. Here we show that CARs differing only in the scFv reprogram T-cell metabolism differently. Even in the absence of antigens, some CARs increase proliferation and nutrient uptake in T cells. Using stable isotope tracers and mass spectrometry, we observe basal metabolic fluxes through glycolysis doubling and amino acid uptake overtaking anaplerosis in CAR-T cells harboring rituximab scFv, unlike other similar anti-CD20 scFvs. Disparate rituximab and 14g2a-based anti-GD2 CAR-T cells are similarly hypermetabolic and channel excess nutrients to nitrogen overflow metabolism. Since CAR-dependent metabolic reprogramming alters cellular energetics, nutrient utilization, and proliferation, metabolic profiling should be an integral part of CAR-T cell development.

DOI: https://doi.org/10.1101/2023.04.03.533021
Geroscience. 2023 Apr 22.

Genetic perturbation of mitochondrial function reveals functional role for specific mitonuclear genes, metabolites, and pathways that regulate lifespan.

Cheryl Zi Jin Phua, Xiaqing Zhao, Lesly Turcios-Hernandez, Morrigan McKernan, Morteza Abyadeh, Siming Ma, Daniel Promislow, Matt Kaeberlein, Alaattin Kaya.

  Altered mitochondrial function is tightly linked to lifespan regulation, but underlying mechanisms remain unclear. Here, we report the chronological and replicative lifespan variation across 167 yeast knock-out strains, each lacking a single nuclear-coded mitochondrial gene, including 144 genes with human homologs, many associated with diseases. We dissected the signatures of observed lifespan differences by analyzing profiles of each strain's proteome, lipidome, and metabolome under fermentative and respiratory culture conditions, which correspond to the metabolic states of replicative and chronologically aging cells, respectively. Examination of the relationships among extended longevity phenotypes, protein, and metabolite levels revealed that although many of these nuclear-encoded mitochondrial genes carry out different functions, their inhibition attenuates a common mechanism that controls cytosolic ribosomal protein abundance, actin dynamics, and proteasome function to regulate lifespan. The principles of lifespan control learned through this work may be applicable to the regulation of lifespan in more complex organisms, since many aspects of mitochondrial function are highly conserved among eukaryotes.

Keywords:  Aging; Metabolism; Mitochondrial proteins; Omics; Yeast

DOI:  https://doi.org/10.1007/s11357-023-00796-4
Sci Adv. 2023 04 21. 9(16): eadf9284

Autophagy supports mitochondrial metabolism through the regulation of iron homeostasis in pancreatic cancer.

Subhadip Mukhopadhyay, Joel Encarnación-Rosado, Elaine Y Lin, Albert S W Sohn, Huan Zhang, Joseph D Mancias, Alec C Kimmelman.

Pancreatic ductal adenocarcinoma (PDAC) cells maintain a high level of autophagy, allowing them to thrive in an austere microenvironment. However, the processes through which autophagy promotes PDAC growth and survival are still not fully understood. Here, we show that autophagy inhibition in PDAC alters mitochondrial function by losing succinate dehydrogenase complex iron sulfur subunit B expression by limiting the availability of the labile iron pool. PDAC uses autophagy to maintain iron homeostasis, while other tumor types assessed require macropinocytosis, with autophagy being dispensable. We observed that cancer-associated fibroblasts can provide bioavailable iron to PDAC cells, promoting resistance to autophagy ablation. To overcome this cross-talk, we used a low-iron diet and demonstrated that this augmented the response to autophagy inhibition therapy in PDAC-bearing mice. Our work highlights a critical link between autophagy, iron metabolism, and mitochondrial function that may have implications for PDAC progression.

DOI: https://doi.org/10.1126/sciadv.adf9284
Sci Adv. 2023 04 21. 9(16): eadf8966

An SPNS1-dependent lysosomal lipid transport pathway that enables cell survival under choline limitation.

Samantha G Scharenberg, Wentao Dong, Ali Ghoochani, Kwamina Nyame, Roni Levin-Konigsberg, Aswini R Krishnan, Eshaan S Rawat, Kaitlyn Spees, Michael C Bassik, Monther Abu-Remaileh.

Lysosomes degrade macromolecules and recycle their nutrient content to support cell function and survival. However, the machineries involved in lysosomal recycling of many nutrients remain to be discovered, with a notable example being choline, an essential metabolite liberated via lipid degradation. Here, we engineered metabolic dependency on lysosome-derived choline in pancreatic cancer cells to perform an endolysosome-focused CRISPR-Cas9 screen for genes mediating lysosomal choline recycling. We identified the orphan lysosomal transmembrane protein SPNS1 as critical for cell survival under choline limitation. SPNS1 loss leads to intralysosomal accumulation of lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE). Mechanistically, we reveal that SPNS1 is a proton gradient-dependent transporter of LPC species from the lysosome for their re-esterification into phosphatidylcholine in the cytosol. Last, we establish that LPC efflux by SPNS1 is required for cell survival under choline limitation. Collectively, our work defines a lysosomal phospholipid salvage pathway that is essential under nutrient limitation and, more broadly, provides a robust platform to deorphan lysosomal gene function.

DOI: https://doi.org/10.1126/sciadv.adf8966
Methods Mol Biol. 2023 ;2662 53-65

Measuring Mitochondrial Uncoupling in Mouse Primary Brown Adipocytes Differentiated Ex Vivo.

Michaela Veliova, Marcus J Tol, Peter Tontonoz, Orian S Shirihai, Marc Liesa.

  Measuring the mitochondrial respiratory capacity of brown adipocytes ex vivo is an essential approach to understand the cell-autonomous regulators of mitochondrial uncoupling in brown adipose tissue. Here, we describe two protocols to isolate brown preadipocytes from mice, their ex vivo differentiation to mature brown adipocytes and the quantification of their mitochondrial uncoupling capacity by respirometry.

Keywords:  Brown adipocytes; Mitochondria; Respirometry; Thermogenesis; Uncoupling

DOI:  https://doi.org/10.1007/978-1-0716-3167-6_5
bioRxiv. 2023 Apr 04. pii: 2023.04.03.535373. [Epub ahead of print]

A rapid microglial metabolic response controls metabolism and improves memory.

Anne Drougard, Eric H Ma, Vanessa Wegert, Ryan Sheldon, Ilaria Panzeri, Naman Vatsa, Stefanos Apostle, Luca Fagnocchi, Judith Schaf, Klaus Gossens, Josephine Völker, Shengru Pang, Anna Bremser, Erez Dror, Francesca Giacona, Sagar, Michael X Henderson, Marco Prinz, Russell G Jones, J Andrew Pospisilik.

Chronic high-fat feeding triggers widespread metabolic dysfunction including obesity, insulin resistance, and diabetes. While these ultimate pathological states are relatively well understood, we have a limited understanding of how high-fat intake first triggers physiological changes. Here, we identify an acute microglial metabolic response that rapidly translates intake of high-fat diet (HFD) to a surprisingly beneficial effect on spatial and learning memory. Acute high-fat intake increases palmitate levels in cerebrospinal fluid and triggers a wave of microglial metabolic activation characterized by mitochondrial membrane activation, fission and metabolic skewing towards aerobic glycolysis. These effects are generalized, detectable in the hypothalamus, hippocampus, and cortex all within 1-3 days of HFD exposure. In vivo microglial ablation and conditional DRP1 deletion experiments show that the microglial metabolic response is necessary for the acute effects of HFD. 13 C-tracing experiments reveal that in addition to processing via β-oxidation, microglia shunt a substantial fraction of palmitate towards anaplerosis and re-release of bioenergetic carbons into the extracellular milieu in the form of lactate, glutamate, succinate, and intriguingly, the neuro-protective metabolite itaconate. Together, these data identify microglial cells as a critical nutrient regulatory node in the brain, metabolizing away harmful fatty acids and liberating the same carbons instead as alternate bioenergetic and protective substrates. The data identify a surprisingly beneficial effect of short-term HFD on learning and memory.

DOI: https://doi.org/10.1101/2023.04.03.535373
Elife. 2023 Apr 19. pii: e87194. [Epub ahead of print]12

Are some mutations more equal than others?

Auden Cote-L'Heureux, Yogesh N K Maithania, Melissa Franco, Konstantin Khrapko.

  A large-scale study of mutations in mitochondrial DNA has revealed a subset that do not accumulate with age.

Keywords:  aging; duplex sequencing; genetics; genomics; mitochondrial DNA; mouse; somatic mutations

DOI:  https://doi.org/10.7554/eLife.87194
Cell Rep. 2023 Apr 21. pii: S2211-1247(23)00422-9. [Epub ahead of print]42(5): 112411

ZFP36-mediated mRNA decay regulates metabolism.

Andrew C Cicchetto, Elsie C Jacobson, Hannah Sunshine, Blake R Wilde, Abigail S Krall, Kelsey E Jarrett, Leslie Sedgeman, Martin Turner, Kathrin Plath, M Luisa Iruela-Arispe, Thomas Q de Aguiar Vallim, Heather R Christofk.

  Cellular metabolism is tightly regulated by growth factor signaling, which promotes metabolic rewiring to support growth and proliferation. While growth factor-induced transcriptional and post-translational modes of metabolic regulation have been well defined, whether post-transcriptional mechanisms impacting mRNA stability regulate this process is less clear. Here, we present the ZFP36/L1/L2 family of RNA-binding proteins and mRNA decay factors as key drivers of metabolic regulation downstream of acute growth factor signaling. We quantitatively catalog metabolic enzyme and nutrient transporter mRNAs directly bound by ZFP36 following growth factor stimulation-many of which encode rate-limiting steps in metabolic pathways. Further, we show that ZFP36 directly promotes the mRNA decay of Enolase 2 (Eno2), altering Eno2 protein expression and enzymatic activity, and provide evidence of a ZFP36/Eno2 axis during VEGF-stimulated developmental retinal angiogenesis. Thus, ZFP36-mediated mRNA decay serves as an important mode of metabolic regulation downstream of growth factor signaling within dynamic cell and tissue states.

Keywords:  CP: Metabolism; CP: Molecular biology; RNA-binding proteins; growth factor signaling; mRNA stability; metabolism

DOI:  https://doi.org/10.1016/j.celrep.2023.112411
PNAS Nexus. 2023 Apr;2(4): pgad105

Reduced methionine synthase expression results in uracil accumulation in mitochondrial DNA and impaired oxidative capacity.

Katarina E Heyden, Joanna L Fiddler, Yuwen Xiu, Olga V Malysheva, Michal K Handzlik, Whitney N Phinney, Linsey Stiles, Sally P Stabler, Christian M Metallo, Marie A Caudill, Martha S Field.

  Adequate thymidylate [deoxythymidine monophosphate (dTMP) or the "T" base in DNA] levels are essential for stability of mitochondrial DNA (mtDNA) and nuclear DNA (nDNA). Folate and vitamin B12 (B12) are essential cofactors in folate-mediated one-carbon metabolism (FOCM), a metabolic network which supports synthesis of nucleotides (including dTMP) and methionine. Perturbations in FOCM impair dTMP synthesis, causing misincorporation of uracil (or a "U" base) into DNA. During B12 deficiency, cellular folate accumulates as 5-methyltetrahdryfolate (5-methyl-THF), limiting nucleotide synthesis. The purpose of this study was to determine how reduced levels of the B12-dpendent enzyme methionine synthase (MTR) and dietary folate interact to affect mtDNA integrity and mitochondrial function in mouse liver. Folate accumulation, uracil levels, mtDNA content, and oxidative phosphorylation capacity were measured in male Mtr+/+ and Mtr+/- mice weaned onto either a folate-sufficient control (C) diet (2 mg/kg folic acid) or a folate-deficient (FD) diet (lacking folic acid) for 7 weeks. Mtr heterozygosity led to increased liver 5-methyl-THF levels. Mtr+/- mice consuming the C diet also exhibited a 40-fold increase in uracil in liver mtDNA. Mtr+/- mice consuming the FD diet exhibited less uracil accumulation in liver mtDNA as compared to Mtr+/+ mice consuming the FD diet. Furthermore, Mtr+/- mice exhibited 25% lower liver mtDNA content and a 20% lower maximal oxygen consumption rates. Impairments in mitochondrial FOCM are known to lead to increased uracil in mtDNA. This study demonstrates that impaired cytosolic dTMP synthesis, induced by decreased Mtr expression, also leads to increased uracil in mtDNA.

Keywords:  DNA; folate; methionine synthase; uracil; vitamin B12

DOI:  https://doi.org/10.1093/pnasnexus/pgad105
Cell Rep. 2023 Apr 20. pii: S2211-1247(23)00383-2. [Epub ahead of print]42(5): 112372

NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency.

Congxin Sun, Elena Seranova, Malkiel A Cohen, Miruna Chipara, Jennie Roberts, Dewi Astuti, Adina M Palhegyi, Animesh Acharjee, Lucia Sedlackova, Tetsushi Kataura, Elsje G Otten, Prashanta K Panda, Samuel Lara-Reyna, Miriam E Korsgen, Kevin J Kauffman, Alejandro Huerta-Uribe, Malgorzata Zatyka, Luiz F S E Silva, Jorge Torresi, Shupei Zhang, Georgina W Hughes, Carl Ward, Erich R Kuechler, David Cartwright, Sergey Trushin, Eugenia Trushina, Gaurav Sahay, Yosef Buganim, Gareth G Lavery, Joerg Gsponer, Daniel G Anderson, Eva-Maria Frickel, Tatiana R Rosenstock, Timothy Barrett, Oliver D K Maddocks, Daniel A Tennant, Haoyi Wang, Rudolf Jaenisch, Viktor I Korolchuk, Sovan Sarkar.

  Autophagy is a homeostatic process critical for cellular survival, and its malfunction is implicated in human diseases including neurodegeneration. Loss of autophagy contributes to cytotoxicity and tissue degeneration, but the mechanistic understanding of this phenomenon remains elusive. Here, we generated autophagy-deficient (ATG5-/-) human embryonic stem cells (hESCs), from which we established a human neuronal platform to investigate how loss of autophagy affects neuronal survival. ATG5-/- neurons exhibit basal cytotoxicity accompanied by metabolic defects. Depletion of nicotinamide adenine dinucleotide (NAD) due to hyperactivation of NAD-consuming enzymes is found to trigger cell death via mitochondrial depolarization in ATG5-/- neurons. Boosting intracellular NAD levels improves cell viability by restoring mitochondrial bioenergetics and proteostasis in ATG5-/- neurons. Our findings elucidate a mechanistic link between autophagy deficiency and neuronal cell death that can be targeted for therapeutic interventions in neurodegenerative and lysosomal storage diseases associated with autophagic defect.

Keywords:  CP: Cell biology; CP: Metabolism; NAD; NADases; NAM; NMN; NR; autophagy; cell death; cell survival, human embryonic stem cell-derived neurons; mitochondria; nicotinamide; nicotinamide adenine dinucleotide; nicotinamide mononucleotide; nicotinamide riboside

DOI:  https://doi.org/10.1016/j.celrep.2023.112372
Proc Natl Acad Sci U S A. 2023 Apr 25. 120(17): e2210929120

The mitochondrion of Plasmodium falciparum is required for cellular acetyl-CoA metabolism and protein acetylation.

Sethu C Nair, Justin T Munro, Alexis Mann, Manuel Llinás, Sean T Prigge.

  Coenzyme A (CoA) biosynthesis is an excellent target for antimalarial intervention. While most studies have focused on the use of CoA to produce acetyl-CoA in the apicoplast and the cytosol of malaria parasites, mitochondrial acetyl-CoA production is less well understood. In the current study, we performed metabolite-labeling experiments to measure endogenous metabolites in Plasmodium falciparum lines with genetic deletions affecting mitochondrial dehydrogenase activity. Our results show that the mitochondrion is required for cellular acetyl-CoA biosynthesis and identify a synthetic lethal relationship between the two main ketoacid dehydrogenase enzymes. The activity of these enzymes is dependent on the lipoate attachment enzyme LipL2, which is essential for parasite survival solely based on its role in supporting acetyl-CoA metabolism. We also find that acetyl-CoA produced in the mitochondrion is essential for the acetylation of histones and other proteins outside of the mitochondrion. Taken together, our results demonstrate that the mitochondrion is required for cellular acetyl-CoA metabolism and protein acetylation essential for parasite survival.

Keywords:  acetyl-CoA; acetylation; lipoic acid; malaria parasites; mitochondrion

DOI:  https://doi.org/10.1073/pnas.2210929120
Nature. 2023 Apr;616(7957): E8-E9

Insufficient evidence for non-neutrality of synonymous mutations.

Leonid Kruglyak, Andreas Beyer, Joshua S Bloom, Jan Grossbach, Tami D Lieberman, Christopher P Mancuso, Matthew S Rich, Gavin Sherlock, Craig D Kaplan.

DOI: https://doi.org/10.1038/s41586-023-05865-4
J Exp Biol. 2023 Apr 17. pii: jeb.245516. [Epub ahead of print]

Low production of mitochondrial reactive oxygen species after anoxia and reoxygenation in turtle hearts.

Amanda Bundgaard, Anja V Gruszczyk, Hiran A Prag, Catherine Williams, Angela McIntyre, Ilan M Ruhr, Andrew M James, Gina L J Galli, Michael P Murphy, Angela Fago.

  Extremely anoxia-tolerant animals, such as freshwater turtles, survive anoxia and reoxygenation without sustaining tissue damage to their hearts. In contrast, for mammals, the ischemia-reperfusion (IR) injury that leads to tissue damage during a heart attack is initiated by a burst of superoxide (O2.-) production from the mitochondrial respiratory chain upon reperfusion of ischemic tissue. Whether turtles avoid oxidative tissue damage because of an absence of mitochondrial superoxide production upon reoxygenation, or because the turtle heart is particularly protected against this damage, is unclear. Here, we investigate whether there was an increase in mitochondrial O2.- production upon the reoxygenation of anoxic red-eared slider turtle hearts in vivo and in vitro. This was done by measuring the production of H2O2, the dismutation product of O2.-, using the mitochondria-targeted mass-spectrometric probe in vivo MitoB, while in parallel assessing changes in the metabolites driving mitochondrial O2.- production succinate, ATP and ADP levels during anoxia and H2O2 consumption and production rates of isolated heart mitochondria. We found that there was no excess production of in vivo H2O2 during 1 h of reoxygenation in turtles after 3 h anoxia at room temperature, suggesting that turtle hearts most likely do not suffer oxidative injury after anoxia because their mitochondria produce no excess O2.- upon reoxygenation. Instead, our data support the conclusion that both the low levels of succinate accumulation and the maintenance of ADP levels in the anoxic turtle heart are key factors in preventing the surge of O2.- production upon reoxygenation.

Keywords:  Anoxia; Heart; Mitochondria; Oxidative damage; Reactive oxygen species; Turtle

DOI:  https://doi.org/10.1242/jeb.245516
Nat Cancer. 2023 Apr 17.

Impact of context-dependent autophagy states on tumor progression.

Mohamad Assi, Alec C Kimmelman.

Macroautophagy is a cellular quality-control process that degrades proteins, protein aggregates and damaged organelles. Autophagy plays a fundamental role in cancer where, in the presence of stressors (for example, nutrient starvation, hypoxia, mechanical pressure), tumor cells activate it to degrade intracellular substrates and provide energy. Cell-autonomous autophagy in tumor cells and cell-nonautonomous autophagy in the tumor microenvironment and in the host converge on mechanisms that modulate metabolic fitness, DNA integrity and immune escape and, consequently, support tumor growth. In this Review, we will discuss insights into the tumor-modulating roles of autophagy in different contexts and reflect on how future studies using physiological culture systems may help to understand the complexity and open new therapeutic avenues.

DOI: https://doi.org/10.1038/s43018-023-00546-7
Science. 2023 Apr 21. 380(6642): eabj5559

Induction of lysosomal and mitochondrial biogenesis by AMPK phosphorylation of FNIP1.

Nazma Malik, Bibiana I Ferreira, Pablo E Hollstein, Stephanie D Curtis, Elijah Trefts, Sammy Weiser Novak, Jingting Yu, Rebecca Gilson, Kristina Hellberg, Lingjing Fang, Arlo Sheridan, Nasun Hah, Gerald S Shadel, Uri Manor, Reuben J Shaw.

Cells respond to mitochondrial poisons with rapid activation of the adenosine monophosphate-activated protein kinase (AMPK), causing acute metabolic changes through phosphorylation and prolonged adaptation of metabolism through transcriptional effects. Transcription factor EB (TFEB) is a major effector of AMPK that increases expression of lysosome genes in response to energetic stress, but how AMPK activates TFEB remains unresolved. We demonstrate that AMPK directly phosphorylates five conserved serine residues in folliculin-interacting protein 1 (FNIP1), suppressing the function of the folliculin (FLCN)-FNIP1 complex. FNIP1 phosphorylation is required for AMPK to induce nuclear translocation of TFEB and TFEB-dependent increases of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and estrogen-related receptor alpha (ERRα) messenger RNAs. Thus, mitochondrial damage triggers AMPK-FNIP1-dependent nuclear translocation of TFEB, inducing sequential waves of lysosomal and mitochondrial biogenesis.

DOI: https://doi.org/10.1126/science.abj5559
Elife. 2023 Apr 21. pii: e85241. [Epub ahead of print]12

The nutrient-sensing GCN2 signaling pathway is essential for circadian clock function by regulating histone acetylation under amino acid starvation.

Xiao-Lan Liu, Yulin Yang, Yue Hu, Jingjing Wu, Chuqiao Han, Qiaojia Lu, Xihui Gan, Shaohua Qi, Jinhu Guo, Qun He, Yi Liu, Xiao Liu.

  Circadian clocks are evolved to adapt to the daily environmental changes under different conditions. The ability to maintain circadian clock functions in response to various stresses and perturbations is important for organismal fitness. Here, we show that the nutrient-sensing GCN2 signaling pathway is required for robust circadian clock function under amino acid starvation in Neurospora. The deletion of GCN2 pathway components disrupts rhythmic transcription of clock gene frq by suppressing WC complex binding at the frq promoter due to its reduced histone H3 acetylation levels. Under amino acid starvation, the activation of GCN2 kinase and its downstream transcription factor CPC-1 establish a proper chromatin state at the frq promoter by recruiting the histone acetyltransferase GCN-5. The arrhythmic phenotype of the GCN2 kinase mutants under amino acid starvation can be rescued by inhibiting histone deacetylation. Finally, genome-wide transcriptional analysis indicates that the GCN2 signaling pathway maintains robust rhythmic expression of metabolic genes under amino acid starvation. Together, these results uncover an essential role of the GCN2 signaling pathway in maintaining the robust circadian clock function in response to amino acid starvation, and demonstrate the importance of histone acetylation at the frq locus in rhythmic gene expression.

Keywords:  N. crassa; cell biology; genetics; genomics

DOI:  https://doi.org/10.7554/eLife.85241
Cell Metab. 2023 Apr 12. pii: S1550-4131(23)00123-7. [Epub ahead of print]

FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity.

Nicolas Wieder, Juliana Coraor Fried, Choah Kim, Eriene-Heidi Sidhom, Matthew R Brown, Jamie L Marshall, Carlos Arevalo, Moran Dvela-Levitt, Maria Kost-Alimova, Jonas Sieber, Katlyn R Gabriel, Julian Pacheco, Clary Clish, Hamdah Shafqat Abbasi, Shantanu Singh, Justine C Rutter, Martine Therrien, Haejin Yoon, Zon Weng Lai, Aaron Baublis, Renuka Subramanian, Ranjan Devkota, Jonnell Small, Vedagopuram Sreekanth, Myeonghoon Han, Donghyun Lim, Anne E Carpenter, Jason Flannick, Hilary Finucane, Marcia C Haigis, Melina Claussnitzer, Eric Sheu, Beth Stevens, Bridget K Wagner, Amit Choudhary, Jillian L Shaw, Juan Lorenzo Pablo, Anna Greka.

  Cellular exposure to free fatty acids (FFAs) is implicated in the pathogenesis of obesity-associated diseases. However, there are no scalable approaches to comprehensively assess the diverse FFAs circulating in human plasma. Furthermore, assessing how FFA-mediated processes interact with genetic risk for disease remains elusive. Here, we report the design and implementation of fatty acid library for comprehensive ontologies (FALCON), an unbiased, scalable, and multimodal interrogation of 61 structurally diverse FFAs. We identified a subset of lipotoxic monounsaturated fatty acids associated with decreased membrane fluidity. Furthermore, we prioritized genes that reflect the combined effects of harmful FFA exposure and genetic risk for type 2 diabetes (T2D). We found that c-MAF-inducing protein (CMIP) protects cells from FFA exposure by modulating Akt signaling. In sum, FALCON empowers the study of fundamental FFA biology and offers an integrative approach to identify much needed targets for diverse diseases associated with disordered FFA metabolism.

Keywords:  CMIP; GWAS; erucic acid; kidney; lipidomics; microglia; obesity; pancreatic β cell; transcriptomics; type 2 diabetes

DOI:  https://doi.org/10.1016/j.cmet.2023.03.018
Cell Rep. 2023 Apr 15. pii: S2211-1247(23)00407-2. [Epub ahead of print]42(4): 112396

AMPK activation protects against prostate cancer by inducing a catabolic cellular state.

Lucy Penfold, Angela Woods, Alice E Pollard, Julia Arizanova, Eneko Pascual-Navarro, Phillip J Muckett, Marian H Dore, Alex Montoya, Chad Whilding, Louise Fets, Joao Mokochinski, Theodora A Constantin, Anabel Varela-Carver, Damien A Leach, Charlotte L Bevan, Alexander Yu Nikitin, Zoe Hall, David Carling.

  Emerging evidence indicates that metabolic dysregulation drives prostate cancer (PCa) progression and metastasis. AMP-activated protein kinase (AMPK) is a master regulator of metabolism, although its role in PCa remains unclear. Here, we show that genetic and pharmacological activation of AMPK provides a protective effect on PCa progression in vivo. We show that AMPK activation induces PGC1α expression, leading to catabolic metabolic reprogramming of PCa cells. This catabolic state is characterized by increased mitochondrial gene expression, increased fatty acid oxidation, decreased lipogenic potential, decreased cell proliferation, and decreased cell invasiveness. Together, these changes inhibit PCa disease progression. Additionally, we identify a gene network involved in cell cycle regulation that is inhibited by AMPK activation. Strikingly, we show a correlation between this gene network and PGC1α gene expression in human PCa. Taken together, our findings support the use of AMPK activators for clinical treatment of PCa to improve patient outcome.

Keywords:  AMPK; CP: Cancer; CP: Metabolism; PGC1α; cell cycle regulation; fatty acid oxidation; high-fat diet; lipogenesis; metabolism; metastasis; mitochondria; prostate cancer

DOI:  https://doi.org/10.1016/j.celrep.2023.112396
Nat Commun. 2023 04 18. 14(1): 2210

Copy number variation in tRNA isodecoder genes impairs mammalian development and balanced translation.

Laetitia A Hughes, Danielle L Rudler, Stefan J Siira, Tim McCubbin, Samuel A Raven, Jasmin M Browne, Judith A Ermer, Jeanette Rientjes, Jennifer Rodger, Esteban Marcellin, Oliver Rackham, Aleksandra Filipovska.

The number of tRNA isodecoders has increased dramatically in mammals, but the specific molecular and physiological reasons for this expansion remain elusive. To address this fundamental question we used CRISPR editing to knockout the seven-membered phenylalanine tRNA gene family in mice, both individually and combinatorially. Using ATAC-Seq, RNA-seq, ribo-profiling and proteomics we observed distinct molecular consequences of single tRNA deletions. We show that tRNA-Phe-1-1 is required for neuronal function and its loss is partially compensated by increased expression of other tRNAs but results in mistranslation. In contrast, the other tRNA-Phe isodecoder genes buffer the loss of each of the remaining six tRNA-Phe genes. In the tRNA-Phe gene family, the expression of at least six tRNA-Phe alleles is required for embryonic viability and tRNA-Phe-1-1 is most important for development and survival. Our results reveal that the multi-copy configuration of tRNA genes is required to buffer translation and viability in mammals.

DOI: https://doi.org/10.1038/s41467-023-37843-9
Cell Syst. 2023 Apr 19. pii: S2405-4712(23)00078-9. [Epub ahead of print]14(4): 252-257

Modeling collective cell behavior in cancer: Perspectives from an interdisciplinary conversation.

Frederick R Adler, Alexander R A Anderson, Abhinav Bhushan, Paul Bogdan, Jose Javier Bravo-Cordero, Amy Brock, Yun Chen, Edna Cukierman, Kathleen E DelGiorno, Gerald V Denis, Meghan C Ferrall-Fairbanks, Zev Jordan Gartner, Ronald N Germain, Deborah M Gordon, Ginger Hunter, Mohit Kumar Jolly, Loukia Georgiou Karacosta, Karthikeyan Mythreye, Parag Katira, Rajan P Kulkarni, Matthew L Kutys, Arthur D Lander, Ashley M Laughney, Herbert Levine, Emil Lou, Pedro R Lowenstein, Kristyn S Masters, Dana Pe'er, Shelly R Peyton, Manu O Platt, Jeremy E Purvis, Gerald Quon, Jennifer K Richer, Nicole C Riddle, Analiz Rodriguez, Joshua C Snyder, Gregory Lee Szeto, Claire J Tomlin, Itai Yanai, Ioannis K Zervantonakis, Hannah Dueck.

Collective cell behavior contributes to all stages of cancer progression. Understanding how collective behavior emerges through cell-cell interactions and decision-making will advance our understanding of cancer biology and provide new therapeutic approaches. Here, we summarize an interdisciplinary discussion on multicellular behavior in cancer, draw lessons from other scientific disciplines, and identify future directions.

DOI: https://doi.org/10.1016/j.cels.2023.03.002
Nature. 2023 Apr 19.

Enzyme lights dual fires to promote cancer.

Anghesom Ghebremedhin, Judith A Varner.



Keywords:  Cancer; Immunology; Medical research

DOI:  https://doi.org/10.1038/d41586-023-01025-w
Cancer Discov. 2023 Apr 17. OF1-OF24

Li-Fraumeni Syndrome-Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death.

Joshua H Choe, Tatsuya Kawase, An Xu, Asja Guzman, Aleksandar Z Obradovic, Ana Maria Low-Calle, Bita Alaghebandan, Ananya Raghavan, Kaitlin Long, Paul M Hwang, Joshua D Schiffman, Yan Zhu, Ruiying Zhao, Dung-Fang Lee, Chen Katz, Carol Prives.

Cancer-relevant mutations in the oligomerization domain (OD) of the p53 tumor suppressor protein, unlike those in the DNA binding domain, have not been well elucidated. Here, we characterized the germline OD mutant p53(A347D), which occurs in cancer-prone Li-Fraumeni syndrome (LFS) patients. Unlike wild-type p53, mutant p53(A347D) cannot form tetramers and exists as a hyperstable dimeric protein. Further, p53(A347D) cannot bind or transactivate the majority of canonical p53 target genes. Isogenic cell lines harboring either p53(A347D) or no p53 yield comparable tumorigenic properties, yet p53(A347D) displays remarkable neomorphic activities. Cells bearing p53(A347D) possess a distinct transcriptional profile and undergo metabolic reprogramming. Further, p53(A347D) induces striking mitochondrial network aberration and associates with mitochondria to drive apoptotic cell death upon topoisomerase II inhibition in the absence of transcription. Thus, dimer-forming p53 demonstrates both loss-of-function (LOF) and gain-of-function (GOF) properties compared with the wild-type form of the protein.SIGNIFICANCE: A mutant p53 (A347D), which can only form dimers, is associated with increased cancer susceptibility in LFS individuals. We found that this mutant wields a double-edged sword, driving tumorigenesis through LOF while gaining enhanced apoptogenic activity as a new GOF, thereby yielding a potential vulnerability to select therapeutic approaches.

DOI: https://doi.org/10.1158/2159-8290.CD-22-0882
Methods Mol Biol. 2023 ;2662 67-75

Assessment of Bioenergetics in BAT Mitochondria.

Alek D Peterlin, Jordan M Johnson, Katsuhiko Funai.

  High-resolution respirometry is commonly used to quantify mitochondrial respiratory rates. In the respirometry chamber, a change in oxygen concentration is measured by a polarographic electrode to derive the rate of oxygen consumption (JO2). Here, we describe our adapted protocol to bioenergetically phenotype mitochondria from mouse brown adipose tissue (BAT). Given the presence of uncoupling protein 1 (UCP1), mitochondria from BAT provide unique challenges and opportunities in applying high-resolution respirometry to understand energy transduction through oxidative phosphorylation (OXPHOS).

Keywords:  Bioenergetics; Mitochondria; Oroboros Oxygraph-2 K respirometry; Oxygen consumption rate; Respiration; Uncoupling protein 1

DOI:  https://doi.org/10.1007/978-1-0716-3167-6_6
J Biol Chem. 2023 Apr 13. pii: S0021-9258(23)01736-2. [Epub ahead of print] 104708

Mitochondrial Membrane Potential Instability on Reperfusion After Ischemia Does Not Depend on Mitochondrial Ca2+ Uptake.

Deepthi Ashok, Kyriakos Papanicolaou, Agnieszka Sidor, Michelle Wang, Soroosh Solhjoo, Ting Liu, Brian O'Rourke.

  Physiologic Ca2+ entry via the Mitochondrial Calcium Uniporter (MCU) participates in energetic adaption to workload but may also contribute to cell death during Ischemia/Reperfusion (I/R) injury. The MCU has been identified as the primary mode of Ca2+ import into mitochondria. Several groups have tested the hypothesis that Ca2+ import via MCU is detrimental during I/R injury using genetically-engineered mouse models, yet the results from these studies are inconclusive. Furthermore, mitochondria exhibit unstable or oscillatory membrane potentials (ΔΨm) when subjected to stress, such as during I/R, but it is unclear if the primary trigger is excess influx of mitochondrial Ca2+ (mCa2+), reactive oxygen species (ROS) accumulation, or other factors. Here, we critically examine whether MCU-mediated mitochondrial Ca2+ uptake during I/R is involved in ΔΨm instability, or sustained mitochondrial depolarization, during reperfusion by acutely knocking out MCU in neonatal mouse ventricular myocyte (NMVM) monolayers subjected to simulated I/R. Unexpectedly, we find that MCU knockout does not significantly alter mCa2+ import during I/R, nor does it affect ΔΨm recovery during reperfusion. In contrast, blocking the mitochondrial sodium-calcium exchanger (mNCE) suppressed the mCa2+ increase during Ischemia but did not affect ΔΨm recovery or the frequency of ΔΨm oscillations during reperfusion, indicating that mitochondrial ΔΨm instability on reperfusion is not triggered by mCa2+. Interestingly, inhibition of mitochondrial electron transport or supplementation with antioxidants stabilized I/R-induced ΔΨm oscillations. The findings are consistent with mCa2+ overload being mediated by reverse-mode mNCE activity and support ROS-induced ROS release as the primary trigger of ΔΨm instability during reperfusion injury.

Keywords:  image processing; ischemia; mitochondrial membrane potential; oscillation; oxidative phosphorylation; reperfusion; time-series analysis; wavelet

DOI:  https://doi.org/10.1016/j.jbc.2023.104708
J Clin Invest. 2023 Apr 17. pii: e163018. [Epub ahead of print]133(8):

Hepatocyte SREBP signaling mediates clock communication within the liver.

Dongyin Guan, Hosung Bae, Dishu Zhou, Ying Chen, Chunjie Jiang, Cam Mong La, Yang Xiao, Kun Zhu, Wenxiang Hu, Trang Minh Trinh, Panpan Liu, Ying Xiong, Bishuang Cai, Cholsoon Jang, Mitchell A Lazar.

  Rhythmic intraorgan communication coordinates environmental signals and the cell-intrinsic clock to maintain organ homeostasis. Hepatocyte-specific KO of core components of the molecular clock Rev-erbα and -β (Reverb-hDKO) alters cholesterol and lipid metabolism in hepatocytes as well as rhythmic gene expression in nonparenchymal cells (NPCs) of the liver. Here, we report that in fatty liver caused by diet-induced obesity (DIO), hepatocyte SREBP cleavage-activating protein (SCAP) was required for Reverb-hDKO-induced diurnal rhythmic remodeling and epigenomic reprogramming in liver macrophages (LMs). Integrative analyses of isolated hepatocytes and LMs revealed that SCAP-dependent lipidomic changes in REV-ERB-depleted hepatocytes led to the enhancement of LM metabolic rhythms. Hepatocytic loss of REV-ERBα and β (REV-ERBs) also attenuated LM rhythms via SCAP-independent polypeptide secretion. These results shed light on the signaling mechanisms by which hepatocytes regulate diurnal rhythms in NPCs in fatty liver disease caused by DIO.

Keywords:  Epigenetics; Hepatology; Homeostasis; Metabolism

DOI:  https://doi.org/10.1172/JCI163018
Adv Protein Chem Struct Biol. 2023 ;pii: S1876-1623(23)00002-0. [Epub ahead of print]135 397-423

Cellular signals integrate cell cycle and metabolic control in cancer.

Chareeporn Akekawatchai, Sarawut Jitrapakdee.

  Growth factors are the small peptides that can promote growth, differentiation, and survival of most living cells. However, aberrant activation of receptor tyrosine kinases by GFs can generate oncogenic signals, resulting in oncogenic transformation. Accumulating evidence support a link between GF/RTK signaling through the major signaling pathways, Ras/Erk and PI3K/Akt, and cell cycle progression. In response to GF signaling, the quiescent cells in the G0 stage can re-enter the cell cycle and become the proliferative stage. While in the proliferative stage, tumor cells undergo profound changes in their metabolism to support biomass production and bioenergetic requirements. Accumulating data show that the cell cycle regulators, specifically cyclin D, cyclin B, Cdk2, Cdk4, and Cdk6, and anaphase-promoting complex/cyclosome (APC/C-Cdh1) play critical roles in modulating various metabolic pathways. These cell cycle regulators can regulate metabolic enzyme activities through post-translational mechanisms or the transcriptional factors that control the expression of the metabolic genes. This fine-tune control allows only the relevant metabolic pathways to be active in a particular phase of the cell cycle, thereby providing suitable amounts of biosynthetic precursors available during the proliferative stage. The imbalance of metabolites in each cell cycle phase can induce cell cycle arrest followed by p53-induced apoptosis.

Keywords:  Apoptosis; Cancer; Cell cycle; Growth factors; Metabolism; Receptor tyrosine kinase

DOI:  https://doi.org/10.1016/bs.apcsb.2023.01.002
Cell Metab. 2023 Apr 12. pii: S1550-4131(23)00124-9. [Epub ahead of print]

Nutrient-sensing AgRP neurons relay control of liver autophagy during energy deprivation.

Weiyi Chen, Oliver Mehlkop, Alexandra Scharn, Hendrik Nolte, Paul Klemm, Sinika Henschke, Lukas Steuernagel, Tamara Sotelo-Hitschfeld, Ecem Kaya, Claudia Maria Wunderlich, Thomas Langer, Natalia L Kononenko, Patrick Giavalisco, Jens Claus Brüning.

  Autophagy represents a key regulator of aging and metabolism in sensing energy deprivation. We find that fasting in mice activates autophagy in the liver paralleled by activation of hypothalamic AgRP neurons. Optogenetic and chemogenetic activation of AgRP neurons induces autophagy, alters phosphorylation of autophagy regulators, and promotes ketogenesis. AgRP neuron-dependent induction of liver autophagy relies on NPY release in the paraventricular nucleus of the hypothalamus (PVH) via presynaptic inhibition of NPY1R-expressing neurons to activate PVHCRH neurons. Conversely, inhibiting AgRP neurons during energy deprivation abrogates induction of hepatic autophagy and rewiring of metabolism. AgRP neuron activation increases circulating corticosterone concentrations, and reduction of hepatic glucocorticoid receptor expression attenuates AgRP neuron-dependent activation of hepatic autophagy. Collectively, our study reveals a fundamental regulatory principle of liver autophagy in control of metabolic adaptation during nutrient deprivation.

Keywords:  AgRP neurons; CRH neurons; HPA axis; NPY1R; autophagy; corticosterone; hypothalamus; liver metabolism; non-cell autonomous; short-term fasting

DOI:  https://doi.org/10.1016/j.cmet.2023.03.019
Nat Commun. 2023 04 18. 14(1): 2201

DNMT1 mutant ants develop normally but have disrupted oogenesis.

Iryna Ivasyk, Leonora Olivos-Cisneros, Stephany Valdés-Rodríguez, Marie Droual, Hosung Jang, Robert J Schmitz, Daniel J C Kronauer.

Although DNA methylation is an important gene regulatory mechanism in mammals, its function in arthropods remains poorly understood. Studies in eusocial insects have argued for its role in caste development by regulating gene expression and splicing. However, such findings are not always consistent across studies, and have therefore remained controversial. Here we use CRISPR/Cas9 to mutate the maintenance DNA methyltransferase DNMT1 in the clonal raider ant, Ooceraea biroi. Mutants have greatly reduced DNA methylation, but no obvious developmental phenotypes, demonstrating that, unlike mammals, ants can undergo normal development without DNMT1 or DNA methylation. Additionally, we find no evidence of DNA methylation regulating caste development. However, mutants are sterile, whereas in wild-type ants, DNMT1 is localized to the ovaries and maternally provisioned into nascent oocytes. This supports the idea that DNMT1 plays a crucial but unknown role in the insect germline.

DOI: https://doi.org/10.1038/s41467-023-37945-4
Br J Cancer. 2023 Apr 19.

Convergent genomic diversity and novel BCAA metabolism in intrahepatic cholangiocarcinoma.

Akihiro Kitagawa, Tsuyoshi Osawa, Miwa Noda, Yuta Kobayashi, Sho Aki, Yusuke Nakano, Tomoko Saito, Dai Shimizu, Hisateru Komatsu, Maki Sugaya, Junichi Takahashi, Keisuke Kosai, Seiichiro Takao, Yushi Motomura, Kuniaki Sato, Qingjiang Hu, Atsushi Fujii, Hiroaki Wakiyama, Taro Tobo, Hiroki Uchida, Keishi Sugimachi, Kohei Shibata, Tohru Utsunomiya, Shogo Kobayashi, Hideshi Ishii, Takanori Hasegawa, Takaaki Masuda, Yusuke Matsui, Atsushi Niida, Tomoyoshi Soga, Yutaka Suzuki, Satoru Miyano, Hiroyuki Aburatani, Yuichiro Doki, Hidetoshi Eguchi, Masaki Mori, Keiichi I Nakayama, Teppei Shimamura, Tatsuhiro Shibata, Koshi Mimori.

BACKGROUND: Driver alterations may represent novel candidates for driver gene-guided therapy; however, intrahepatic cholangiocarcinoma (ICC) with multiple genomic aberrations makes them intractable. Therefore, the pathogenesis and metabolic changes of ICC need to be understood to develop new treatment strategies. We aimed to unravel the evolution of ICC and identify ICC-specific metabolic characteristics to investigate the metabolic pathway associated with ICC development using multiregional sampling to encompass the intra- and inter-tumoral heterogeneity.METHODS: We performed the genomic, transcriptomic, proteomic and metabolomic analysis of 39-77 ICC tumour samples and eleven normal samples. Further, we analysed their cell proliferation and viability.
RESULTS: We demonstrated that intra-tumoral heterogeneity of ICCs with distinct driver genes per case exhibited neutral evolution, regardless of their tumour stage. Upregulation of BCAT1 and BCAT2 indicated the involvement of 'Val Leu Ile degradation pathway'. ICCs exhibit the accumulation of ubiquitous metabolites, such as branched-chain amino acids including valine, leucine, and isoleucine, to negatively affect cancer prognosis. We revealed that this metabolic pathway was almost ubiquitously altered in all cases with genomic diversity and might play important roles in tumour progression and overall survival.
CONCLUSIONS: We propose a novel ICC onco-metabolic pathway that could enable the development of new therapeutic interventions.

DOI: https://doi.org/10.1038/s41416-023-02256-4
Nat Commun. 2023 04 19. 14(1): 2247

Allosteric role of the citrate synthase homology domain of ATP citrate lyase.

Xuepeng Wei, Kollin Schultz, Hannah L Pepper, Emily Megill, Austin Vogt, Nathaniel W Snyder, Ronen Marmorstein.

ATP citrate lyase (ACLY) is the predominant nucleocytosolic source of acetyl-CoA and is aberrantly regulated in many diseases making it an attractive therapeutic target. Structural studies of ACLY reveal a central homotetrameric core citrate synthase homology (CSH) module flanked by acyl-CoA synthetase homology (ASH) domains, with ATP and citrate binding the ASH domain and CoA binding the ASH-CSH interface to produce acetyl-CoA and oxaloacetate products. The specific catalytic role of the CSH module and an essential D1026A residue contained within it has been a matter of debate. Here, we report biochemical and structural analysis of an ACLY-D1026A mutant demonstrating that this mutant traps a (3S)-citryl-CoA intermediate in the ASH domain in a configuration that is incompatible with the formation of acetyl-CoA, is able to convert acetyl-CoA and OAA to (3S)-citryl-CoA in the ASH domain, and can load CoA and unload acetyl-CoA in the CSH module. Together, this data support an allosteric role for the CSH module in ACLY catalysis.

DOI: https://doi.org/10.1038/s41467-023-37986-9
Nat Metab. 2023 Apr 20.

Amino acids downregulate SIRT4 to detoxify ammonia through the urea cycle.

Song-Hua Hu, Yu-Yang Feng, Yuan-Xin Yang, Hui-Da Ma, Shu-Xian Zhou, Ya-Nan Qiao, Kai-Hui Zhang, Lei Zhang, Lin Huang, Yi-Yuan Yuan, Yan Lin, Xin-Yan Zhang, Yao Li, Hai-Tao Li, Jian-Yuan Zhao, Wei Xu, Shi-Min Zhao.

Ammonia production via glutamate dehydrogenase is inhibited by SIRT4, a sirtuin that displays both amidase and non-amidase activities. The processes underlying the regulation of ammonia removal by amino acids remain unclear. Here, we report that SIRT4 acts as a decarbamylase that responds to amino acid sufficiency and regulates ammonia removal. Amino acids promote lysine 307 carbamylation (OTCCP-K307) of ornithine transcarbamylase (OTC), which activates OTC and the urea cycle. Proteomic and interactome screening identified OTC as a substrate of SIRT4. SIRT4 decarbamylates OTCCP-K307 and inactivates OTC in an NAD+-dependent manner. SIRT4 expression was transcriptionally upregulated by the amino acid insufficiency-activated GCN2-eIF2α-ATF4 axis. SIRT4 knockout in cultured cells caused higher OTCCP-K307 levels, activated OTC, elevated urea cycle intermediates and urea production via amino acid catabolism. Sirt4 ablation decreased male mouse blood ammonia levels and ameliorated CCl4-induced hepatic encephalopathy phenotypes. We reveal that SIRT4 safeguards cellular ammonia toxicity during amino acid catabolism.

DOI: https://doi.org/10.1038/s42255-023-00784-0
Methods Mol Biol. 2023 ;2662 117-124

Thermogenic Phenotyping in Mice.

Donghua Hu, Irfan J Lodhi.

  Thermogenesis mediated by brown adipose tissue (BAT) and brown-like fat plays an important role in regulating metabolic homeostasis in mammals. Accurate measurement of metabolic responses to brown fat activation, including heat generation and increased energy expenditure is essential for characterizing thermogenic phenotypes in preclinical studies. Here, we describe two methods for assessing thermogenic phenotypes in mice under non-basal states. First, we describe a protocol for measuring body temperature in cold-treated mice using implantable temperature transponders, which allow for continuous monitoring of body temperature. Second, we describe a method for using indirect calorimetry to measure β3-adrenergic agonist-stimulated changes in oxygen consumption, a proxy for thermogenic fat activation.

Keywords:  Body temperature; Energy expenditure; Indirect calorimetry; Metabolic cages; Oxygen consumption; Thermogenesis

DOI:  https://doi.org/10.1007/978-1-0716-3167-6_10
Trends Biochem Sci. 2023 Apr 18. pii: S0968-0004(23)00080-4. [Epub ahead of print]

The metabolic cross-talk between cancer and T cells.

Silvia Cadenas-De Miguel, Giulia Lucianer, Ilaria Elia.

  The metabolic cross-talk between cancer cells and T cells dictates cancer formation and progression. These cells possess metabolic plasticity. Thus, they adapt their metabolic profile to meet their phenotypic requirements. However, the nutrient microenvironment of a tumor is a very hostile niche in which these cells are forced to compete for the available nutrients. The hyperactive metabolism of tumor cells often outcompetes the antitumorigenic CD8+ T cells while promoting the protumorigenic exhausted CD8+ T cells and T regulatory (Treg) cells. Thus, cancer cells elude the immune response and spread in an uncontrolled manner. Identifying the metabolic pathways necessary to shift the balance from a protumorigenic to an antitumorigenic immune phenotype is essential to potentiate antitumor immunity.

Keywords:  antitumorigenic T cells; immunometabolism; protumorigenic T cells; tumor microenvironment

DOI:  https://doi.org/10.1016/j.tibs.2023.03.004
Cell Rep. 2023 Apr 18. pii: S2211-1247(23)00420-5. [Epub ahead of print]42(5): 112409

Integrated glycoproteomic characterization of clear cell renal cell carcinoma.

T Mamie Lih, Kyung-Cho Cho, Michael Schnaubelt, Yingwei Hu, Hui Zhang.

  Clear cell renal cell carcinoma (ccRCC), a common form of RCC, is responsible for the high mortality rate of kidney cancer. Dysregulations of glycoproteins have been shown to associate with ccRCC. However, the molecular mechanism has not been well characterized. Here, a comprehensive glycoproteomic analysis is conducted using 103 tumors and 80 paired normal adjacent tissues. Altered glycosylation enzymes and corresponding protein glycosylation are observed, while two of the major ccRCC mutations, BAP1 and PBRM1, show distinct glycosylation profiles. Additionally, inter-tumor heterogeneity and cross-correlation between glycosylation and phosphorylation are observed. The relation of glycoproteomic features to genomic, transcriptomic, proteomic, and phosphoproteomic changes shows the role of glycosylation in ccRCC development with potential for therapeutic interventions. This study reports a large-scale tandem mass tag (TMT)-based quantitative glycoproteomic analysis of ccRCC that can serve as a valuable resource for the community.

Keywords:  CP: Cancer; N-linked glycosylation; clear cell renal cell carcinoma; cross-correlation; glycoproteomics; mass spectrometry

DOI:  https://doi.org/10.1016/j.celrep.2023.112409
Nat Commun. 2023 04 15. 14(1): 2173

Dynamic fluctuations in a bacterial metabolic network.

Shuangyu Bi, Manika Kargeti, Remy Colin, Niklas Farke, Hannes Link, Victor Sourjik.

The operation of the central metabolism is typically assumed to be deterministic, but dynamics and high connectivity of the metabolic network make it potentially prone to generating fluctuations. However, time-resolved measurements of metabolite levels in individual cells that are required to characterize such fluctuations remained a challenge, particularly in small bacterial cells. Here we use single-cell metabolite measurements based on Förster resonance energy transfer, combined with computer simulations, to explore the real-time dynamics of the metabolic network of Escherichia coli. We observe that steplike exposure of starved E. coli to glycolytic carbon sources elicits large periodic fluctuations in the intracellular concentration of pyruvate in individual cells. These fluctuations are consistent with predicted oscillatory dynamics of E. coli metabolic network, and they are primarily controlled by biochemical reactions around the pyruvate node. Our results further indicate that fluctuations in glycolysis propagate to other cellular processes, possibly leading to temporal heterogeneity of cellular states within a population.

DOI: https://doi.org/10.1038/s41467-023-37957-0
Nature. 2023 Apr 19.

PI3Kβ controls immune evasion in PTEN-deficient breast tumours.

Johann S Bergholz, Qiwei Wang, Qi Wang, Michelle Ramseier, Sanjay Prakadan, Weihua Wang, Rong Fang, Sheheryar Kabraji, Qian Zhou, G Kenneth Gray, Kayley Abell-Hart, Shaozhen Xie, Xiaocan Guo, Hao Gu, Thanh Von, Tao Jiang, Shuang Tang, Gordon J Freeman, Hye-Jung Kim, Alex K Shalek, Thomas M Roberts, Jean J Zhao.

Loss of the PTEN tumour suppressor is one of the most common oncogenic drivers across all cancer types1. PTEN is the major negative regulator of PI3K signalling. The PI3Kβ isoform has been shown to play an important role in PTEN-deficient tumours, but the mechanisms underlying the importance of PI3Kβ activity remain elusive. Here, using a syngeneic genetically engineered mouse model of invasive breast cancer driven by ablation of both Pten and Trp53 (which encodes p53), we show that genetic inactivation of PI3Kβ led to a robust anti-tumour immune response that abrogated tumour growth in syngeneic immunocompetent mice, but not in immunodeficient mice. Mechanistically, PI3Kβ inactivation in the PTEN-null setting led to reduced STAT3 signalling and increased the expression of immune stimulatory molecules, thereby promoting anti-tumour immune responses. Pharmacological PI3Kβ inhibition also elicited anti-tumour immunity and synergized with immunotherapy to inhibit tumour growth. Mice with complete responses to the combined treatment displayed immune memory and rejected tumours upon re-challenge. Our findings demonstrate a molecular mechanism linking PTEN loss and STAT3 activation in cancer and suggest that PI3Kβ controls immune escape in PTEN-null tumours, providing a rationale for combining PI3Kβ inhibitors with immunotherapy for the treatment of PTEN-deficient breast cancer.

DOI: https://doi.org/10.1038/s41586-023-05940-w
Cell. 2023 Apr 17. pii: S0092-8674(23)00300-8. [Epub ahead of print]

The proteomic landscape of genome-wide genetic perturbations.

Christoph B Messner, Vadim Demichev, Julia Muenzner, Simran K Aulakh, Natalie Barthel, Annika Röhl, Lucía Herrera-Domínguez, Anna-Sophia Egger, Stephan Kamrad, Jing Hou, Guihong Tan, Oliver Lemke, Enrica Calvani, Lukasz Szyrwiel, Michael Mülleder, Kathryn S Lilley, Charles Boone, Georg Kustatscher, Markus Ralser.

  Functional genomic strategies have become fundamental for annotating gene function and regulatory networks. Here, we combined functional genomics with proteomics by quantifying protein abundances in a genome-scale knockout library in Saccharomyces cerevisiae, using data-independent acquisition mass spectrometry. We find that global protein expression is driven by a complex interplay of (1) general biological properties, including translation rate, protein turnover, the formation of protein complexes, growth rate, and genome architecture, followed by (2) functional properties, such as the connectivity of a protein in genetic, metabolic, and physical interaction networks. Moreover, we show that functional proteomics complements current gene annotation strategies through the assessment of proteome profile similarity, protein covariation, and reverse proteome profiling. Thus, our study reveals principles that govern protein expression and provides a genome-spanning resource for functional annotation.

Keywords:  Saccharomyces cerevisiae; data-independent acquisition; deletion; functional genomics; functional proteomics; gene annotation; high throughput; knockout; quantitative proteomics; systems biology

DOI:  https://doi.org/10.1016/j.cell.2023.03.026
Nat Rev Endocrinol. 2023 Apr 17.

Succinate signalling regulates leptin production in adipocytes.

Olivia Tysoe.

DOI: https://doi.org/10.1038/s41574-023-00838-z
bioRxiv. 2023 Apr 05. pii: 2023.04.05.535723. [Epub ahead of print]

Characterization of methionine dependence in melanoma cells.

Sarita Garg, Lauren C Morehead, Jordan T Bird, Stefan Graw, Allen Gies, Aaron J Storey, Alan J Tackett, Rick D Edmondson, Samuel G Mackintosh, Stephanie D Byrum, Isabelle R Miousse.

Dietary methionine restriction is associated with a reduction in tumor growth in preclinical studies and an increase in lifespan in animal models. The mechanism by which methionine restriction inhibits tumor growth while sparing normal cells is incompletely understood. We do know that normal cells can utilize methionine or homocysteine interchangeably (methionine independence) while most cancer cells are strictly dependent on methionine availability. Here, we compared a typical methionine dependent and a rare methionine independent melanoma cell line. We show that replacing methionine, a methyl donor, with its precursor homocysteine generally induced hypomethylation in gene promoters. This decrease was similar in methionine dependent and methionine independent cells. There was only a low level of pathway enrichment, suggesting that the hypomethylation is generalized rather than gene specific. Whole proteome and transcriptome were also analyzed. This analysis revealed that contrarily to the effect on methylation, the replacement of methionine with homocysteine had a much greater effect on the transcriptome and proteome of methionine dependent cells than methionine independent cells. Interestingly, methionine adenosyltransferase 2A (MAT2A), responsible for the synthesis of s-adenosylmethionine from methionine, was equally strongly upregulated in both cell lines. This suggests that the absence of methionine is equally detected but triggers different outcomes in methionine dependent versus independent cells. Our analysis reveals the importance of cell cycle control, DNA damage repair, translation, nutrient sensing, oxidative stress and immune functions in the cellular response to methionine stress in melanoma.

DOI: https://doi.org/10.1101/2023.04.05.535723
Cell Rep. 2023 Apr 20. pii: S2211-1247(23)00377-7. [Epub ahead of print]42(5): 112366

Mechanisms of division of labor in mammalian tissue.

Farah Abdul-Rahman.

Mammalian tissues function by dividing the labor of task performance between their cells. In this issue, Adler et al. use modeling approaches to determine if division of labor is coordinated by environmental or cell-to-cell signals.

DOI: https://doi.org/10.1016/j.celrep.2023.112366
Science. 2023 Apr 21. 380(6642): eabn7625

Oncogenic CDK13 mutations impede nuclear RNA surveillance.

Megan L Insco, Brian J Abraham, Sara J Dubbury, Ines H Kaltheuner, Sofia Dust, Constance Wu, Kevin Y Chen, David Liu, Stanislav Bellaousov, Anna M Cox, Benjamin J E Martin, Tongwu Zhang, Calvin G Ludwig, Tania Fabo, Rodsy Modhurima, Dakarai E Esgdaille, Telmo Henriques, Kevin M Brown, Stephen J Chanock, Matthias Geyer, Karen Adelman, Phillip A Sharp, Richard A Young, Paul L Boutz, Leonard I Zon.

RNA surveillance pathways detect and degrade defective transcripts to ensure RNA fidelity. We found that disrupted nuclear RNA surveillance is oncogenic. Cyclin-dependent kinase 13 (CDK13) is mutated in melanoma, and patient-mutated CDK13 accelerates zebrafish melanoma. CDK13 mutation causes aberrant RNA stabilization. CDK13 is required for ZC3H14 phosphorylation, which is necessary and sufficient to promote nuclear RNA degradation. Mutant CDK13 fails to activate nuclear RNA surveillance, causing aberrant protein-coding transcripts to be stabilized and translated. Forced aberrant RNA expression accelerates melanoma in zebrafish. We found recurrent mutations in genes encoding nuclear RNA surveillance components in many malignancies, establishing nuclear RNA surveillance as a tumor-suppressive pathway. Activating nuclear RNA surveillance is crucial to avoid accumulation of aberrant RNAs and their ensuing consequences in development and disease.

DOI: https://doi.org/10.1126/science.abn7625