bims-camemi 2023-06-25 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2023‒06‒25
thirty-six papers selected by
Christian Frezza, Universität zu Köln

Enhanced BCAT1 activity and BCAA metabolism promotes RhoC activity in cancer progression.
Quantitative analysis of metabolic fluxes in brown fat and skeletal muscle during thermogenesis.
The crisscross between p53 and metabolism in cancer.
Mitochondrial aconitase suppresses immunity by modulating oxaloacetate and the mitochondrial unfolded protein response.
13 C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 + T cells.
A multimodal atlas of tumour metabolism reveals the architecture of gene-metabolite covariation.
NADPH increase in mitosis in aneuploid tumour cells protects against genomic aberrations.
Patch-clamp technique to study mitochondrial membrane biophysics.
Rethinking our approach to cancer metabolism to deliver patient benefit.
Essential Amino Acid Metabolites as Chemical Mediators of Host-Microbe Interaction in the Gut.
Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity.
Modulation of cellular metabolism by protein crotonylation regulates pancreatic cancer progression.
SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells.
Deciphering ADP-ribosylation signalling.
Two-Step Tag-Free Isolation of Mitochondria for Improved Protein Discovery and Quantification.
A DEFECT IN MITOCHONDRIAL COMPLEX III BUT NOT IN COMPLEXES I OR IV CAUSES EARLY BETA CELL DYSFUNCTION AND HYPERGLYCEMIA IN MICE.
Alfred L. Goldberg (1942-2023).
Proton leak through the UCPs and ANT carriers and beyond: A breath for the electron transport chain.
Splice variants of mitofusin 2 shape the endoplasmic reticulum and tether it to mitochondria.
Genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner.
Pancreatic islet protection at the expense of secretory function involves serine-linked mitochondrial one-carbon metabolism.
Single cell-cell communication.
Differential Effects of Glutamine Inhibition Strategies on Antitumor CD8 T Cells.
Diverse biological functions of vitamin K: from coagulation to ferroptosis.
Injury prevents Ras mutant cell expansion in mosaic skin.
A mitotic NADPH upsurge promotes chromosome segregation and tumour progression in aneuploid cancer cells.
Epithelial tissue confinement inhibits cell growth and leads to volume-reducing divisions.
Mitochondrial matrix protein LETMD1 maintains thermogenic capacity of brown adipose tissue in male mice.
Developing an Ideal Risk Stratification Model for Metastatic Renal Cell Carcinoma.
Y chromosome loss in cancer drives growth by evasion of adaptive immunity.
Adipogenic and SWAT cells separate from a common progenitor in human brown and white adipose depots.
Enhanced mitochondrial G-quadruplex formation impedes replication fork progression leading to mtDNA loss in human cells.
Signalling by senescent melanocytes hyperactivates hair growth.
Rapid and reversible optical switching of cell membrane area by an amphiphilic azobenzene.
Transcriptional landscape of mitochondrial electron transport chain inhibition in renal cells.
Disruption of proteome by an oncogenic fusion kinase alters metabolism in fibrolamellar hepatocellular carcinoma.

Nat Metab. 2023 Jun 19.

Enhanced BCAT1 activity and BCAA metabolism promotes RhoC activity in cancer progression.

Lin Qian, Na Li, Xiao-Chen Lu, Midie Xu, Ying Liu, Kaiyue Li, Yi Zhang, Kewen Hu, Yu-Ting Qi, Jun Yao, Ying-Li Wu, Wenyu Wen, Shenglin Huang, Zheng-Jun Chen, Miao Yin, Qun-Ying Lei.

Increased expression of branched-chain amino acid transaminase 1 or 2 (BCAT1 and BCAT2) has been associated with aggressive phenotypes of different cancers. Here we identify a gain of function of BCAT1 glutamic acid to alanine mutation at codon 61 (BCAT1E61A) enriched around 2.8% in clinical gastric cancer samples. We found that BCAT1E61A confers higher enzymatic activity to boost branched-chain amino acid (BCAA) catabolism, accelerate cell growth and motility and contribute to tumor development. BCAT1 directly interacts with RhoC, leading to elevation of RhoC activity. Notably, the BCAA-derived metabolite, branched-chain α-keto acid directly binds to the small GTPase protein RhoC and promotes its activity. BCAT1 knockout-suppressed cell motility could be rescued by expressing BCAT1E61A or adding branched-chain α-keto acid. We also identified that candesartan acts as an inhibitor of BCAT1E61A, thus repressing RhoC activity and cancer cell motility in vitro and preventing peritoneal metastasis in vivo. Our study reveals a link between BCAA metabolism and cell motility and proliferation through regulating RhoC activation, with potential therapeutic implications for cancers.

DOI: https://doi.org/10.1038/s42255-023-00818-7
Nat Metab. 2023 Jun 19.

Quantitative analysis of metabolic fluxes in brown fat and skeletal muscle during thermogenesis.

Grace Park, John A Haley, Johnny Le, Su Myung Jung, Timothy P Fitzgibbons, Ekaterina D Korobkina, Huawei Li, Shelagh M Fluharty, Qingbo Chen, Jessica B Spinelli, Chinmay M Trivedi, Cholsoon Jang, David A Guertin.

Adaptive thermogenesis by brown adipose tissue (BAT) dissipates calories as heat, making it an attractive anti-obesity target. Yet how BAT contributes to circulating metabolite exchange remains unclear. Here, we quantified metabolite exchange in BAT and skeletal muscle by arteriovenous metabolomics during cold exposure in fed male mice. This identified unexpected metabolites consumed, released and shared between organs. Quantitative analysis of tissue fluxes showed that glucose and lactate provide ~85% of carbon for adaptive thermogenesis and that cold and CL316,243 trigger markedly divergent fuel utilization profiles. In cold adaptation, BAT also dramatically increases nitrogen uptake by net consuming amino acids, except glutamine. Isotope tracing and functional studies suggest glutamine catabolism concurrent with synthesis via glutamine synthetase, which avoids ammonia buildup and boosts fuel oxidation. These data underscore the ability of BAT to function as a glucose and amino acid sink and provide a quantitative and comprehensive landscape of BAT fuel utilization to guide translational studies.

DOI: https://doi.org/10.1038/s42255-023-00825-8
Acta Biochim Biophys Sin (Shanghai). 2023 Jun 19.

The crisscross between p53 and metabolism in cancer.

Youxiang Mao, Peng Jiang.

  As the guardian of the genome, p53 is well known for its tumor suppressor function in humans, controlling cell proliferation, senescence, DNA repair and cell death in cancer through transcriptional and non-transcriptional activities. p53 is the most frequently mutated gene in human cancer, but how its mutation or depletion leads to tumorigenesis still remains poorly understood. Recently, there has been increasing evidence that p53 plays a vital role in regulating cellular metabolism as well as in metabolic adaptation to nutrient starvation. In contrast, mutant p53 proteins, especially those harboring missense mutations, have completely different functions compared to wild-type p53. In this review, we briefly summarize what is known about p53 mediating anabolic and catabolic metabolism in cancer, and in particular discuss recent findings describing how metabolites regulate p53 functions. To illustrate the variability and complexity of p53 function in metabolism, we will also review the differential regulation of metabolism by wild-type and mutant p53.

Keywords:  cancer; gene regulation; metabolic reprogramming; metabolite sensing; p53

DOI:  https://doi.org/10.3724/abbs.2023109
Nat Commun. 2023 Jun 22. 14(1): 3716

Mitochondrial aconitase suppresses immunity by modulating oxaloacetate and the mitochondrial unfolded protein response.

Eunah Kim, Andrea Annibal, Yujin Lee, Hae-Eun H Park, Seokjin Ham, Dae-Eun Jeong, Younghun Kim, Sangsoon Park, Sujeong Kwon, Yoonji Jung, JiSoo Park, Sieun S Kim, Adam Antebi, Seung-Jae V Lee.

Accumulating evidence indicates that mitochondria play crucial roles in immunity. However, the role of the mitochondrial Krebs cycle in immunity remains largely unknown, in particular at the organism level. Here we show that mitochondrial aconitase, ACO-2, a Krebs cycle enzyme that catalyzes the conversion of citrate to isocitrate, inhibits immunity against pathogenic bacteria in C. elegans. We find that the genetic inhibition of aco-2 decreases the level of oxaloacetate. This increases the mitochondrial unfolded protein response, subsequently upregulating the transcription factor ATFS-1, which contributes to enhanced immunity against pathogenic bacteria. We show that the genetic inhibition of mammalian ACO2 increases immunity against pathogenic bacteria by modulating the mitochondrial unfolded protein response and oxaloacetate levels in cultured cells. Because mitochondrial aconitase is highly conserved across phyla, a therapeutic strategy targeting ACO2 may eventually help properly control immunity in humans.

DOI: https://doi.org/10.1038/s41467-023-39393-6
bioRxiv. 2023 Jun 11. pii: 2023.06.09.544407. [Epub ahead of print]

13 C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 + T cells.

Eric H Ma, Michael S Dahabieh, Lisa M DeCamp, Irem Kaymak, Susan M Kitchen-Goosen, Dominic G Roy, Mark J Verway, Radia M Johnson, Bozena Samborska, Catherine A Scullion, Mya Steadman, Matthew Vos, Thomas P Roddy, Connie M Krawczyk, Kelsey S Williams, Ryan D Sheldon, Russell G Jones.

Infusion of 13C-labeled metabolites provides a gold-standard for understanding the metabolic processes used by T cells during immune responses in vivo . Through infusion of 13C-labeled metabolites (glucose, glutamine, acetate) in Listeria monocytogenes ( Lm )-infected mice, we demonstrate that CD8+ T effector (Teff) cells utilize metabolites for specific pathways during specific phases of activation. Highly proliferative early Teff cells in vivo shunt glucose primarily towards nucleotide synthesis and leverage glutamine anaplerosis in the tricarboxylic acid (TCA) cycle to support ATP and de novo pyrimidine synthesis. Additionally, early Teff cells rely on glutamic-oxaloacetic transaminase 1 (Got1)-which regulates de novo aspartate synthesis-for effector cell expansion in vivo . Importantly, Teff cells change fuel preference over the course of infection, switching from glutamine-to acetate-dependent TCA cycle metabolism late in infection. This study provides insights into the dynamics of Teff metabolism, illuminating distinct pathways of fuel consumption associated with Teff cell function in vivo .Teaser: Interrogating dynamics of fuel utilization by CD8 + T cells in vivo reveals new metabolic checkpoints for immune function in vivo .

DOI: https://doi.org/10.1101/2023.06.09.544407
Nat Metab. 2023 Jun 19.

A multimodal atlas of tumour metabolism reveals the architecture of gene-metabolite covariation.

Elisa Benedetti, Eric Minwei Liu, Cerise Tang, Fengshen Kuo, Mustafa Buyukozkan, Tricia Park, Jinsung Park, Fabian Correa, A Ari Hakimi, Andrew M Intlekofer, Jan Krumsiek, Ed Reznik.

Tumour metabolism is controlled by coordinated changes in metabolite abundance and gene expression, but simultaneous quantification of metabolites and transcripts in primary tissue is rare. To overcome this limitation and to study gene-metabolite covariation in cancer, we assemble the Cancer Atlas of Metabolic Profiles of metabolomic and transcriptomic data from 988 tumour and control specimens spanning 11 cancer types in published and newly generated datasets. Meta-analysis of the Cancer Atlas of Metabolic Profiles reveals two classes of gene-metabolite covariation that transcend cancer types. The first corresponds to gene-metabolite pairs engaged in direct enzyme-substrate interactions, identifying putative genes controlling metabolite pool sizes. A second class of gene-metabolite covariation represents a small number of hub metabolites, including quinolinate and nicotinamide adenine dinucleotide, which correlate to many genes specifically expressed in immune cell populations. These results provide evidence that gene-metabolite covariation in cellularly heterogeneous tissue arises, in part, from both mechanistic interactions between genes and metabolites, and from remodelling of the bulk metabolome in specific immune microenvironments.

DOI: https://doi.org/10.1038/s42255-023-00817-8
Nat Metab. 2023 Jun 22.

NADPH increase in mitosis in aneuploid tumour cells protects against genomic aberrations.

DOI: https://doi.org/10.1038/s42255-023-00848-1
J Gen Physiol. 2023 Aug 07. pii: e202313347. [Epub ahead of print]155(8):

Patch-clamp technique to study mitochondrial membrane biophysics.

Anshu Kumari, Dung M Nguyen, Vivek Garg.

Mitochondria are double-membrane organelles crucial for oxidative phosphorylation, enabling efficient ATP synthesis by eukaryotic cells. Both of the membranes, the highly selective inner mitochondrial membrane (IMM) and a relatively porous outer membrane (OMM), harbor a number of integral membrane proteins that help in the transport of biological molecules. These transporters are especially enriched in the IMM, where they help maintain transmembrane gradients for H+, K+, Ca2+, PO43-, and metabolites like ADP/ATP, citrate, etc. Impaired activity of these transporters can affect the efficiency of energy-transducing processes and can alter cellular redox state, leading to activation of cell-death pathways or metabolic syndromes in vivo. Although several methodologies are available to study ion flux through membrane proteins, the patch-clamp technique remains the gold standard for quantitatively analyzing electrogenic ion exchange across membranes. Direct patch-clamp recordings of mitoplasts (mitochondria devoid of outer membrane) in different modes, such as whole-mitoplast or excised-patch mode, allow researchers the opportunity to study the biophysics of mitochondrial transporters in the native membrane, in real time, in isolation from other fluxes or confounding factors due to changes in ion gradients, pH, or mitochondrial potential (ΔΨ). Here, we summarize the use of patch clamp to investigate several membrane proteins of mitochondria. We demonstrate how this technique can be reliably applied to record whole-mitoplast Ca2+ currents mediated via mitochondrial calcium uniporter or H+ currents mediated by uncoupling protein 1 and discuss critical considerations while recording currents from these small vesicles of the IMM (mitoplast diameter = 2-5 µm).

DOI: https://doi.org/10.1085/jgp.202313347
Br J Cancer. 2023 Jun 21.

Rethinking our approach to cancer metabolism to deliver patient benefit.

Saverio Tardito, Craig MacKay.

Altered cellular metabolism is a major mechanism by which tumours support nutrient consumption associated with increased cellular proliferation. Selective dependency on specific metabolic pathways provides a therapeutic vulnerability that can be targeted in cancer therapy. Anti-metabolites have been used clinically since the 1940s and several agents targeting nucleotide metabolism are now well established as standard of care treatment in a range of indications. However, despite great progress in our understanding of the metabolic requirements of cancer and non-cancer cells within the tumour microenvironment, there has been limited clinical success for novel agents targeting pathways outside of nucleotide metabolism. We believe that there is significant therapeutic potential in targeting metabolic processes within cancer that is yet to be fully realised. However, current approaches to identify novel targets, test novel therapies and select patient populations most likely to benefit are sub-optimal. We highlight recent advances in technologies and understanding that will support the identification and validation of novel targets, re-evaluation of existing targets and design of optimal clinical positioning strategies to deliver patient benefit.

DOI: https://doi.org/10.1038/s41416-023-02324-9
Annu Rev Microbiol. 2023 Jun 20.

Essential Amino Acid Metabolites as Chemical Mediators of Host-Microbe Interaction in the Gut.

Jessica R McCann, John F Rawls.

Amino acids are indispensable substrates for protein synthesis in all organisms and incorporated into diverse aspects of metabolic physiology and signaling. However, animals lack the ability to synthesize several of them and must acquire these essential amino acids from their diet or perhaps their associated microbial communities. The essential amino acids therefore occupy a unique position in the health of animals and their relationships with microbes. Here we review recent work connecting microbial production and metabolism of essential amino acids to host biology, and the reciprocal impacts of host metabolism of essential amino acids on their associated microbes. We focus on the roles of the branched-chain amino acids (valine, leucine, and isoleucine) and tryptophan on host-microbe communication in the intestine of humans and other vertebrates. We then conclude by highlighting research questions surrounding the less-understood aspects of microbial essential amino acid synthesis in animal hosts. Expected final online publication date for the Annual Review of Microbiology, Volume 77 is September 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-micro-032421-111819
Cell. 2023 Jun 19. pii: S0092-8674(23)00591-3. [Epub ahead of print]

Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity.

Yuanjiu Lei, Jordyn J VanPortfliet, Yi-Fan Chen, Joshua D Bryant, Ying Li, Danielle Fails, Sylvia Torres-Odio, Katherine B Ragan, Jingti Deng, Armaan Mohan, Bing Wang, Olivia N Brahms, Shawn D Yates, Michael Spencer, Carl W Tong, Marcus W Bosenberg, Laura Ciaccia West, Gerald S Shadel, Timothy E Shutt, Jason W Upton, Pingwei Li, A Phillip West.

  Mitochondrial DNA (mtDNA) is a potent agonist of the innate immune system; however, the exact immunostimulatory features of mtDNA and the kinetics of detection by cytosolic nucleic acid sensors remain poorly defined. Here, we show that mitochondrial genome instability promotes Z-form DNA accumulation. Z-DNA binding protein 1 (ZBP1) stabilizes Z-form mtDNA and nucleates a cytosolic complex containing cGAS, RIPK1, and RIPK3 to sustain STAT1 phosphorylation and type I interferon (IFN-I) signaling. Elevated Z-form mtDNA, ZBP1 expression, and IFN-I signaling are observed in cardiomyocytes after exposure to Doxorubicin, a first-line chemotherapeutic agent that induces frequent cardiotoxicity in cancer patients. Strikingly, mice lacking ZBP1 or IFN-I signaling are protected from Doxorubicin-induced cardiotoxicity. Our findings reveal ZBP1 as a cooperative partner for cGAS that sustains IFN-I responses to mitochondrial genome instability and highlight ZBP1 as a potential target in heart failure and other disorders where mtDNA stress contributes to interferon-related pathology.

Keywords:  STING; Z-DNA; ZBP1; cGAS; cardiotoxicity; heart failure; mitochondrial DNA; type I interferon

DOI:  https://doi.org/10.1016/j.cell.2023.05.039
Cell Rep. 2023 Jun 21. pii: S2211-1247(23)00677-0. [Epub ahead of print]42(7): 112666

Modulation of cellular metabolism by protein crotonylation regulates pancreatic cancer progression.

Yan Zheng, Le Zhu, Zhao-Yu Qin, Yu Guo, Shun Wang, Min Xue, Ke-Yu Shen, Bei-Yuan Hu, Xu-Feng Wang, Chao-Qun Wang, Lun-Xiu Qin, Qiong-Zhu Dong.

  Protein lysine crotonylation has been recently identified as a vital posttranslational modification in cellular processes, particularly through the modification of histones. We show that lysine crotonylation is an important modification of the cytoplastic and mitochondria proteins. Enzymes in glycolysis, the tricarboxylic acid (TCA) cycle, fatty acid metabolism, glutamine metabolism, glutathione metabolism, the urea cycle, one-carbon metabolism, and mitochondrial fusion/fission dynamics are found to be extensively crotonylated in pancreatic cancer cells. This modulation is mainly controlled by a pair of crotonylation writers and erasers including CBP/p300, HDAC1, and HDAC3. The dynamic crotonylation of metabolic enzymes is involved in metabolism regulation, which is linked with tumor progression. Interestingly, the activation of MTHFD1 by decrotonylation at Lys354 and Lys553 promotes the development of pancreatic cancer by increasing resistance to ferroptosis. Our study suggests that crotonylation represents a metabolic regulatory mechanism in pancreatic cancer progression.

Keywords:  CP: Cancer; CP: Molecular biology; MTHFD1; crotonylation; metabolism; pancreatic cancer; tumor progression

DOI:  https://doi.org/10.1016/j.celrep.2023.112666
Nat Commun. 2023 Jun 21. 14(1): 3673

SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells.

Yuelong Yan, Hongqi Teng, Qinglei Hang, Lavanya Kondiparthi, Guang Lei, Amber Horbath, Xiaoguang Liu, Chao Mao, Shiqi Wu, Li Zhuang, M James You, Masha V Poyurovsky, Li Ma, Kellen Olszewski, Boyi Gan.

The cystine transporter solute carrier family 7 member 11 (SLC7A11; also called xCT) protects cancer cells from oxidative stress and is overexpressed in many cancers. Here we report a surprising finding that, whereas moderate overexpression of SLC7A11 is beneficial for cancer cells treated with H2O2, a common oxidative stress inducer, its high overexpression dramatically increases H2O2-induced cell death. Mechanistically, high cystine uptake in cancer cells with high overexpression of SLC7A11 in combination with H2O2 treatment results in toxic buildup of intracellular cystine and other disulfide molecules, NADPH depletion, redox system collapse, and rapid cell death (likely disulfidptosis). We further show that high overexpression of SLC7A11 promotes tumor growth but suppresses tumor metastasis, likely because metastasizing cancer cells with high expression of SLC7A11 are particularly susceptible to oxidative stress. Our findings reveal that SLC7A11 expression level dictates cancer cells' sensitivity to oxidative stress and suggests a context-dependent role for SLC7A11 in tumor biology.

DOI: https://doi.org/10.1038/s41467-023-39401-9
Nat Rev Mol Cell Biol. 2023 Jun 21.

Deciphering ADP-ribosylation signalling.

Edoardo José Longarini, Helen Dauben.

DOI: https://doi.org/10.1038/s41580-023-00630-x
J Vis Exp. 2023 Jun 02.

Two-Step Tag-Free Isolation of Mitochondria for Improved Protein Discovery and Quantification.

Joan Blanco-Fernandez, Alexis A Jourdain.

Most physiological and disease processes, from central metabolism to immune response to neurodegeneration, involve mitochondria. The mitochondrial proteome is composed of more than 1,000 proteins, and the abundance of each can vary dynamically in response to external stimuli or during disease progression. Here, we describe a protocol for isolating high-quality mitochondria from primary cells and tissues. The two-step procedure comprises (1) mechanical homogenization and differential centrifugation to isolate crude mitochondria, and (2) tag-free immune capture of mitochondria to isolate pure organelles and eliminate contaminants. Mitochondrial proteins from each purification stage are analyzed by quantitative mass spectrometry, and enrichment yields are calculated, allowing the discovery of novel mitochondrial proteins by subtractive proteomics. Our protocol provides a sensitive and comprehensive approach to studying mitochondrial content in cell lines, primary cells, and tissues.

DOI: https://doi.org/10.3791/65252
Diabetes. 2023 Jun 21. pii: db220728. [Epub ahead of print]

A DEFECT IN MITOCHONDRIAL COMPLEX III BUT NOT IN COMPLEXES I OR IV CAUSES EARLY BETA CELL DYSFUNCTION AND HYPERGLYCEMIA IN MICE.

Anna L Lang, Nadee Nissanka, Ruy A Louzada, Alejandro Tamayo, Elizabeth Pereira, Carlos T Moraes, Alejandro Caicedo.

Mitochondrial metabolism and oxidative respiration are crucial for pancreatic beta cell function and stimulus secretion coupling. Oxidative phosphorylation (OxPhos) produces ATP and other metabolites that potentiate insulin secretion. However, the contribution of individual OxPhos complexes to beta cell function is unknown. We generated beta cell specific, inducible OxPhos complex KO mouse models to investigate the effects of disrupting Complex I, Complex III, or Complex IV on beta cell function. Although all KO models had similar mitochondrial respiratory defects, Complex III caused early hyperglycemia, glucose intolerance, and loss of glucose-stimulated insulin secretion in vivo. However, ex vivo insulin secretion did not change. Complex I and IV KO models showed diabetic phenotypes much later. Mitochondrial Ca2+ responses to glucose stimulation 3 weeks after gene deletion ranged from not affected to severely disrupted depending on the complex targeted, supporting the unique roles of each complex in beta cell signaling. Mitochondrial antioxidant enzyme immunostaining increased in islets from Complex III KO, but not from Complex I or IV KO mice, indicating that severe diabetic phenotype in the Complex III deficient mice is causing alterations in cellular redox status. The current study highlights that defects in individual OxPhos complexes lead to different pathogenic outcomes.

DOI: https://doi.org/10.2337/db22-0728
Cell. 2023 Jun 22. pii: S0092-8674(23)00539-1. [Epub ahead of print]186(13): 2719-2721

Alfred L. Goldberg (1942-2023).

Daniel Finley, David J Glass.

DOI: https://doi.org/10.1016/j.cell.2023.05.020
Biochimie. 2023 Jun 17. pii: S0300-9084(23)00146-3. [Epub ahead of print]214(Pt B): 77-85

Proton leak through the UCPs and ANT carriers and beyond: A breath for the electron transport chain.

Salvatore Nesci.

  Mitochondria produce heat as a result of an ineffective H+ cycling of mitochondria respiration across the inner mitochondrial membrane (IMM). This event present in all mitochondria, known as proton leak, can decrease protonmotive force (Δp) and restore mitochondrial respiration by partially uncoupling the substrate oxidation from the ADP phosphorylation. During impaired conditions of ATP generation with F1FO-ATPase, the Δp increases and IMM is hyperpolarized. In this bioenergetic state, the respiratory complexes support H+ transport until the membrane potential stops the H+ pump activity. Consequently, the electron transfer is stalled and the reduced form of electron carriers of the respiratory chain can generate O2∙¯ triggering the cascade of ROS formation and oxidative stress. The physiological function to attenuate the production of O2∙¯ by Δp dissipation can be attributed to the proton leak supported by the translocases of IMM.

Keywords:  Electron transport chain; Mitochondria; Proton conductance; Proton leak; Proton-motive force; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.biochi.2023.06.008
Science. 2023 Jun 23. 380(6651): eadh9351

Splice variants of mitofusin 2 shape the endoplasmic reticulum and tether it to mitochondria.

Déborah Naón, María Isabel Hernández-Alvarez, Satoko Shinjo, Milosz Wieczor, Saska Ivanova, Olga Martins de Brito, Albert Quintana, Juan Hidalgo, Manuel Palacín, Pilar Aparicio, Juan Castellanos, Luis Lores, David Sebastián, Sonia Fernández-Veledo, Joan Vendrell, Jorge Joven, Modesto Orozco, Antonio Zorzano, Luca Scorrano.

In eukaryotic cells, different organelles interact at membrane contact sites stabilized by tethers. Mitochondrial mitofusin 2 (MFN2) acts as a membrane tether that interacts with an unknown partner on the endoplasmic reticulum (ER). In this work, we identified the MFN2 splice variant ERMIT2 as the ER tethering partner of MFN2. Splicing of MFN2 produced ERMIT2 and ERMIN2, two ER-specific variants. ERMIN2 regulated ER morphology, whereas ERMIT2 localized at the ER-mitochondria interface and interacted with mitochondrial mitofusins to tether ER and mitochondria. This tethering allowed efficient mitochondrial calcium ion uptake and phospholipid transfer. Expression of ERMIT2 ameliorated the ER stress, inflammation, and fibrosis typical of liver-specific Mfn2 knockout mice. Thus, ER-specific MFN2 variants display entirely extramitochondrial MFN2 functions involved in interorganellar tethering and liver metabolic activities.

DOI: https://doi.org/10.1126/science.adh9351
Mol Cell. 2023 Jun 15. pii: S1097-2765(23)00419-7. [Epub ahead of print]

Genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner.

Meng Wang, Laura T L Brandt, Xiaonan Wang, Holly Russell, Emily Mitchell, Ashley N Kamimae-Lanning, Jill M Brown, Felix A Dingler, Juan I Garaycoechea, Tomoya Isobe, Sarah J Kinston, Muxin Gu, George S Vassiliou, Nicola K Wilson, Berthold Göttgens, Ketan J Patel.

  Aged hematopoietic stem cells (HSCs) display diminished self-renewal and a myeloid differentiation bias. However, the drivers and mechanisms that underpin this fundamental switch are not understood. HSCs produce genotoxic formaldehyde that requires protection by the detoxification enzymes ALDH2 and ADH5 and the Fanconi anemia (FA) DNA repair pathway. We find that the HSCs in young Aldh2-/-Fancd2-/- mice harbor a transcriptomic signature equivalent to aged wild-type HSCs, along with increased epigenetic age, telomere attrition, and myeloid-biased differentiation quantified by single HSC transplantation. In addition, the p53 response is vigorously activated in Aldh2-/-Fancd2-/- HSCs, while p53 deletion rescued this aged HSC phenotype. To further define the origins of the myeloid differentiation bias, we use a GFP genetic reporter to find a striking enrichment of Vwf+ myeloid and megakaryocyte-lineage-biased HSCs. These results indicate that metabolism-derived formaldehyde-DNA damage stimulates the p53 response in HSCs to drive accelerated aging.

Keywords:  DNA damage; DNA-damage response; aging; aldehydes; hematopoiesis; myeloid bias; p53

DOI:  https://doi.org/10.1016/j.molcel.2023.05.035
Cell Rep. 2023 Jun 22. pii: S2211-1247(23)00714-3. [Epub ahead of print]42(7): 112703

Pancreatic islet protection at the expense of secretory function involves serine-linked mitochondrial one-carbon metabolism.

Angela Pelligra, Jessica Mrugala, Kerstin Griess, Philip Kirschner, Oliver Nortmann, Barbara Bartosinska, Andrea Köster, Natalia I Krupenko, Dominik Gebel, Philipp Westhoff, Bodo Steckel, Daniel Eberhard, Diran Herebian, Bengt-Frederik Belgardt, Jürgen Schrader, Andreas P M Weber, Sergey A Krupenko, Eckhard Lammert.

DOI: https://doi.org/10.1016/j.celrep.2023.112703
Nat Rev Genet. 2023 Jun 23.

Single cell-cell communication.

Dorothy Clyde.

DOI: https://doi.org/10.1038/s41576-023-00631-8
J Immunol. 2023 Jun 21. pii: ji2200715. [Epub ahead of print]

Differential Effects of Glutamine Inhibition Strategies on Antitumor CD8 T Cells.

Matthew Z Madden, Xiang Ye, Channing Chi, Emilie L Fisher, Melissa M Wolf, Gabriel A Needle, Jackie E Bader, Andrew R Patterson, Bradley I Reinfeld, Madelyn D Landis, Emma S Hathaway, Jason E Muka, Richard T O'Neil, John Karijolich, Mary Philip, Jeffrey C Rathmell.

Activated T cells undergo metabolic reprogramming to meet anabolic, differentiation, and functional demands. Glutamine supports many processes in activated T cells, and inhibition of glutamine metabolism alters T cell function in autoimmune disease and cancer. Multiple glutamine-targeting molecules are under investigation, yet the precise mechanisms of glutamine-dependent CD8 T cell differentiation remain unclear. We show that distinct strategies of glutamine inhibition by glutaminase-specific inhibition with small molecule CB-839, pan-glutamine inhibition with 6-diazo-5-oxo-l-norleucine (DON), or by glutamine-depleted conditions (No Q) produce distinct metabolic differentiation trajectories in murine CD8 T cells. T cell activation with CB-839 treatment had a milder effect than did DON or No Q treatment. A key difference was that CB-839-treated cells compensated with increased glycolytic metabolism, whereas DON and No Q-treated cells increased oxidative metabolism. However, all glutamine treatment strategies elevated CD8 T cell dependence on glucose metabolism, and No Q treatment caused adaptation toward reduced glutamine dependence. DON treatment reduced histone modifications and numbers of persisting cells in adoptive transfer studies, but those T cells that remained could expand normally upon secondary Ag encounter. In contrast, No Q-treated cells persisted well yet demonstrated decreased secondary expansion. Consistent with reduced persistence, CD8 T cells activated in the presence of DON had reduced ability to control tumor growth and reduced tumor infiltration in adoptive cell therapy. Overall, each approach to inhibit glutamine metabolism confers distinct effects on CD8 T cells and highlights that targeting the same pathway in different ways can elicit opposing metabolic and functional outcomes.

DOI: https://doi.org/10.4049/jimmunol.2200715
Nat Metab. 2023 Jun 19.

Diverse biological functions of vitamin K: from coagulation to ferroptosis.

Eikan Mishima, Adam Wahida, Tobias Seibt, Marcus Conrad.

Vitamin K is essential for several physiological processes, such as blood coagulation, in which it serves as a cofactor for the conversion of peptide-bound glutamate to γ-carboxyglutamate in vitamin K-dependent proteins. This process is driven by the vitamin K cycle facilitated by γ-carboxyglutamyl carboxylase, vitamin K epoxide reductase and ferroptosis suppressor protein-1, the latter of which was recently identified as the long-sought-after warfarin-resistant vitamin K reductase. In addition, vitamin K has carboxylation-independent functions. Akin to ubiquinone, vitamin K acts as an electron carrier for ATP production in some organisms and prevents ferroptosis, a type of cell death hallmarked by lipid peroxidation. In this Perspective, we provide an overview of the diverse functions of vitamin K in physiology and metabolism and, at the same time, offer a perspective on its role in ferroptosis together with ferroptosis suppressor protein-1. A comparison between vitamin K and ubiquinone, from an evolutionary perspective, may offer further insights into the manifold roles of vitamin K in biology.

DOI: https://doi.org/10.1038/s42255-023-00821-y
Nature. 2023 Jun 21.

Injury prevents Ras mutant cell expansion in mosaic skin.

Sara Gallini, Karl Annusver, Nur-Taz Rahman, David G Gonzalez, Sangwon Yun, Catherine Matte-Martone, Tianchi Xin, Elizabeth Lathrop, Kathleen C Suozzi, Maria Kasper, Valentina Greco.

Healthy skin is a mosaic of wild-type and mutant clones1,2. Although injury can cooperate with mutated Ras family proteins to promote tumorigenesis3-12, the consequences in genetically mosaic skin are unknown. Here we show that after injury, wild-type cells suppress aberrant growth induced by oncogenic Ras. HrasG12V/+ and KrasG12D/+ cells outcompete wild-type cells in uninjured, mosaic tissue but their expansion is prevented after injury owing to an increase in the fraction of proliferating wild-type cells. Mechanistically, we show that, unlike HrasG12V/+ cells, wild-type cells respond to autocrine and paracrine secretion of EGFR ligands, and this differential activation of the EGFR pathway explains the competitive switch during injury repair. Inhibition of EGFR signalling via drug or genetic approaches diminishes the proportion of dividing wild-type cells after injury, leading to the expansion of HrasG12V/+ cells. Increased proliferation of wild-type cells via constitutive loss of the cell cycle inhibitor p21 counteracts the expansion of HrasG12V/+ cells even in the absence of injury. Thus, injury has a role in switching the competitive balance between oncogenic and wild-type cells in genetically mosaic skin.

DOI: https://doi.org/10.1038/s41586-023-06198-y
Nat Metab. 2023 Jun 22.

A mitotic NADPH upsurge promotes chromosome segregation and tumour progression in aneuploid cancer cells.

Aoxing Cheng, Tian Xu, Weiyi You, Ting Wang, Dongming Zhang, Huimin Guo, Haiyan Zhang, Xin Pan, Yucai Wang, Liu Liu, Kaiguang Zhang, Jue Shi, Xuebiao Yao, Jing Guo, Zhenye Yang.

Redox metabolites have been observed to fluctuate through the cell cycle in cancer cells, but the functional impacts of such metabolic oscillations remain unknown. Here, we uncover a mitosis-specific nicotinamide adenine dinucleotide phosphate (NADPH) upsurge that is essential for tumour progression. Specifically, NADPH is produced by glucose 6-phosphate dehydrogenase (G6PD) upon mitotic entry, which neutralizes elevated reactive oxygen species (ROS) and prevents ROS-mediated inactivation of mitotic kinases and chromosome missegregation. Mitotic activation of G6PD depends on the phosphorylation of its co-chaperone protein BAG3 at threonine 285, which results in dissociation of inhibitory BAG3. Blocking BAG3T285 phosphorylation induces tumour suppression. A mitotic NADPH upsurge is present in aneuploid cancer cells with high levels of ROS, while nearly unobservable in near-diploid cancer cells. High BAG3T285 phosphorylation is associated with worse prognosis in a cohort of patients with microsatellite-stable colorectal cancer. Our study reveals that aneuploid cancer cells with high levels of ROS depend on a G6PD-mediated NADPH upsurge in mitosis to protect them from ROS-induced chromosome missegregation.

DOI: https://doi.org/10.1038/s42255-023-00832-9
Dev Cell. 2023 Jun 14. pii: S1534-5807(23)00266-6. [Epub ahead of print]

Epithelial tissue confinement inhibits cell growth and leads to volume-reducing divisions.

John Devany, Martin J Falk, Liam J Holt, Arvind Murugan, Margaret L Gardel.

  Cell proliferation is a central process in tissue development, homeostasis, and disease, yet how proliferation is regulated in the tissue context remains poorly understood. Here, we introduce a quantitative framework to elucidate how tissue growth dynamics regulate cell proliferation. Using MDCK epithelial monolayers, we show that a limiting rate of tissue expansion creates confinement that suppresses cell growth; however, this confinement does not directly affect the cell cycle. This leads to uncoupling between rates of cell growth and division in epithelia and, thereby, reduces cell volume. Division becomes arrested at a minimal cell volume, which is consistent across diverse epithelia in vivo. Here, the nucleus approaches the minimum volume capable of packaging the genome. Loss of cyclin D1-dependent cell-volume regulation results in an abnormally high nuclear-to-cytoplasmic volume ratio and DNA damage. Overall, we demonstrate how epithelial proliferation is regulated by the interplay between tissue confinement and cell-volume regulation.

Keywords:  G1 sizer; cell cycle; cell growth; cell proliferation; cell volume; contact inhibition of proliferation; epithelial monolayer; epithelium; tissue confinement; tissue growth

DOI:  https://doi.org/10.1016/j.devcel.2023.05.018
Nat Commun. 2023 Jun 23. 14(1): 3746

Mitochondrial matrix protein LETMD1 maintains thermogenic capacity of brown adipose tissue in male mice.

Anna Park, Kwang-Eun Kim, Isaac Park, Sang Heon Lee, Kun-Young Park, Minkyo Jung, Xiaoxu Li, Maroun Bou Sleiman, Su Jeong Lee, Dae-Soo Kim, Jaehoon Kim, Dae-Sik Lim, Eui-Jeon Woo, Eun Woo Lee, Baek Soo Han, Kyoung-Jin Oh, Sang Chul Lee, Johan Auwerx, Ji Young Mun, Hyun-Woo Rhee, Won Kon Kim, Kwang-Hee Bae, Jae Myoung Suh.

Brown adipose tissue (BAT) has abundant mitochondria with the unique capability of generating heat via uncoupled respiration. Mitochondrial uncoupling protein 1 (UCP1) is activated in BAT during cold stress and dissipates mitochondrial proton motive force generated by the electron transport chain to generate heat. However, other mitochondrial factors required for brown adipocyte respiration and thermogenesis under cold stress are largely unknown. Here, we show LETM1 domain-containing protein 1 (LETMD1) is a BAT-enriched and cold-induced protein required for cold-stimulated respiration and thermogenesis of BAT. Proximity labeling studies reveal that LETMD1 is a mitochondrial matrix protein. Letmd1 knockout male mice display aberrant BAT mitochondria and fail to carry out adaptive thermogenesis under cold stress. Letmd1 knockout BAT is deficient in oxidative phosphorylation (OXPHOS) complex proteins and has impaired mitochondrial respiration. In addition, BAT-specific Letmd1 deficient mice exhibit phenotypes identical to those observed in Letmd1 knockout mice. Collectively, we demonstrate that the BAT-enriched mitochondrial matrix protein LETMD1 plays a tissue-autonomous role that is essential for BAT mitochondrial function and thermogenesis.

DOI: https://doi.org/10.1038/s41467-023-39106-z
JAMA Oncol. 2023 Jun 22.

Developing an Ideal Risk Stratification Model for Metastatic Renal Cell Carcinoma.

Georges Gebrael, Gliceida Galarza Fortuna, Neeraj Agarwal.

DOI: https://doi.org/10.1001/jamaoncol.2023.1764
Nature. 2023 Jun 21.

Y chromosome loss in cancer drives growth by evasion of adaptive immunity.

Hany A Abdel-Hafiz, Johanna M Schafer, Xingyu Chen, Tong Xiao, Timothy D Gauntner, Zihai Li, Dan Theodorescu.

Loss of the Y chromosome (LOY) is observed in multiple cancer types, including 10-40% of bladder cancers1-6, but its clinical and biological significance is unknown. Here, using genomic and transcriptomic studies, we report that LOY correlates with poor prognoses in patients with bladder cancer. We performed in-depth studies of naturally occurring LOY mutant bladder cancer cells as well as those with targeted deletion of Y chromosome by CRISPR-Cas9. Y-positive (Y+) and Y-negative (Y-) tumours grew similarly in vitro, whereas Y- tumours were more aggressive than Y+ tumours in immune-competent hosts in a T cell-dependent manner. High-dimensional flow cytometric analyses demonstrated that Y- tumours promote striking dysfunction or exhaustion of CD8+ T cells in the tumour microenvironment. These findings were validated using single-nuclei RNA sequencing and spatial proteomic evaluation of human bladder cancers. Of note, compared with Y+ tumours, Y- tumours exhibited an increased response to anti-PD-1 immune checkpoint blockade therapy in both mice and patients with cancer. Together, these results demonstrate that cancer cells with LOY mutations alter T cell function, promoting T cell exhaustion and sensitizing them to PD-1-targeted immunotherapy. This work provides insights into the basic biology of LOY mutation and potential biomarkers for improving cancer immunotherapy.

DOI: https://doi.org/10.1038/s41586-023-06234-x
Nat Metab. 2023 Jun 19.

Adipogenic and SWAT cells separate from a common progenitor in human brown and white adipose depots.

Nagendra P Palani, Carla Horvath, Pascal N Timshel, Pytrik Folkertsma, Alexander G B Grønning, Tora I Henriksen, Lone Peijs, Verena H Jensen, Wenfei Sun, Naja Z Jespersen, Christian Wolfrum, Tune H Pers, Søren Nielsen, Camilla Scheele.

Adipocyte function is a major determinant of metabolic disease, warranting investigations of regulating mechanisms. We show at single-cell resolution that progenitor cells from four human brown and white adipose depots separate into two main cell fates, an adipogenic and a structural branch, developing from a common progenitor. The adipogenic gene signature contains mitochondrial activity genes, and associates with genome-wide association study traits for fat distribution. Based on an extracellular matrix and developmental gene signature, we name the structural branch of cells structural Wnt-regulated adipose tissue-resident (SWAT) cells. When stripped from adipogenic cells, SWAT cells display a multipotent phenotype by reverting towards progenitor state or differentiating into new adipogenic cells, dependent on media. Label transfer algorithms recapitulate the cell types in human adipose tissue datasets. In conclusion, we provide a differentiation map of human adipocytes and define the multipotent SWAT cell, providing a new perspective on adipose tissue regulation.

DOI: https://doi.org/10.1038/s42255-023-00820-z
Nucleic Acids Res. 2023 Jun 23. pii: gkad535. [Epub ahead of print]

Enhanced mitochondrial G-quadruplex formation impedes replication fork progression leading to mtDNA loss in human cells.

Mara Doimo, Namrata Chaudhari, Sanna Abrahamsson, Valentin L'Hôte, Tran V H Nguyen, Andreas Berner, Mama Ndi, Alva Abrahamsson, Rabindra Nath Das, Koit Aasumets, Steffi Goffart, Jaakko L O Pohjoismäki, Marcela Dávila López, Erik Chorell, Sjoerd Wanrooij.

Mitochondrial DNA (mtDNA) replication stalling is considered an initial step in the formation of mtDNA deletions that associate with genetic inherited disorders and aging. However, the molecular details of how stalled replication forks lead to mtDNA deletions accumulation are still unclear. Mitochondrial DNA deletion breakpoints preferentially occur at sequence motifs predicted to form G-quadruplexes (G4s), four-stranded nucleic acid structures that can fold in guanine-rich regions. Whether mtDNA G4s form in vivo and their potential implication for mtDNA instability is still under debate. In here, we developed new tools to map G4s in the mtDNA of living cells. We engineered a G4-binding protein targeted to the mitochondrial matrix of a human cell line and established the mtG4-ChIP method, enabling the determination of mtDNA G4s under different cellular conditions. Our results are indicative of transient mtDNA G4 formation in human cells. We demonstrate that mtDNA-specific replication stalling increases formation of G4s, particularly in the major arc. Moreover, elevated levels of G4 block the progression of the mtDNA replication fork and cause mtDNA loss. We conclude that stalling of the mtDNA replisome enhances mtDNA G4 occurrence, and that G4s not resolved in a timely manner can have a negative impact on mtDNA integrity.

DOI: https://doi.org/10.1093/nar/gkad535
Nature. 2023 Jun;618(7966): 808-817

Signalling by senescent melanocytes hyperactivates hair growth.

Xiaojie Wang, Raul Ramos, Anne Q Phan, Kosuke Yamaga, Jessica L Flesher, Shan Jiang, Ji Won Oh, Suoqin Jin, Sohail Jahid, Chen-Hsiang Kuan, Truman Kt Nguyen, Heidi Y Liang, Nitish Udupi Shettigar, Renzhi Hou, Kevin H Tran, Andrew Nguyen, Kimberly N Vu, Jennie L Phung, Jonard P Ingal, Katelyn M Levitt, Xiaoling Cao, Yingzi Liu, Zhili Deng, Nobuhiko Taguchi, Vanessa M Scarfone, Guangfang Wang, Kara Nicole Paolilli, Xiaoyang Wang, Christian F Guerrero-Juarez, Ryan T Davis, Elyse Noelani Greenberg, Rolando Ruiz-Vega, Priya Vasudeva, Rabi Murad, Lily Halida Putri Widyastuti, Hye-Lim Lee, Kevin J McElwee, Alain-Pierre Gadeau, Devon A Lawson, Bogi Andersen, Ali Mortazavi, Zhengquan Yu, Qing Nie, Takahiro Kunisada, Michael Karin, Jan Tuckermann, Jeffrey D Esko, Anand K Ganesan, Ji Li, Maksim V Plikus.

Niche signals maintain stem cells in a prolonged quiescence or transiently activate them for proper regeneration1. Altering balanced niche signalling can lead to regenerative disorders. Melanocytic skin nevi in human often display excessive hair growth, suggesting hair stem cell hyperactivity. Here, using genetic mouse models of nevi2,3, we show that dermal clusters of senescent melanocytes drive epithelial hair stem cells to exit quiescence and change their transcriptome and composition, potently enhancing hair renewal. Nevus melanocytes activate a distinct secretome, enriched for signalling factors. Osteopontin, the leading nevus signalling factor, is both necessary and sufficient to induce hair growth. Injection of osteopontin or its genetic overexpression is sufficient to induce robust hair growth in mice, whereas germline and conditional deletions of either osteopontin or CD44, its cognate receptor on epithelial hair cells, rescue enhanced hair growth induced by dermal nevus melanocytes. Osteopontin is overexpressed in human hairy nevi, and it stimulates new growth of human hair follicles. Although broad accumulation of senescent cells, such as upon ageing or genotoxic stress, is detrimental for the regenerative capacity of tissue4, we show that signalling by senescent cell clusters can potently enhance the activity of adjacent intact stem cells and stimulate tissue renewal. This finding identifies senescent cells and their secretome as an attractive therapeutic target in regenerative disorders.

DOI: https://doi.org/10.1038/s41586-023-06172-8
Nat Commun. 2023 Jun 23. 14(1): 3760

Rapid and reversible optical switching of cell membrane area by an amphiphilic azobenzene.

Fabian Höglsperger, Bart E Vos, Arne D Hofemeier, Maximilian D Seyfried, Bastian Stövesand, Azadeh Alavizargar, Leon Topp, Andreas Heuer, Timo Betz, Bart Jan Ravoo.

Cellular membrane area is a key parameter for any living cell that is tightly regulated to avoid membrane damage. Changes in area-to-volume ratio are known to be critical for cell shape, but are mostly investigated by changing the cell volume via osmotic shocks. In turn, many important questions relating to cellular shape, membrane tension homeostasis and local membrane area cannot be easily addressed because experimental tools for controlled modulation of cell membrane area are lacking. Here we show that photoswitching an amphiphilic azobenzene can trigger its intercalation into the plasma membrane of various mammalian cells ranging from erythrocytes to myoblasts and cancer cells. The photoisomerization leads to a rapid (250-500 ms) and highly reversible membrane area change (ca 2 % for erythrocytes) that triggers a dramatic shape modulation of living cells.

DOI: https://doi.org/10.1038/s41467-023-39032-0
Cell Biol Toxicol. 2023 Jun 23.

Transcriptional landscape of mitochondrial electron transport chain inhibition in renal cells.

Giada Carta, Wanda van der Stel, Emma W J Scuric, Liliana Capinha, Johannes Delp, Susanne Hougaard Bennekou, Anna Forsby, Paul Walker, Marcel Leist, Bob van de Water, Paul Jennings.

  Analysis of the transcriptomic alterations upon chemical challenge, provides in depth mechanistic information on the compound's toxic mode of action, by revealing specific pathway activation and other transcriptional modulations. Mapping changes in cellular behaviour to chemical insult, facilitates the characterisation of chemical hazard. In this study, we assessed the transcriptional landscape of mitochondrial impairment through the inhibition of the electron transport chain (ETC) in a human renal proximal tubular cell line (RPTEC/TERT1). We identified the unfolded protein response pathway (UPR), particularly the PERK/ATF4 branch as a common cellular response across ETC I, II and III inhibitions. This finding and the specific genes elaborated may aid the identification of mitochondrial liabilities of chemicals in both legacy data and prospective transcriptomic studies.

Keywords:  In vitro; Mitochondria; Renal; Stress pathway; Transcriptomic

DOI:  https://doi.org/10.1007/s10565-023-09816-7
Sci Adv. 2023 Jun 23. 9(25): eadg7038

Disruption of proteome by an oncogenic fusion kinase alters metabolism in fibrolamellar hepatocellular carcinoma.

Solomon N Levin, Michael D Tomasini, James Knox, Mahsa Shirani, Bassem Shebl, David Requena, Jackson Clark, Søren Heissel, Hanan Alwaseem, Rodrigo Surjan, Ron Lahasky, Henrik Molina, Michael S Torbenson, Barbara Lyons, Rachael D Migler, Philip Coffino, Sanford M Simon.

Fibrolamellar hepatocellular carcinoma (FLC) is a usually lethal primary liver cancer driven by a somatic dysregulation of protein kinase A. We show that the proteome of FLC tumors is distinct from that of adjacent nontransformed tissue. These changes can account for some of the cell biological and pathological alterations in FLC cells, including their drug sensitivity and glycolysis. Hyperammonemic encephalopathy is a recurrent problem in these patients, and established treatments based on the assumption of liver failure are unsuccessful. We show that many of the enzymes that produce ammonia are increased and those that consume ammonia are decreased. We also demonstrate that the metabolites of these enzymes change as expected. Thus, hyperammonemic encephalopathy in FLC may require alternative therapeutics.

DOI: https://doi.org/10.1126/sciadv.adg7038