bims-camemi 2024-05-05 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2024–05–05
43 papers selected by
Christian Frezza, Universität zu Köln

Cycling back to folate metabolism in cancer.
A model of mitochondrial superoxide production during ischaemia-reperfusion injury for therapeutic development and mechanistic understanding.
Inhibition of mammalian mtDNA transcription acts paradoxically to reverse diet-induced hepatosteatosis and obesity.
Acetate reprogrammes tumour metabolism and promotes PD-L1 expression and immune evasion by upregulating c-Myc.
Mitochondrial redox state, bioenergetics, and calcium transport in caloric restriction: A metabolic nexus.
A dynamin superfamily-like pseudoenzyme coordinates with MICOS to promote cristae architecture.
Mesoscale Metabolic Channeling Revealed by Multimodal Microscopy.
Mitochondrial genome transfer drives metabolic reprogramming in adjacent colonic epithelial cells promoting TGFβ1-mediated tumor progression.
The epidermal circadian clock integrates and subverts brain signals to guarantee skin homeostasis.
Unprocessed genomic uracil as a source of DNA replication stress in cancer cells.
Inhibition of asparagine synthetase effectively retards polycystic kidney disease progression.
An aldehyde-crosslinking mitochondrial probe for STED imaging in fixed cells.
PARKIN is not required to sustain OXPHOS function in adult mammalian tissues.
Image-based quantification of mitochondrial iron uptake via Mitoferrin-2.
Mitochondria and Cancer.
Dietary intake and glutamine-serine metabolism control pathologic vascular stiffness.
The mitochondrial multi-omic response to exercise training across rat tissues.
The factor inhibiting HIF regulates T cell differentiation and anti-tumour efficacy.
Cold-induced expression of a truncated adenylyl cyclase 3 acts as rheostat to brown fat function.
MCU genetically altered mice suggest how mitochondrial Ca2+ regulates metabolism.
A MTA2-SATB2 chromatin complex restrains colonic plasticity toward small intestine by retaining HNF4A at colonic chromatin.
Macrophage-fibroblast JAK/STAT dependent crosstalk promotes liver metastatic outgrowth in pancreatic cancer.
Ferroptosis Biology.
Immunometabolism of CD8+ T cell differentiation in cancer.
Senescent CAFs Mediate Immunosuppression and Drive Breast Cancer Progression.
Investigating the thermal sensitivity of key enzymes involved in the energetic metabolism of three insect species.
SAH is a major metabolic sensor mediating worsening metabolic crosstalk in metabolic syndrome.
Nitric oxide-mediated regulation of Aspergillus flavus asexual development by targeting TCA cycle and mitochondrial function.
Smooth muscle cell-derived Cxcl12 directs macrophage accrual and sympathetic innervation to control thermogenic adipose tissue.
OTUB2 silencing promotes ovarian cancer via mitochondrial metabolic reprogramming and can be synthetically targeted by CA9 inhibition.
Mitochondrial transfer mediates endothelial cell engraftment through mitophagy.
Fundamentals of redox regulation in biology.
Cyclodipeptide oxidase is an enzyme filament.
Microbial metabolite steers intestinal stem cell fate under stress.
Bile acids for diabetic cardiomyopathy.
Itaconate alleviates diet-induced obesity via activation of brown adipocyte thermogenesis.
Airway hillocks are injury-resistant reservoirs of unique plastic stem cells.
Transient Zn2+ deficiency induces replication stress and compromises daughter cell proliferation.
Senescence Defines a Distinct Subset of Myofibroblasts That Orchestrates Immunosuppression in Pancreatic Cancer.
Post-translational modification-centric base editor screens to assess phosphorylation site functionality in high throughput.
Oncogenic Kras induces spatiotemporally specific tissue deformation through converting pulsatile into sustained ERK activation.
Paternal microbiome perturbations impact offspring fitness.
Safety in numbers?

Nat Cancer. 2024 May 02.

Cycling back to folate metabolism in cancer.

Younghwan Lee, Karen H Vousden, Marc Hennequart.

Metabolic changes contribute to cancer initiation and progression through effects on cancer cells, the tumor microenvironment and whole-body metabolism. Alterations in serine metabolism and the control of one-carbon cycles have emerged as critical for the development of many tumor types. In this Review, we focus on the mitochondrial folate cycle. We discuss recent evidence that, in addition to supporting nucleotide synthesis, mitochondrial folate metabolism also contributes to metastasis through support of antioxidant defense, mitochondrial protein synthesis and the overflow of excess formate. These observations offer potential therapeutic opportunities, including the modulation of formate metabolism through dietary interventions and the use of circulating folate cycle metabolites as biomarkers for cancer detection.

DOI: https://doi.org/10.1038/s43018-024-00739-8
Redox Biol. 2024 Apr 24. pii: S2213-2317(24)00137-X. [Epub ahead of print]72 103161

A model of mitochondrial superoxide production during ischaemia-reperfusion injury for therapeutic development and mechanistic understanding.

Annabel Sorby-Adams, Tracy A Prime, Jan Lj Miljkovic, Hiran A Prag, Thomas Krieg, Michael P Murphy.

  Ischaemia-reperfusion (IR) injury is the paradoxical consequence of the rapid restoration of blood flow to an ischaemic organ. Although reperfusion is essential for tissue survival in conditions such as myocardial infarction and stroke, the excessive production of mitochondrial reactive oxygen species (ROS) upon reperfusion initiates the oxidative damage that underlies IR injury, by causing cell death and inflammation. This ROS production is caused by an accumulation of the mitochondrial metabolite succinate during ischaemia, followed by its rapid oxidation upon reperfusion by succinate dehydrogenase (SDH), driving superoxide production at complex I by reverse electron transport. Inhibitors of SDH, such as malonate, show therapeutic potential by decreasing succinate oxidation and superoxide production upon reperfusion. To better understand the mechanism of mitochondrial ROS production upon reperfusion and to assess potential therapies, we set up an in vitro model of IR injury. For this, isolated mitochondria were incubated anoxically with succinate to mimic ischaemia and then rapidly reoxygenated to replicate reperfusion, driving a burst of ROS formation. Using this system, we assess the factors that contribute to the magnitude of mitochondrial ROS production in heart, brain, and kidney mitochondria, as well as screening for inhibitors of succinate oxidation with therapeutic potential.

Keywords:  Complex I; Ischaemia-reperfusion injury; Malonate; Mitochondria; Reverse electron transport; Succinate

DOI:  https://doi.org/10.1016/j.redox.2024.103161
Nat Metab. 2024 Apr 30.

Inhibition of mammalian mtDNA transcription acts paradoxically to reverse diet-induced hepatosteatosis and obesity.

Shan Jiang, Taolin Yuan, Florian A Rosenberger, Arnaud Mourier, Nathalia R V Dragano, Laura S Kremer, Diana Rubalcava-Gracia, Fynn M Hansen, Melissa Borg, Mara Mennuni, Roberta Filograna, David Alsina, Jelena Misic, Camilla Koolmeister, Polyxeni Papadea, Martin Hrabe de Angelis, Lipeng Ren, Olov Andersson, Anke Unger, Tim Bergbrede, Raffaella Di Lucrezia, Rolf Wibom, Juleen R Zierath, Anna Krook, Patrick Giavalisco, Matthias Mann, Nils-Göran Larsson.

The oxidative phosphorylation system1 in mammalian mitochondria plays a key role in transducing energy from ingested nutrients2. Mitochondrial metabolism is dynamic and can be reprogrammed to support both catabolic and anabolic reactions, depending on physiological demands or disease states. Rewiring of mitochondrial metabolism is intricately linked to metabolic diseases and promotes tumour growth3-5. Here, we demonstrate that oral treatment with an inhibitor of mitochondrial transcription (IMT)6 shifts whole-animal metabolism towards fatty acid oxidation, which, in turn, leads to rapid normalization of body weight, reversal of hepatosteatosis and restoration of normal glucose tolerance in male mice on a high-fat diet. Paradoxically, the IMT treatment causes a severe reduction of oxidative phosphorylation capacity concomitant with marked upregulation of fatty acid oxidation in the liver, as determined by proteomics and metabolomics analyses. The IMT treatment leads to a marked reduction of complex I, the main dehydrogenase feeding electrons into the ubiquinone (Q) pool, whereas the levels of electron transfer flavoprotein dehydrogenase and other dehydrogenases connected to the Q pool are increased. This rewiring of metabolism caused by reduced mtDNA expression in the liver provides a principle for drug treatment of obesity and obesity-related pathology.

DOI: https://doi.org/10.1038/s42255-024-01038-3
Nat Metab. 2024 May 03.

Acetate reprogrammes tumour metabolism and promotes PD-L1 expression and immune evasion by upregulating c-Myc.

Juhong Wang, Yannan Yang, Fei Shao, Ying Meng, Dong Guo, Jie He, Zhimin Lu.

Acetate, a precursor of acetyl-CoA, is instrumental in energy production, lipid synthesis and protein acetylation. However, whether acetate reprogrammes tumour metabolism and plays a role in tumour immune evasion remains unclear. Here, we show that acetate is the most abundant short-chain fatty acid in human non-small cell lung cancer tissues, with increased tumour-enriched acetate uptake. Acetate-derived acetyl-CoA induces c-Myc acetylation, which is mediated by the moonlighting function of the metabolic enzyme dihydrolipoamide S-acetyltransferase. Acetylated c-Myc increases its stability and subsequent transcription of the genes encoding programmed death-ligand 1, glycolytic enzymes, monocarboxylate transporter 1 and cell cycle accelerators. Dietary acetate supplementation promotes tumour growth and inhibits CD8+ T cell infiltration, whereas disruption of acetate uptake inhibits immune evasion, which increases the efficacy of anti-PD-1-based therapy. These findings highlight a critical role of acetate promoting tumour growth beyond its metabolic role as a carbon source by reprogramming tumour metabolism and immune evasion, and underscore the potential of controlling acetate metabolism to curb tumour growth and improve the response to immune checkpoint blockade therapy.

DOI: https://doi.org/10.1038/s42255-024-01037-4
Free Radic Biol Med. 2024 Apr 25. pii: S0891-5849(24)00421-0. [Epub ahead of print]219 195-214

Mitochondrial redox state, bioenergetics, and calcium transport in caloric restriction: A metabolic nexus.

Eloisa A Vilas-Boas, Alicia J Kowaltowski.

Mitochondria congregate central reactions in energy metabolism, many of which involve electron transfer. As such, they are expected to both respond to changes in nutrient supply and demand and also provide signals that integrate energy metabolism intracellularly. In this review, we discuss how mitochondrial bioenergetics and reactive oxygen species production is impacted by dietary interventions that change nutrient availability and impact on aging, such as calorie restriction. We also discuss how dietary interventions alter mitochondrial Ca2+ transport, regulating both mitochondrial and cytosolic processes modulated by this ion. Overall, a plethora of literature data support the idea that mitochondrial oxidants and calcium transport act as integrating signals coordinating the response to changes in nutritional supply and demand in cells, tissues, and animals.

DOI: https://doi.org/10.1016/j.freeradbiomed.2024.04.234
Curr Biol. 2024 Apr 24. pii: S0960-9822(24)00468-8. [Epub ahead of print]

A dynamin superfamily-like pseudoenzyme coordinates with MICOS to promote cristae architecture.

Abhishek Kumar, Mehmet Oguz Gok, Kailey N Nguyen, Olivia M Connor, Michael L Reese, Jeremy G Wideman, Sergio A Muñoz-Gómez, Jonathan R Friedman.

  Mitochondrial cristae architecture is crucial for optimal respiratory function of the organelle. Cristae shape is maintained in part by the mitochondrial contact site and cristae organizing system (MICOS) complex. While MICOS is required for normal cristae morphology, the precise mechanistic role of each of the seven human MICOS subunits, and how the complex coordinates with other cristae-shaping factors, has not been fully determined. Here, we examine the MICOS complex in Schizosaccharomyces pombe, a minimal model whose genome only encodes for four core subunits. Using an unbiased proteomics approach, we identify a poorly characterized inner mitochondrial membrane protein that interacts with MICOS and is required to maintain cristae morphology, which we name Mmc1. We demonstrate that Mmc1 works in concert with MICOS to promote normal mitochondrial morphology and respiratory function. Mmc1 is a distant relative of the dynamin superfamily of proteins (DSPs), GTPases, which are well established to shape and remodel membranes. Similar to DSPs, Mmc1 self-associates and forms high-molecular-weight assemblies. Interestingly, however, Mmc1 is a pseudoenzyme that lacks key residues required for GTP binding and hydrolysis, suggesting that it does not dynamically remodel membranes. These data are consistent with the model that Mmc1 stabilizes cristae architecture by acting as a scaffold to support cristae ultrastructure on the matrix side of the inner membrane. Our study reveals a new class of proteins that evolved early in fungal phylogeny and is required for the maintenance of cristae architecture. This highlights the possibility that functionally analogous proteins work with MICOS to establish cristae morphology in metazoans.

Keywords:  MICOS; cristae; dynamin; fission yeast; membrane remodeling; mitochondria; pseudoenzyme

DOI:  https://doi.org/10.1016/j.cub.2024.04.028
Res Sq. 2024 Apr 17. pii: rs.3.rs-4096781. [Epub ahead of print]

Mesoscale Metabolic Channeling Revealed by Multimodal Microscopy.

Rafael Arrojo E Drigo, Aliyah Habashy, Christopher Acree, Keun-Young Kim, Thomas Deerinck, Emilee Patterson, Louise Lantier, Owen McGuinness, Mark Ellisman.

Metabolic homeostasis within cells and tissues requires engagement of catabolic and anabolic pathways consuming nutrients needed to generate energy to drive these and other subcellular processes. However, the current understanding of cell homeostasis and metabolism, including how cells utilize nutrients, comes largely from tissue and cell models analyzed after fractionation. These bulk strategies do not reveal the spatial characteristics of cell metabolism at the single cell level, and how these aspects relate to the location of cells and organelles within the complexity of the tissue they reside within. Here we pioneer the use of high-resolution electron and stable isotope microscopy (MIMS-EM) to quantitatively map the fate of nutrient-derived 13 C atoms at subcellular scale. When combined with machine-learning image segmentation, our approach allows us to establish the cellular and organellar spatial pattern of glucose 13 C flux in hepatocytes in situ . We applied network analysis algorithms to chart the landscape of organelle-organelle contact networks and identified subpopulations of mitochondria and lipid droplets that have distinct organelle interactions and 13 C enrichment levels. In addition, we revealed a new relationship between the initiation of glycogenesis and proximity of lipid droplets. Our results establish MIMS-EM as a new tool for tracking and quantifying nutrient metabolism at the subcellular scale, and to identify the spatial channeling of nutrient-derived atoms in the context of organelle-organelle interactions in situ .

DOI: https://doi.org/10.21203/rs.3.rs-4096781/v1
Nat Commun. 2024 Apr 30. 15(1): 3653

Mitochondrial genome transfer drives metabolic reprogramming in adjacent colonic epithelial cells promoting TGFβ1-mediated tumor progression.

Bingjie Guan, Youdong Liu, Bowen Xie, Senlin Zhao, Abudushalamu Yalikun, Weiwei Chen, Menghua Zhou, Qi Gu, Dongwang Yan.

Although nontumor components play an essential role in colon cancer (CC) progression, the intercellular communication between CC cells and adjacent colonic epithelial cells (CECs) remains poorly understood. Here, we show that intact mitochondrial genome (mitochondrial DNA, mtDNA) is enriched in serum extracellular vesicles (EVs) from CC patients and positively correlated with tumor stage. Intriguingly, circular mtDNA transferred via tumor cell-derived EVs (EV-mtDNA) enhances mitochondrial respiration and reactive oxygen species (ROS) production in CECs. Moreover, the EV-mtDNA increases TGFβ1 expression in CECs, which in turn promotes tumor progression. Mechanistically, the intercellular mtDNA transfer activates the mitochondrial respiratory chain to induce the ROS-driven RelA nuclear translocation in CECs, thereby transcriptionally regulating TGFβ1 expression and promoting tumor progression via the TGFβ/Smad pathway. Hence, this study highlights EV-mtDNA as a major driver of paracrine metabolic crosstalk between CC cells and adjacent CECs, possibly identifying it as a potential biomarker and therapeutic target for CC.

DOI: https://doi.org/10.1038/s41467-024-48100-y
Cell Stem Cell. 2024 Apr 27. pii: S1934-5909(24)00140-1. [Epub ahead of print]

The epidermal circadian clock integrates and subverts brain signals to guarantee skin homeostasis.

Thomas Mortimer, Valentina M Zinna, Muge Atalay, Carmelo Laudanna, Oleg Deryagin, Guillem Posas, Jacob G Smith, Elisa García-Lara, Mireia Vaca-Dempere, Leonardo Vinícius Monteiro de Assis, Isabel Heyde, Kevin B Koronowski, Paul Petrus, Carolina M Greco, Stephen Forrow, Henrik Oster, Paolo Sassone-Corsi, Patrick-Simon Welz, Pura Muñoz-Cánoves, Salvador Aznar Benitah.

  In mammals, the circadian clock network drives daily rhythms of tissue-specific homeostasis. To dissect daily inter-tissue communication, we constructed a mouse minimal clock network comprising only two nodes: the peripheral epidermal clock and the central brain clock. By transcriptomic and functional characterization of this isolated connection, we identified a gatekeeping function of the peripheral tissue clock with respect to systemic inputs. The epidermal clock concurrently integrates and subverts brain signals to ensure timely execution of epidermal daily physiology. Timely cell-cycle termination in the epidermal stem cell compartment depends upon incorporation of clock-driven signals originating from the brain. In contrast, the epidermal clock corrects or outcompetes potentially disruptive feeding-related signals to ensure the optimal timing of DNA replication. Together, we present an approach for cataloging the systemic dependencies of daily temporal organization in a tissue and identify an essential gate-keeping function of peripheral circadian clocks that guarantees tissue homeostasis.

Keywords:  aging; circadian; homeostasis; peripheral clocks; stem cells; systemic communication

DOI:  https://doi.org/10.1016/j.stem.2024.04.013
Mol Cell. 2024 Apr 22. pii: S1097-2765(24)00282-X. [Epub ahead of print]

Unprocessed genomic uracil as a source of DNA replication stress in cancer cells.

Sneha Saxena, Christopher S Nabel, Turner W Seay, Parasvi S Patel, Ajinkya S Kawale, Caroline R Crosby, Helene Tigro, Eugene Oh, Matthew G Vander Heiden, Aaron N Hata, Zucai Suo, Lee Zou.

  Alterations of bases in DNA constitute a major source of genomic instability. It is believed that base alterations trigger base excision repair (BER), generating DNA repair intermediates interfering with DNA replication. Here, we show that genomic uracil, a common type of base alteration, induces DNA replication stress (RS) without being processed by BER. In the absence of uracil DNA glycosylase (UNG), genomic uracil accumulates to high levels, DNA replication forks slow down, and PrimPol-mediated repriming is enhanced, generating single-stranded gaps in nascent DNA. ATR inhibition in UNG-deficient cells blocks the repair of uracil-induced gaps, increasing replication fork collapse and cell death. Notably, a subset of cancer cells upregulates UNG2 to suppress genomic uracil and limit RS, and these cancer cells are hypersensitive to co-treatment with ATR inhibitors and drugs increasing genomic uracil. These results reveal unprocessed genomic uracil as an unexpected source of RS and a targetable vulnerability of cancer cells.

Keywords:  ATR; BER; PrimPol; UNG; cancer therapy; gaps; lung cancer; permetrexed; replication fork; replication stress; ssDNA gaps; synthetic lethality; uracil

DOI:  https://doi.org/10.1016/j.molcel.2024.04.004
EMBO Mol Med. 2024 Apr 29.

Inhibition of asparagine synthetase effectively retards polycystic kidney disease progression.

Sara Clerici, Christine Podrini, Davide Stefanoni, Gianfranco Distefano, Laura Cassina, Maria Elena Steidl, Laura Tronci, Tamara Canu, Marco Chiaravalli, Daniel Spies, Thomas A Bell, Ana Sh Costa, Antonio Esposito, Angelo D'Alessandro, Christian Frezza, Angela Bachi, Alessandra Boletta.

  Polycystic kidney disease (PKD) is a genetic disorder characterized by bilateral cyst formation. We showed that PKD cells and kidneys display metabolic alterations, including the Warburg effect and glutaminolysis, sustained in vitro by the enzyme asparagine synthetase (ASNS). Here, we used antisense oligonucleotides (ASO) against Asns in orthologous and slowly progressive PKD murine models and show that treatment leads to a drastic reduction of total kidney volume (measured by MRI) and a prominent rescue of renal function in the mouse. Mechanistically, the upregulation of an ATF4-ASNS axis in PKD is driven by the amino acid response (AAR) branch of the integrated stress response (ISR). Metabolic profiling of PKD or control kidneys treated with Asns-ASO or Scr-ASO revealed major changes in the mutants, several of which are rescued by Asns silencing in vivo. Indeed, ASNS drives glutamine-dependent de novo pyrimidine synthesis and proliferation in cystic epithelia. Notably, while several metabolic pathways were completely corrected by Asns-ASO, glycolysis was only partially restored. Accordingly, combining the glycolytic inhibitor 2DG with Asns-ASO further improved efficacy. Our studies identify a new therapeutic target and novel metabolic vulnerabilities in PKD.

Keywords:  ADPKD; Antisense Oligonucleotides; Glutamine Metabolism; Glycolysis; Metabolic Reprogramming

DOI:  https://doi.org/10.1038/s44321-024-00071-9
Proc Natl Acad Sci U S A. 2024 May 07. 121(19): e2317703121

An aldehyde-crosslinking mitochondrial probe for STED imaging in fixed cells.

Jingting Chen, Till Stephan, Felix Gaedke, Tianyan Liu, Yiyan Li, Astrid Schauss, Peng Chen, Veronika Wulff, Stefan Jakobs, Christian Jüngst, Zhixing Chen.

  Fluorescence labeling of chemically fixed specimens, especially immunolabeling, plays a vital role in super-resolution imaging as it offers a convenient way to visualize cellular structures like mitochondria or the distribution of biomolecules with high detail. Despite the development of various distinct probes that enable super-resolved stimulated emission depletion (STED) imaging of mitochondria in live cells, most of these membrane-potential-dependent fluorophores cannot be retained well in mitochondria after chemical fixation. This lack of suitable mitochondrial probes has limited STED imaging of mitochondria to live cell samples. In this study, we introduce a mitochondria-specific probe, PK Mito Orange FX (PKMO FX), which features a fixation-driven cross-linking motif and accumulates in the mitochondrial inner membrane. It exhibits high fluorescence retention after chemical fixation and efficient depletion at 775 nm, enabling nanoscopic imaging both before and after aldehyde fixation. We demonstrate the compatibility of this probe with conventional immunolabeling and other strategies commonly used for fluorescence labeling of fixed samples. Moreover, we show that PKMO FX facilitates correlative super-resolution light and electron microscopy, enabling the correlation of multicolor fluorescence images and transmission EM images via the characteristic mitochondrial pattern. Our probe further expands the mitochondrial toolkit for multimodal microscopy at nanometer resolutions.

Keywords:  CLEM; fixation; mitochondrial imaging; super-resolution imaging

DOI:  https://doi.org/10.1073/pnas.2317703121
NPJ Parkinsons Dis. 2024 Apr 29. 10(1): 93

PARKIN is not required to sustain OXPHOS function in adult mammalian tissues.

Roberta Filograna, Jule Gerlach, Hae-Na Choi, Giovanni Rigoni, Michela Barbaro, Mikael Oscarson, Seungmin Lee, Katarina Tiklova, Markus Ringnér, Camilla Koolmeister, Rolf Wibom, Sara Riggare, Inger Nennesmo, Thomas Perlmann, Anna Wredenberg, Anna Wedell, Elisa Motori, Per Svenningsson, Nils-Göran Larsson.

Loss-of-function variants in the PRKN gene encoding the ubiquitin E3 ligase PARKIN cause autosomal recessive early-onset Parkinson's disease (PD). Extensive in vitro and in vivo studies have reported that PARKIN is involved in multiple pathways of mitochondrial quality control, including mitochondrial degradation and biogenesis. However, these findings are surrounded by substantial controversy due to conflicting experimental data. In addition, the existing PARKIN-deficient mouse models have failed to faithfully recapitulate PD phenotypes. Therefore, we have investigated the mitochondrial role of PARKIN during ageing and in response to stress by employing a series of conditional Parkin knockout mice. We report that PARKIN loss does not affect oxidative phosphorylation (OXPHOS) capacity and mitochondrial DNA (mtDNA) levels in the brain, heart, and skeletal muscle of aged mice. We also demonstrate that PARKIN deficiency does not exacerbate the brain defects and the pro-inflammatory phenotype observed in mice carrying high levels of mtDNA mutations. To rule out compensatory mechanisms activated during embryonic development of Parkin-deficient mice, we generated a mouse model where loss of PARKIN was induced in adult dopaminergic (DA) neurons. Surprisingly, also these mice did not show motor impairment or neurodegeneration, and no major transcriptional changes were found in isolated midbrain DA neurons. Finally, we report a patient with compound heterozygous PRKN pathogenic variants that lacks PARKIN and has developed PD. The PARKIN deficiency did not impair OXPHOS activities or induce mitochondrial pathology in skeletal muscle from the patient. Altogether, our results argue that PARKIN is dispensable for OXPHOS function in adult mammalian tissues.

DOI: https://doi.org/10.1038/s41531-024-00707-0
Mitochondrion. 2024 Apr 29. pii: S1567-7249(24)00047-3. [Epub ahead of print] 101889

Image-based quantification of mitochondrial iron uptake via Mitoferrin-2.

Marcello Polesel, Mattheus H E Wildschut, Cédric Doucerain, Michael Kuhn, Anna Flace, Anna-Lena Steck, Maria Wilhelm, Alvaro Ingles-Prieto, Tabea Wiedmer, Giulio Superti-Furga, Vania Manolova, Franz Dürrenberger.

  Iron is a trace element that is critical for most living organisms and plays a key role in a wide variety of metabolic processes. In the mitochondrion, iron is involved in producing iron-sulfur clusters and synthesis of heme and kept within physiological ranges by concerted activity of multiple molecules. Mitochondrial iron uptake is mediated by the solute carrier transporters Mitoferrin-1 (SLC25A37) and Mitoferrin-2 (SLC25A28). While Mitoferrin-1 is mainly involved in erythropoiesis, the cellular function of the ubiquitously expressed Mitoferrin-2 remains less well defined. Furthermore, Mitoferrin-2 is associated with several human diseases, including cancer, cardiovascular and metabolic diseases, hence representing a potential therapeutic target. Here, we developed a robust approach to quantify mitochondrial iron uptake mediated by Mitoferrin-2 in living cells. We utilize HEK293 cells with inducible expression of Mitoferrin-2 and measure iron-induced quenching of rhodamine B[(1,10-phenanthroline-5-yl)-aminocarbonyl]benzyl ester (RPA) fluorescence and validate this assay for medium-throughput screening. This assay may allow identification and characterization of Mitoferrin-2 modulators and could enable drug discovery for this target.

Keywords:  Iron; Medium throughput screening assay; Mitoferrin-2; RPA; Rhodamine B[(1,10-phenanthroline-5-yl)-aminocarbonyl]benzyl ester; SLC25A28

DOI:  https://doi.org/10.1016/j.mito.2024.101889
Cold Spring Harb Perspect Med. 2024 May 01. pii: a041534. [Epub ahead of print]

Mitochondria and Cancer.

Timothy C Kenny, Kıvanç Birsoy.

Mitochondria are semiautonomous organelles with diverse metabolic and cellular functions including anabolism and energy production through oxidative phosphorylation. Following the pioneering observations of Otto Warburg nearly a century ago, an immense body of work has examined the role of mitochondria in cancer pathogenesis and progression. Here, we summarize the current state of the field, which has coalesced around the position that functional mitochondria are required for cancer cell proliferation. In this review, we discuss how mitochondria influence tumorigenesis by impacting anabolism, intracellular signaling, and the tumor microenvironment. Consistent with their critical functions in tumor formation, mitochondria have become an attractive target for cancer therapy. We provide a comprehensive update on the numerous therapeutic modalities targeting the mitochondria of cancer cells making their way through clinical trials.

DOI: https://doi.org/10.1101/cshperspect.a041534
Cell Metab. 2024 Apr 24. pii: S1550-4131(24)00130-X. [Epub ahead of print]

Dietary intake and glutamine-serine metabolism control pathologic vascular stiffness.

Nesrine S Rachedi, Ying Tang, Yi-Yin Tai, Jingsi Zhao, Caroline Chauvet, Julien Grynblat, Kouamé Kan Firmin Akoumia, Leonard Estephan, Stéphanie Torrino, Chaima Sbai, Amel Ait-Mouffok, Joseph D Latoche, Yassmin Al Aaraj, Frederic Brau, Sophie Abélanet, Stephan Clavel, Yingze Zhang, Christelle Guillermier, Naveen V G Kumar, Sina Tavakoli, Olaf Mercier, Michael G Risbano, Zhong-Ke Yao, Guangli Yang, Ouathek Ouerfelli, Jason S Lewis, David Montani, Marc Humbert, Matthew L Steinhauser, Carolyn J Anderson, William M Oldham, Frédéric Perros, Thomas Bertero, Stephen Y Chan.

  Perivascular collagen deposition by activated fibroblasts promotes vascular stiffening and drives cardiovascular diseases such as pulmonary hypertension (PH). Whether and how vascular fibroblasts rewire their metabolism to sustain collagen biosynthesis remains unknown. Here, we found that inflammation, hypoxia, and mechanical stress converge on activating the transcriptional coactivators YAP and TAZ (WWTR1) in pulmonary arterial adventitial fibroblasts (PAAFs). Consequently, YAP and TAZ drive glutamine and serine catabolism to sustain proline and glycine anabolism and promote collagen biosynthesis. Pharmacologic or dietary intervention on proline and glycine anabolic demand decreases vascular stiffening and improves cardiovascular function in PH rodent models. By identifying the limiting metabolic pathways for vascular collagen biosynthesis, our findings provide guidance for incorporating metabolic and dietary interventions for treating cardiopulmonary vascular disease.

Keywords:  cardiovascular disease; collagen metabolism; fibrosis; glutamine metabolism; metabolism; nutrition; pulmonary hypertension; serine metabolism; vascular fibroblast

DOI:  https://doi.org/10.1016/j.cmet.2024.04.010
Cell Metab. 2024 Apr 15. pii: S1550-4131(23)00472-2. [Epub ahead of print]

The mitochondrial multi-omic response to exercise training across rat tissues.

MoTrPAC Study Group

  Mitochondria have diverse functions critical to whole-body metabolic homeostasis. Endurance training alters mitochondrial activity, but systematic characterization of these adaptations is lacking. Here, the Molecular Transducers of Physical Activity Consortium mapped the temporal, multi-omic changes in mitochondrial analytes across 19 tissues in male and female rats trained for 1, 2, 4, or 8 weeks. Training elicited substantial changes in the adrenal gland, brown adipose, colon, heart, and skeletal muscle. The colon showed non-linear response dynamics, whereas mitochondrial pathways were downregulated in brown adipose and adrenal tissues. Protein acetylation increased in the liver, with a shift in lipid metabolism, whereas oxidative proteins increased in striated muscles. Exercise-upregulated networks were downregulated in human diabetes and cirrhosis. Knockdown of the central network protein 17-beta-hydroxysteroid dehydrogenase 10 (HSD17B10) elevated oxygen consumption, indicative of metabolic stress. We provide a multi-omic, multi-tissue, temporal atlas of the mitochondrial response to exercise training and identify candidates linked to mitochondrial dysfunction.

Keywords:  HSD17B10; acetylome; aerobic; exercise; metabolism; metabolomics; mitochondria; multi-omics; proteomics; transcriptomics

DOI:  https://doi.org/10.1016/j.cmet.2023.12.021
Front Immunol. 2024 ;15 1293723

The factor inhibiting HIF regulates T cell differentiation and anti-tumour efficacy.

David Bargiela, Pedro P Cunha, Pedro Veliça, Lena C M Krause, Madara Brice, Laura Barbieri, Milos Gojkovic, Iosifina P Foskolou, Helene Rundqvist, Randall S Johnson.

  T cells must adapt to variations in tissue microenvironments; these adaptations include the degree of oxygen availability. The hypoxia-inducible factor (HIF) transcription factors control much of this adaptation, and thus regulate many aspects of T cell activation and function. The HIFs are in turn regulated by oxygen-dependent hydroxylases: both the prolyl hydroxylases (PHDs) which interact with the VHL tumour suppressor and control HIF turnover, and the asparaginyl hydroxylase known as the Factor inhibiting HIF (FIH), which modulates HIF transcriptional activity. To determine the role of this latter factor in T cell function, we generated T cell-specific FIH knockout mice. We found that FIH regulates T cell fate and function in a HIF-dependent manner and show that the effects of FIH activity occur predominantly at physiological oxygen concentrations. T cell-specific loss of FIH boosts T cell cytotoxicity, augments T cell expansion in vivo, and improves anti-tumour immunotherapy in mice. Specifically inhibiting FIH in T cells may therefore represent a promising strategy for cancer immunotherapy.

Keywords:  T cells; factor inhibiting HIF; hypoxia-inducible factor; immunotherapy; imunometabolism

DOI:  https://doi.org/10.3389/fimmu.2024.1293723
Nat Metab. 2024 Apr 29.

Cold-induced expression of a truncated adenylyl cyclase 3 acts as rheostat to brown fat function.

Sajjad Khani, Hande Topel, Ronja Kardinal, Ana Rita Tavanez, Ajeetha Josephrajan, Bjørk Ditlev Marcher Larsen, Michael James Gaudry, Philipp Leyendecker, Nadia Meincke Egedal, Aylin Seren Güller, Natasa Stanic, Phillip M M Ruppert, Isabella Gaziano, Nils Rouven Hansmeier, Elena Schmidt, Paul Klemm, Lara-Marie Vagliano, Rainer Stahl, Fraser Duthie, Jens-Henning Krause, Ana Bici, Christoph Andreas Engelhard, Sabrina Gohlke, Peter Frommolt, Thorsten Gnad, Alvaro Rada-Iglesias, Marta Pradas-Juni, Tim Julius Schulz, Frank Thomas Wunderlich, Alexander Pfeifer, Alexander Bartelt, Martin Jastroch, Dagmar Wachten, Jan-Wilhelm Kornfeld.

Promoting brown adipose tissue (BAT) activity innovatively targets obesity and metabolic disease. While thermogenic activation of BAT is well understood, the rheostatic regulation of BAT to avoid excessive energy dissipation remains ill-defined. Here, we demonstrate that adenylyl cyclase 3 (AC3) is key for BAT function. We identified a cold-inducible promoter that generates a 5' truncated AC3 mRNA isoform (Adcy3-at), whose expression is driven by a cold-induced, truncated isoform of PPARGC1A (PPARGC1A-AT). Male mice lacking Adcy3-at display increased energy expenditure and are resistant to obesity and ensuing metabolic imbalances. Mouse and human AC3-AT are retained in the endoplasmic reticulum, unable to translocate to the plasma membrane and lack enzymatic activity. AC3-AT interacts with AC3 and sequesters it in the endoplasmic reticulum, reducing the pool of adenylyl cyclases available for G-protein-mediated cAMP synthesis. Thus, AC3-AT acts as a cold-induced rheostat in BAT, limiting adverse consequences of cAMP activity during chronic BAT activation.

DOI: https://doi.org/10.1038/s42255-024-01033-8
Trends Endocrinol Metab. 2024 Apr 29. pii: S1043-2760(24)00088-2. [Epub ahead of print]

MCU genetically altered mice suggest how mitochondrial Ca2+ regulates metabolism.

Jiuzhou Huo, Jeffery D Molkentin.

  Skeletal muscle has a major impact on total body metabolism and obesity, and is characterized by dynamic regulation of substrate utilization. While it is accepted that acute increases in mitochondrial matrix Ca2+ increase carbohydrate usage to augment ATP production, recent studies in mice with deleted genes for components of the mitochondrial Ca2+ uniporter (MCU) complex have suggested a more complicated regulatory scenario. Indeed, mice with a deleted Mcu gene in muscle, which lack acute mitochondrial Ca2+ uptake, have greater fatty acid oxidation (FAO) and less adiposity. By contrast, mice deleted for the inhibitory Mcub gene in skeletal muscle, which have greater acute mitochondrial Ca2+ uptake, antithetically display reduced FAO and progressive obesity. In this review we discuss the emerging concept that dynamic fluxing of mitochondrial matrix Ca2+ regulates metabolism.

Keywords:  Ca(2+) signaling; metabolism; mitochondria; obesity; skeletal muscle

DOI:  https://doi.org/10.1016/j.tem.2024.04.005
Nat Commun. 2024 Apr 27. 15(1): 3595

A MTA2-SATB2 chromatin complex restrains colonic plasticity toward small intestine by retaining HNF4A at colonic chromatin.

Wei Gu, Xiaofeng Huang, Pratik N P Singh, Sanlan Li, Ying Lan, Min Deng, Lauretta A Lacko, Jesus M Gomez-Salinero, Shahin Rafii, Michael P Verzi, Ramesh A Shivdasani, Qiao Zhou.

Plasticity among cell lineages is a fundamental, but poorly understood, property of regenerative tissues. In the gut tube, the small intestine absorbs nutrients, whereas the colon absorbs electrolytes. In a striking display of inherent plasticity, adult colonic mucosa lacking the chromatin factor SATB2 is converted to small intestine. Using proteomics and CRISPR-Cas9 screening, we identify MTA2 as a crucial component of the molecular machinery that, together with SATB2, restrains colonic plasticity. MTA2 loss in the adult mouse colon activated lipid absorptive genes and functional lipid uptake. Mechanistically, MTA2 co-occupies DNA with HNF4A, an activating pan-intestinal transcription factor (TF), on colonic chromatin. MTA2 loss leads to HNF4A release from colonic chromatin, and accumulation on small intestinal chromatin. SATB2 similarly restrains colonic plasticity through an HNF4A-dependent mechanism. Our study provides a generalizable model of lineage plasticity in which broadly-expressed TFs are retained on tissue-specific enhancers to maintain cell identity and prevent activation of alternative lineages, and their release unleashes plasticity.

DOI: https://doi.org/10.1038/s41467-024-47738-y
Nat Commun. 2024 Apr 27. 15(1): 3593

Macrophage-fibroblast JAK/STAT dependent crosstalk promotes liver metastatic outgrowth in pancreatic cancer.

Meirion Raymant, Yuliana Astuti, Laura Alvaro-Espinosa, Daniel Green, Valeria Quaranta, Gaia Bellomo, Mark Glenn, Vatshala Chandran-Gorner, Daniel H Palmer, Christopher Halloran, Paula Ghaneh, Neil C Henderson, Jennifer P Morton, Manuel Valiente, Ainhoa Mielgo, Michael C Schmid.

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease for which better therapies are urgently needed. Fibroblasts and macrophages are heterogeneous cell populations able to enhance metastasis, but the role of a macrophage-fibroblast crosstalk in regulating their pro-metastatic functions remains poorly understood. Here we deconvolve how macrophages regulate metastasis-associated fibroblast (MAF) heterogeneity in the liver. We identify three functionally distinct MAF populations, among which the generation of pro-metastatic and immunoregulatory myofibroblastic-MAFs (myMAFs) critically depends on macrophages. Mechanistically, myMAFs are induced through a STAT3-dependent mechanism driven by macrophage-derived progranulin and cancer cell-secreted leukaemia inhibitory factor (LIF). In a reciprocal manner, myMAF secreted osteopontin promotes an immunosuppressive macrophage phenotype resulting in the inhibition of cytotoxic T cell functions. Pharmacological blockade of STAT3 or myMAF-specific genetic depletion of STAT3 restores an anti-tumour immune response and reduces metastases. Our findings provide molecular insights into the complex macrophage-fibroblast interactions in tumours and reveal potential targets to inhibit PDAC liver metastasis.

DOI: https://doi.org/10.1038/s41467-024-47949-3
Nephrol Dial Transplant. 2024 Apr 29. pii: gfae097. [Epub ahead of print]

Ferroptosis Biology.

Tobias Seibt, Adam Wahida, Konrad Hoeft, Stephan Kemmner, Andreas Linkermann, Eikan Mishima, Marcus Conrad.

  Ferroptosis is a regulated cell death modality triggered by iron-dependent lipid peroxidation. Ferroptosis plays a causal role in the pathophysiology of various diseases, making it a promising therapeutic target. Unlike all other cell death modalities dependent on distinct signaling cues, ferroptosis occurs when cellular antioxidative defense mechanisms fail to suppress the oxidative destruction of cellular membranes, eventually leading to cell membrane rupture. Physiologically, only two such surveillance systems are known to efficiently prevent the lipid peroxidation chain reaction by reducing (phospho)lipid hydroperoxides to their corresponding alcohols or by reducing radicals in phospholipid bilayers, thus maintaining the integrity of lipid membranes. Mechanistically, these two systems are linked to the reducing capacity of glutathione peroxidase 4 (GPX4) by consuming glutathione (GSH) on the one and ferroptosis suppressor protein 1 (FSP1, formerly AIFM2) on the other hand. Notably, the importance of ferroptosis suppression in physiological contexts has been linked to a particular vulnerability of renal tissue. In fact, early work has shown that mice genetically lacking Gpx4 rapidly succumb to acute renal failure with pathohistological features of acute tubular necrosis. Promising research attempting to implicate ferroptosis in various renal disease entities, particularly those with proximal tubular involvement, has generated a wealth of knowledge with widespread potential for clinical translation. Here, we provide a brief overview of the involvement of ferroptosis in nephrology. Our goal is to introduce this expanding field for clinically versed nephrologists in the hope of spurring future efforts to prevent ferroptosis in the pathophysiological processes of the kidney.

Keywords:  GPX4; acute kidney injury; ferroptosis; iron metabolism; lipid peroxidation

DOI:  https://doi.org/10.1093/ndt/gfae097
Trends Cancer. 2024 Apr 30. pii: S2405-8033(24)00059-1. [Epub ahead of print]

Immunometabolism of CD8+ T cell differentiation in cancer.

Hao Shi, Sidi Chen, Hongbo Chi.

  CD8+ cytotoxic T lymphocytes (CTLs) are central mediators of tumor immunity and immunotherapies. Upon tumor antigen recognition, CTLs differentiate from naive/memory-like toward terminally exhausted populations with more limited function against tumors. Such differentiation is regulated by both immune signals, including T cell receptors (TCRs), co-stimulation, and cytokines, and metabolism-associated processes. These immune signals shape the metabolic landscape via signaling, transcriptional and post-transcriptional mechanisms, while metabolic processes in turn exert spatiotemporal effects to modulate the strength and duration of immune signaling. Here, we review the bidirectional regulation between immune signals and metabolic processes, including nutrient uptake and intracellular metabolic pathways, in shaping CTL differentiation and exhaustion. We also discuss the mechanisms underlying how specific nutrient sources and metabolite-mediated signaling events orchestrate CTL biology. Understanding how metabolic programs and their interplay with immune signals instruct CTL differentiation and exhaustion is crucial to uncover tumor-immune interactions and design novel immunotherapies.

Keywords:  T cell differentiation; TCR; antitumor function; cytokines; exhaustion; mitochondrial fitness

DOI:  https://doi.org/10.1016/j.trecan.2024.03.010
Cancer Discov. 2024 Apr 17. OF1-OF22

Senescent CAFs Mediate Immunosuppression and Drive Breast Cancer Progression.

Jiayu Ye, John M Baer, Douglas V Faget, Vasilios A Morikis, Qihao Ren, Anupama Melam, Ana Paula Delgado, Xianmin Luo, Satarupa Mullick Bagchi, Jad I Belle, Edward Campos, Michael Friedman, Deborah J Veis, Erik S Knudsen, Agnieszka K Witkiewicz, Scott Powers, Gregory D Longmore, David G DeNardo, Sheila A Stewart.

The tumor microenvironment (TME) profoundly influences tumorigenesis, with gene expression in the breast TME capable of predicting clinical outcomes. The TME is complex and includes distinct cancer-associated fibroblast (CAF) subtypes whose contribution to tumorigenesis remains unclear. Here, we identify a subset of myofibroblast CAFs (myCAF) that are senescent (senCAF) in mouse and human breast tumors. Utilizing the MMTV-PyMT;INK-ATTAC (INK) mouse model, we found that senCAF-secreted extracellular matrix specifically limits natural killer (NK) cell cytotoxicity to promote tumor growth. Genetic or pharmacologic senCAF elimination unleashes NK cell killing, restricting tumor growth. Finally, we show that senCAFs are present in HER2+, ER+, and triple-negative breast cancer and in ductal carcinoma in situ (DCIS) where they predict tumor recurrence. Together, these findings demonstrate that senCAFs are potently tumor promoting and raise the possibility that targeting them by senolytic therapy could restrain breast cancer development.
SIGNIFICANCE: senCAFs limit NK cell-mediated killing, thereby contributing to breast cancer progression. Thus, targeting senCAFs could be a clinically viable approach to limit tumor progression.

DOI: https://doi.org/10.1158/2159-8290.CD-23-0426
J Exp Biol. 2024 Apr 29. pii: jeb.247221. [Epub ahead of print]

Investigating the thermal sensitivity of key enzymes involved in the energetic metabolism of three insect species.

Adèle Léger, Simon B Cormier, Arianne Blanchard, Hichem A Menail, Nicolas Pichaud.

  The metabolic responses of insects to high temperatures have been linked to their mitochondrial substrate oxidation capacity. However, the mechanism behind this mitochondrial flexibility is not well understood. Here, we used three insect species with different thermal tolerances (the honey bee, Apis mellifera; the fruit fly, Drosophila melanogaster; and the potato beetle, Leptinotarsa decemlineata) to characterise the thermal sensitivity of different metabolic enzymes. Specifically, we measured activities of enzymes involved in glycolysis (hexokinase, HK; pyruvate kinase, PK; and lactate dehydrogenase, LDH), pyruvate oxidation and the tricarboxylic acid cycle (pyruvate dehydrogenase, PDH; citrate synthase, CS; malate dehydrogenase, MDH; and aspartate aminotransferase, AAT), the electron transport system (Complex I, CI; Complex II, CII; mitochondrial glycerol-3-phosphate dehydrogenase, mG3PDH; Proline dehydrogenase, ProDH; and Complex IV, CIV) as well as ATP synthase (CV) at 18, 24, 30, 36, 42 and 45˚C. Our results show that at high temperature, all three species have important increased activity of enzymes linked to FADH2 oxidation, specifically CII and mG3PDH. In Drosophila and honey bees, this coincides with an important decrease of PDH and CS activity, respectively, that would limit NADH production. This is in line with the switch from NADH-linked substrates to FADH2-linked substrates previously observed with mitochondrial oxygen consumption. Thus, we demonstrate that even though the three insect species have a different metabolic regulation, a similar response to high temperature involving CII and mG3PDH is observed, denoting the importance of these proteins for thermal tolerance in insects.

Keywords:  Drosophila; Glycolysis; Honey bee; Metabolic pathways; Mitochondria; Potato beetle; Temperature; Tricarboxylic acid cycle

DOI:  https://doi.org/10.1242/jeb.247221
Redox Biol. 2024 Apr 27. pii: S2213-2317(24)00115-0. [Epub ahead of print]73 103139

SAH is a major metabolic sensor mediating worsening metabolic crosstalk in metabolic syndrome.

Ramon Cueto, Wen Shen, Lu Liu, Xianwei Wang, Sheng Wu, Sadia Mohsin, Ling Yang, Mohsin Khan, Wenhui Hu, Nathaniel Snyder, Qinghua Wu, Yong Ji, Xiao-Feng Yang, Hong Wang.

  In this study, we observed worsening metabolic crosstalk in mouse models with concomitant metabolic disorders such as hyperhomocysteinemia (HHcy), hyperlipidemia, and hyperglycemia and in human coronary artery disease by analyzing metabolic profiles. We found that HHcy worsening is most sensitive to other metabolic disorders. To identify metabolic genes and metabolites responsible for the worsening metabolic crosstalk, we examined mRNA levels of 324 metabolic genes in Hcy, glucose-related and lipid metabolic systems. We examined Hcy-metabolites (Hcy, SAH and SAM) by LS-ESI-MS/MS in 6 organs (heart, liver, brain, lung, spleen, and kidney) from C57BL/6J mice. Through linear regression analysis of Hcy-metabolites and metabolic gene mRNA levels, we discovered that SAH-responsive genes were responsible for most metabolic changes and all metabolic crosstalk mediated by Serine, Taurine, and G3P. SAH-responsive genes worsen glucose metabolism and cause upper glycolysis activation and lower glycolysis suppression, indicative of the accumulation of glucose/glycogen and G3P, Serine synthesis inhibition, and ATP depletion. Insufficient Serine due to negative correlation of PHGDH with SAH concentration may inhibit the folate cycle and transsulfurarion pathway and consequential reduced antioxidant power, including glutathione, taurine, NADPH, and NAD+. Additionally, we identified SAH-activated pathological TG loop as the consequence of increased fatty acid (FA) uptake, FA β-oxidation and Ac-CoA production along with lysosomal damage. We concluded that HHcy is most responsive to other metabolic changes in concomitant metabolic disorders and mediates worsening metabolic crosstalk mainly via SAH-responsive genes, that organ-specific Hcy metabolism determines organ-specific worsening metabolic reprogramming, and that SAH, acetyl-CoA, Serine and Taurine are critical metabolites mediating worsening metabolic crosstalk, redox disturbance, hypomethylation and hyperacetylation linking worsening metabolic reprogramming in metabolic syndrome.

Keywords:  Hyperhomocysteinemia; Metabolic syndrome; Redox; S-Adenosyl-homocysteine (SAH); Serine; Taurine

DOI:  https://doi.org/10.1016/j.redox.2024.103139
J Hazard Mater. 2024 Apr 23. pii: S0304-3894(24)00964-6. [Epub ahead of print]471 134385

Nitric oxide-mediated regulation of Aspergillus flavus asexual development by targeting TCA cycle and mitochondrial function.

Kunlong Yang, Yue Luo, Tongzheng Sun, Han Qiu, Qingru Geng, Yongxin Li, Man Liu, Nancy P Keller, Fengqin Song, Jun Tian.

  Nitric oxide (NO) is a signaling molecule with diverse roles in various organisms. However, its role in the opportunistic pathogen Aspergillus flavus remains unclear. This study investigates the potential of NO, mediated by metabolites from A. oryzae (AO), as an antifungal strategy against A. flavus. We demonstrated that AO metabolites effectively suppressed A. flavus asexual development, a critical stage in its lifecycle. Transcriptomic analysis revealed that AO metabolites induced NO synthesis genes, leading to increased intracellular NO levels. Reducing intracellular NO content rescued A. flavus spores from germination inhibition caused by AO metabolites. Furthermore, exogenous NO treatment and dysfunction of flavohemoglobin Fhb1, a key NO detoxification enzyme, significantly impaired A. flavus asexual development. RNA-sequencing and metabolomic analyses revealed significant metabolic disruptions within tricarboxylic acid (TCA) cycle upon AO treatment. NO treatment significantly reduced mitochondrial membrane potential (Δψm) and ATP generation. Additionally, aberrant metabolic flux within the TCA cycle was observed upon NO treatment. Further analysis revealed that NO induced S-nitrosylation of five key TCA cycle enzymes. Genetic analysis demonstrated that the S-nitrosylated Aconitase Acon and one subunit of succinate dehydrogenase Sdh2 played crucial roles in A. flavus development by regulating ATP production. This study highlights the potential of NO as a novel antifungal strategy to control A. flavus by compromising its mitochondrial function and energy metabolism.

Keywords:  Aconitase; Aflatoxin; Aspergillus flavus; Nitric oxide; TCA cycle

DOI:  https://doi.org/10.1016/j.jhazmat.2024.134385
Cell Rep. 2024 Apr 27. pii: S2211-1247(24)00497-2. [Epub ahead of print]43(5): 114169

Smooth muscle cell-derived Cxcl12 directs macrophage accrual and sympathetic innervation to control thermogenic adipose tissue.

Derek Lee, Abigail M Benvie, Benjamin M Steiner, Nikolai J Kolba, Josie G Ford, Sean M McCabe, Yuwei Jiang, Daniel C Berry.

  Sympathetic innervation of brown adipose tissue (BAT) controls mammalian adaptative thermogenesis. However, the cellular and molecular underpinnings contributing to BAT innervation remain poorly defined. Here, we show that smooth muscle cells (SMCs) support BAT growth, lipid utilization, and thermogenic plasticity. Moreover, we find that BAT SMCs express and control the bioavailability of Cxcl12. SMC deletion of Cxcl12 fosters brown adipocyte lipid accumulation, reduces energy expenditure, and increases susceptibility to diet-induced metabolic dysfunction. Mechanistically, we find that Cxcl12 stimulates CD301+ macrophage recruitment and supports sympathetic neuronal maintenance. Administering recombinant Cxcl12 to obese mice or leptin-deficient (Ob/Ob) mice is sufficient to boost macrophage presence and drive sympathetic innervation to restore BAT morphology and thermogenic responses. Altogether, our data reveal an SMC chemokine-dependent pathway linking immunological infiltration and sympathetic innervation as a rheostat for BAT maintenance and thermogenesis.

Keywords:  CP: Immunology; CP: Metabolism; Cxcl2; brown adipocytes; macrophage; smooth muscle cells; sympathetic innervation; thermogenesis

DOI:  https://doi.org/10.1016/j.celrep.2024.114169
Proc Natl Acad Sci U S A. 2024 May 07. 121(19): e2315348121

OTUB2 silencing promotes ovarian cancer via mitochondrial metabolic reprogramming and can be synthetically targeted by CA9 inhibition.

Yabing Nan, Xiaowei Wu, Qingyu Luo, Wan Chang, Pengfei Zhao, Lingqiang Zhang, Zhihua Liu.

  Ovarian cancer is an aggressive gynecological tumor characterized by a high relapse rate and chemoresistance. Ovarian cancer exhibits the cancer hallmark of elevated glycolysis, yet effective strategies targeting cancer cell metabolic reprogramming to overcome therapeutic resistance in ovarian cancer remain elusive. Here, we revealed that epigenetic silencing of Otubain 2 (OTUB2) is a driving force for mitochondrial metabolic reprogramming in ovarian cancer, which promotes tumorigenesis and chemoresistance. Mechanistically, OTUB2 silencing destabilizes sorting nexin 29 pseudogene 2 (SNX29P2), which subsequently prevents hypoxia-inducible factor-1 alpha (HIF-1α) from von Hippel-Lindau tumor suppressor-mediated degradation. Elevated HIF-1α activates the transcription of carbonic anhydrase 9 (CA9) and drives ovarian cancer progression and chemoresistance by promoting glycolysis. Importantly, pharmacological inhibition of CA9 substantially suppressed tumor growth and synergized with carboplatin in the treatment of OTUB2-silenced ovarian cancer. Thus, our study highlights the pivotal role of OTUB2/SNX29P2 in suppressing ovarian cancer development and proposes that targeting CA9-mediated glycolysis is an encouraging strategy for the treatment of ovarian cancer.

Keywords:  chemoresistance; metabolic reprogramming; ovarian cancer; tumorigenesis; ubiquitination

DOI:  https://doi.org/10.1073/pnas.2315348121
Nature. 2024 May 01.

Mitochondrial transfer mediates endothelial cell engraftment through mitophagy.

Ruei-Zeng Lin, Gwang-Bum Im, Allen Chilun Luo, Yonglin Zhu, Xuechong Hong, Joseph Neumeyer, Hong-Wen Tang, Norbert Perrimon, Juan M Melero-Martin.

Ischaemic diseases such as critical limb ischaemia and myocardial infarction affect millions of people worldwide1. Transplanting endothelial cells (ECs) is a promising therapy in vascular medicine, but engrafting ECs typically necessitates co-transplanting perivascular supporting cells such as mesenchymal stromal cells (MSCs), which makes clinical implementation complicated2,3. The mechanisms that enable MSCs to facilitate EC engraftment remain elusive. Here we show that, under cellular stress, MSCs transfer mitochondria to ECs through tunnelling nanotubes, and that blocking this transfer impairs EC engraftment. We devised a strategy to artificially transplant mitochondria, transiently enhancing EC bioenergetics and enabling them to form functional vessels in ischaemic tissues without the support of MSCs. Notably, exogenous mitochondria did not integrate into the endogenous EC mitochondrial pool, but triggered mitophagy after internalization. Transplanted mitochondria co-localized with autophagosomes, and ablation of the PINK1-Parkin pathway negated the enhanced engraftment ability of ECs. Our findings reveal a mechanism that underlies the effects of mitochondrial transfer between mesenchymal and endothelial cells, and offer potential for a new approach for vascular cell therapy.

DOI: https://doi.org/10.1038/s41586-024-07340-0
Nat Rev Mol Cell Biol. 2024 Apr 30.

Fundamentals of redox regulation in biology.

Helmut Sies, Ryan J Mailloux, Ursula Jakob.

Oxidation-reduction (redox) reactions are central to the existence of life. Reactive species of oxygen, nitrogen and sulfur mediate redox control of a wide range of essential cellular processes. Yet, excessive levels of oxidants are associated with ageing and many diseases, including cardiological and neurodegenerative diseases, and cancer. Hence, maintaining the fine-tuned steady-state balance of reactive species production and removal is essential. Here, we discuss new insights into the dynamic maintenance of redox homeostasis (that is, redox homeodynamics) and the principles underlying biological redox organization, termed the 'redox code'. We survey how redox changes result in stress responses by hormesis mechanisms, and how the lifelong cumulative exposure to environmental agents, termed the 'exposome', is communicated to cells through redox signals. Better understanding of the molecular and cellular basis of redox biology will guide novel redox medicine approaches aimed at preventing and treating diseases associated with disturbed redox regulation.

DOI: https://doi.org/10.1038/s41580-024-00730-2
Nat Commun. 2024 Apr 27. 15(1): 3574

Cyclodipeptide oxidase is an enzyme filament.

Michael P Andreas, Tobias W Giessen.

Modified cyclic dipeptides represent a widespread class of secondary metabolites with diverse pharmacological activities, including antibacterial, antifungal, and antitumor. Here, we report the structural characterization of the Streptomyces noursei enzyme AlbAB, a cyclodipeptide oxidase (CDO) carrying out α,β-dehydrogenations during the biosynthesis of the antibiotic albonoursin. We show that AlbAB is a megadalton heterooligomeric enzyme filament containing covalently bound flavin mononucleotide cofactors. We highlight that AlbAB filaments consist of alternating dimers of AlbA and AlbB and that enzyme activity is crucially dependent on filament formation. We show that AlbA-AlbB interactions are highly conserved suggesting that other CDO-like enzymes are likely enzyme filaments. As CDOs have been employed in the structural diversification of cyclic dipeptides, our results will be useful for future applications of CDOs in biocatalysis and chemoenzymatic synthesis.

DOI: https://doi.org/10.1038/s41467-024-48030-9
Cell Stem Cell. 2024 May 02. pii: S1934-5909(24)00133-4. [Epub ahead of print]31(5): 591-592

Microbial metabolite steers intestinal stem cell fate under stress.

Shu Zhu, Wen Pan.

Recently in Cell Metabolism, Wei et al.1 unveiled a brain-to-gut pathway that conveys psychological stress to intestinal epithelial cells, leading to their dysfunction. This gut-brain axis involves a microbial metabolite, indole-3-acetate (IAA), as a niche signal that hampers mitochondrial respiration to skew intestinal stem cell (ISC) fate.

DOI: https://doi.org/10.1016/j.stem.2024.04.006
Nat Metab. 2024 May 02.

Bile acids for diabetic cardiomyopathy.

David Weissman, Christoph Maack.

DOI: https://doi.org/10.1038/s42255-024-01032-9
Cell Rep. 2024 Apr 30. pii: S2211-1247(24)00470-4. [Epub ahead of print]43(5): 114142

Itaconate alleviates diet-induced obesity via activation of brown adipocyte thermogenesis.

Zihan Yu, Xianju Li, Yanni Quan, Jiawen Chen, Jiarui Liu, Nairen Zheng, Shuwen Liu, Yini Wang, Wanlin Liu, Chen Qiu, Yi Wang, Ruimao Zheng, Jun Qin.

  Despite medical advances, there remains an unmet need for better treatment of obesity. Itaconate, a product of the decarboxylation of the tricarboxylic acid cycle intermediate cis-aconitate, plays a regulatory role in both metabolism and immunity. Here, we show that itaconate, as an endogenous compound, counteracts high-fat-diet (HFD)-induced obesity through leptin-independent mechanisms in three mouse models. Specifically, itaconate reduces weight gain, reverses hyperlipidemia, and improves glucose tolerance in HFD-fed mice. Additionally, itaconate enhances energy expenditure and the thermogenic capacity of brown adipose tissue (BAT). Unbiased proteomic analysis reveals that itaconate upregulates key proteins involved in fatty acid oxidation and represses the expression of lipogenic genes. Itaconate may provoke a major metabolic reprogramming by inducing fatty acid oxidation and suppression of fatty acid synthesis in BAT. These findings highlight itaconate as a potential activator of BAT-mediated thermogenesis and a promising candidate for anti-obesity therapy.

Keywords:  CP: Metabolism; brown adipocyte; itaconate; obesity; proteomics; thermogenesis

DOI:  https://doi.org/10.1016/j.celrep.2024.114142
Nature. 2024 May 01.

Airway hillocks are injury-resistant reservoirs of unique plastic stem cells.

Brian Lin, Viral S Shah, Chaim Chernoff, Jiawei Sun, Gergana G Shipkovenska, Vladimir Vinarsky, Avinash Waghray, Jiajie Xu, Andrew D Leduc, Constantin A Hintschich, Manalee Vishnu Surve, Yanxin Xu, Diane E Capen, Jorge Villoria, Zhixun Dou, Lida P Hariri, Jayaraj Rajagopal.

Airway hillocks are stratified epithelial structures of unknown function1. Hillocks persist for months and have a unique population of basal stem cells that express genes associated with barrier function and cell adhesion. Hillock basal stem cells continually replenish overlying squamous barrier cells. They exhibit dramatically higher turnover than the abundant, largely quiescent classic pseudostratified airway epithelium. Hillocks resist a remarkably broad spectrum of injuries, including toxins, infection, acid and physical injury because hillock squamous cells shield underlying hillock basal stem cells from injury. Hillock basal stem cells are capable of massive clonal expansion that is sufficient to resurface denuded airway, and eventually regenerate normal airway epithelium with each of its six component cell types. Hillock basal stem cells preferentially stratify and keratinize in the setting of retinoic acid signalling inhibition, a known cause of squamous metaplasia2,3. Here we show that mouse hillock expansion is the cause of vitamin A deficiency-induced squamous metaplasia. Finally, we identify human hillocks whose basal stem cells generate functional squamous barrier structures in culture. The existence of hillocks reframes our understanding of airway epithelial regeneration. Furthermore, we show that hillocks are one origin of 'squamous metaplasia', which is long thought to be a precursor of lung cancer.

DOI: https://doi.org/10.1038/s41586-024-07377-1
Proc Natl Acad Sci U S A. 2024 May 07. 121(19): e2321216121

Transient Zn2+ deficiency induces replication stress and compromises daughter cell proliferation.

Samuel E Holtzen, Elnaz Navid, Joseph D Kainov, Amy E Palmer.

  Cells must replicate their genome quickly and accurately, and they require metabolites and cofactors to do so. Ionic zinc (Zn2+) is an essential micronutrient that is required for hundreds of cellular processes, including DNA synthesis and adequate proliferation. Deficiency in this micronutrient impairs DNA synthesis and inhibits proliferation, but the mechanism is unknown. Using fluorescent reporters to track single cells via long-term live-cell imaging, we find that Zn2+ is required at the G1/S transition and during S phase for timely completion of S phase. A short pulse of Zn2+ deficiency impairs DNA synthesis and increases markers of replication stress. These markers of replication stress are reversed upon resupply of Zn2+. Finally, we find that if Zn2+ is chelated during the mother cell's S phase, daughter cells enter a transient quiescent state, maintained by sustained expression of p21, which disappears upon reentry into the cell cycle. In summary, short pulses of mild Zn2+ deficiency in S phase specifically induce replication stress, which causes downstream proliferation impairments in daughter cells.

Keywords:  cell cycle; replication stress; single cell; zinc; zinc deficiency

DOI:  https://doi.org/10.1073/pnas.2321216121
Cancer Discov. 2024 Apr 29. OF1-OF32

Senescence Defines a Distinct Subset of Myofibroblasts That Orchestrates Immunosuppression in Pancreatic Cancer.

Jad I Belle, Devashish Sen, John M Baer, Xiuting Liu, Varintra E Lander, Jiayu Ye, Blake E Sells, Brett L Knolhoff, Ahmad Faiz, Liang-I Kang, Guhan Qian, Ryan C Fields, Li Ding, Hyun Kim, Paolo P Provenzano, Sheila A Stewart, David G DeNardo.

Pancreatic ductal adenocarcinoma (PDAC) therapeutic resistance is largely attributed to a unique tumor microenvironment embedded with an abundance of cancer-associated fibroblasts (CAF). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify a subpopulation of senescent myofibroblastic CAFs (SenCAF) in mouse and human PDAC. These SenCAFs are a phenotypically distinct subset of myofibroblastic CAFs that localize near tumor ducts and accumulate with PDAC progression. To assess the impact of endogenous SenCAFs in PDAC, we used an LSL-KRASG12D;p53flox;p48-CRE;INK-ATTAC (KPPC-IA) mouse model of spontaneous PDAC with inducible senescent cell depletion. Depletion of senescent stromal cells in genetic and pharmacologic PDAC models relieved immune suppression by macrophages, delayed tumor progression, and increased responsiveness to chemotherapy. Collectively, our findings demonstrate that SenCAFs promote PDAC progression and immune cell dysfunction.
SIGNIFICANCE: CAF heterogeneity in PDAC remains poorly understood. In this study, we identify a novel subpopulation of senescent CAFs that promotes PDAC progression and immunosuppression. Targeting CAF senescence in combination therapies could increase tumor vulnerability to chemo- or immunotherapy. See related article by Ye et al.

DOI: https://doi.org/10.1158/2159-8290.CD-23-0428
Nat Methods. 2024 Apr 29.

Post-translational modification-centric base editor screens to assess phosphorylation site functionality in high throughput.

Patrick H Kennedy, Amin Alborzian Deh Sheikh, Matthew Balakar, Alexander C Jones, Meagan E Olive, Mudra Hegde, Maria I Matias, Natan Pirete, Rajan Burt, Jonathan Levy, Tamia Little, Patrick G Hogan, David R Liu, John G Doench, Alexandra C Newton, Rachel A Gottschalk, Carl G de Boer, Suzie Alarcón, Gregory A Newby, Samuel A Myers.

Signaling pathways that drive gene expression are typically depicted as having a dozen or so landmark phosphorylation and transcriptional events. In reality, thousands of dynamic post-translational modifications (PTMs) orchestrate nearly every cellular function, and we lack technologies to find causal links between these vast biochemical pathways and genetic circuits at scale. Here we describe the high-throughput, functional assessment of phosphorylation sites through the development of PTM-centric base editing coupled to phenotypic screens, directed by temporally resolved phosphoproteomics. Using T cell activation as a model, we observe hundreds of unstudied phosphorylation sites that modulate NFAT transcriptional activity. We identify the phosphorylation-mediated nuclear localization of PHLPP1, which promotes NFAT but inhibits NFκB activity. We also find that specific phosphosite mutants can alter gene expression in subtle yet distinct patterns, demonstrating the potential for fine-tuning transcriptional responses. Overall, base editor screening of PTM sites provides a powerful platform to dissect PTM function within signaling pathways.

DOI: https://doi.org/10.1038/s41592-024-02256-z
Nat Cell Biol. 2024 Apr 30.

Oncogenic Kras induces spatiotemporally specific tissue deformation through converting pulsatile into sustained ERK activation.

Tianchi Xin, Sara Gallini, Haoyang Wei, David G Gonzalez, Catherine Matte-Martone, Hiroki Machida, Hironobu Fujiwara, H Amalia Pasolli, Kathleen C Suozzi, Lauren E Gonzalez, Sergi Regot, Valentina Greco.

Tissue regeneration and maintenance rely on coordinated stem cell behaviours. This orchestration can be impaired by oncogenic mutations leading to cancer. However, it is largely unclear how oncogenes perturb stem cells' orchestration to disrupt tissue. Here we used intravital imaging to investigate the mechanisms by which oncogenic Kras mutation causes tissue disruption in the hair follicle. Through longitudinally tracking hair follicles in live mice, we found that KrasG12D, a mutation that can lead to squamous cell carcinoma, induces epithelial tissue deformation in a spatiotemporally specific manner, linked with abnormal cell division and migration. Using a reporter mouse capture real-time ERK signal dynamics at the single-cell level, we discovered that KrasG12D, but not a closely related mutation HrasG12V, converts ERK signal in stem cells from pulsatile to sustained. Finally, we demonstrated that interrupting sustained ERK signal reverts KrasG12D-induced tissue deformation through modulating specific features of cell migration and division.

DOI: https://doi.org/10.1038/s41556-024-01413-y
Nature. 2024 May 01.

Paternal microbiome perturbations impact offspring fitness.

Ayele Argaw-Denboba, Thomas S B Schmidt, Monica Di Giacomo, Bobby Ranjan, Saravanan Devendran, Eleonora Mastrorilli, Catrin T Lloyd, Danilo Pugliese, Violetta Paribeni, Juliette Dabin, Alessandra Pisaniello, Sergio Espinola, Alvaro Crevenna, Subhanita Ghosh, Neil Humphreys, Olga Boruc, Peter Sarkies, Michael Zimmermann, Peer Bork, Jamie A Hackett.

The gut microbiota operates at the interface of host-environment interactions to influence human homoeostasis and metabolic networks1-4. Environmental factors that unbalance gut microbial ecosystems can therefore shape physiological and disease-associated responses across somatic tissues5-9. However, the systemic impact of the gut microbiome on the germline-and consequently on the F1 offspring it gives rise to-is unexplored10. Here we show that the gut microbiota act as a key interface between paternal preconception environment and intergenerational health in mice. Perturbations to the gut microbiota of prospective fathers increase the probability of their offspring presenting with low birth weight, severe growth restriction and premature mortality. Transmission of disease risk occurs via the germline and is provoked by pervasive gut microbiome perturbations, including non-absorbable antibiotics or osmotic laxatives, but is rescued by restoring the paternal microbiota before conception. This effect is linked with a dynamic response to induced dysbiosis in the male reproductive system, including impaired leptin signalling, altered testicular metabolite profiles and remapped small RNA payloads in sperm. As a result, dysbiotic fathers trigger an elevated risk of in utero placental insufficiency, revealing a placental origin of mammalian intergenerational effects. Our study defines a regulatory 'gut-germline axis' in males, which is sensitive to environmental exposures and programmes offspring fitness through impacting placenta function.

DOI: https://doi.org/10.1038/s41586-024-07336-w
EMBO Rep. 2024 May 02.

Safety in numbers?

Howy Jacobs.

DOI: https://doi.org/10.1038/s44319-024-00146-1