bims-camemi 2023-12-03 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2023‒12‒03
forty-five papers selected by
Christian Frezza, Universität zu Köln

Mitochondrial DNA editing with mitoARCUS.
Efferocytosis-induced lactate enables the proliferation of pro-resolving macrophages to mediate tissue repair.
Metabolic immunity against microbes.
Metabolic Rewiring and Communication: An Integrative View of Kidney Proximal Tubule Function.
PRMT1 orchestrates with SAMTOR to govern mTORC1 methionine sensing via Arg-methylation of NPRL2.
Metabolic control of mitophagy.
Hypermetabolic state is associated with circadian rhythm disruption in mouse and human cancer cells.
The immunometabolic ecosystem in cancer.
Metabolic signals influence cell-fate decisions in Dictyostelium discoideum.
MicroRNA-mediated attenuation of branched-chain amino acid catabolism promotes ferroptosis in chronic kidney disease.
SMARCB1 loss activates patient-specific distal oncogenic enhancers in malignant rhabdoid tumors.
Boveri and beyond: Chromothripsis and genomic instability from mitotic errors.
Methylmalonic acid in aging and disease.
Telomerase reverse transcriptase induces targetable alterations in glutathione and nucleotide biosynthesis in glioblastomas.
Kidney cancer: Links between hereditary syndromes and sporadic tumorigenesis.
The poxvirus F17 protein counteracts mitochondrially orchestrated antiviral responses.
Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.
Negative modulation of mitochondrial calcium uniporter complex protects neurons against ferroptosis.
Epigenetic remodelling under hypoxia.
Lysine-372-dependent SUMOylation inhibits the enzymatic activity of glutamine synthases.
Mitochondria possess a large, non-selective ionic current that is enhanced during cardiac injury.
Tachycardia-induced metabolic rewiring as a driver of contractile dysfunction.
Review title: Mechanisms of mitochondrial reorganization.
Fatty acid elongation regulates mitochondrial β-oxidation and cell viability in prostate cancer by controlling malonyl-CoA levels.
Olfaction: an emerging regulator of longevity and metabolism.
CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice.
Organic Selenium induces ferroptosis in pancreatic cancer cells.
Mitochondrial E3 ligase MARCH5 is a safeguard against DNA-PKcs-mediated immune signaling in mitochondria-damaged cells.
In vivo reprogramming leads to premature death linked to hepatic and intestinal failure.
Cutting Edge: STING Induces ACLY Activation and Metabolic Adaptations in Human Macrophages through TBK1.
Adipose triglyceride lipase is a therapeutic target in advanced prostate cancer that promotes metabolic plasticity.
Trehalose enhances mitochondria deficits in human NPC1 mutant fibroblasts but disrupts mouse Purkinje cell dendritic growth ex vivo.
Bidirectional interplay between metabolism and epigenetics in hematopoietic stem cells and leukemia.
Acetyl-CoA is a key molecule for nephron progenitor cell pool maintenance.
Contribution of pks+ E. coli mutations to colorectal carcinogenesis.
Tumor endothelial cell autophagy is a key vascular-immune checkpoint in melanoma.
Metabolic Control of Cardiomyocyte Cell Cycle.
Noncanonical MAVS signaling restrains dendritic cell-driven antitumor immunity by inhibiting IL-12.
Impact of NAD+ metabolism on ovarian aging.
Understanding differential aspects of microdiffusion (channeling) in the Coenzyme Q and Cytochrome c regions of the mitochondrial respiratory system.
Disruption of redox balance in glutaminolytic triple negative breast cancer by inhibition of glutamate export and glutaminase.
Expression of the vesicular GABA transporter within neuromedin S+ neurons sustains behavioral circadian rhythms.
Comparison of colorimetric, fluorometric, and liquid chromatography-mass spectrometry assays for acetyl-coenzyme A.
Mitochondria as a sensor, a central hub and a biological clock in psychological stress-accelerated aging.
Membrane transporters in cell physiology, cancer metabolism and drug response.

Nat Metab. 2023 Nov 30.

Mitochondrial DNA editing with mitoARCUS.

Denisa Hathazi, Rita Horvath.

DOI: https://doi.org/10.1038/s42255-023-00933-5
Nat Metab. 2023 Nov 27.

Efferocytosis-induced lactate enables the proliferation of pro-resolving macrophages to mediate tissue repair.

David Ngai, Maaike Schilperoort, Ira Tabas.

The clearance of apoptotic cells by macrophages (efferocytosis) prevents necrosis and inflammation and activates pro-resolving pathways, including continual efferocytosis. A key resolution process in vivo is efferocytosis-induced macrophage proliferation (EIMP), in which apoptotic cell-derived nucleotides trigger Myc-mediated proliferation of pro-resolving macrophages. Here we show that EIMP requires a second input that is integrated with cellular metabolism, notably efferocytosis-induced lactate production. Lactate signalling via GPR132 promotes Myc protein stabilization and subsequent macrophage proliferation. This mechanism is validated in vivo using a mouse model of dexamethasone-induced thymocyte apoptosis, which elevates apoptotic cell burden and requires efferocytosis to prevent inflammation and necrosis. Thus, EIMP, a key process in tissue resolution, requires inputs from two independent processes: a signalling pathway induced by apoptotic cell-derived nucleotides and a cellular metabolism pathway involving lactate production. These findings illustrate how seemingly distinct pathways in efferocytosing macrophages are integrated to carry out a key process in tissue resolution.

DOI: https://doi.org/10.1038/s42255-023-00921-9
Trends Cell Biol. 2023 Nov 28. pii: S0962-8924(23)00231-3. [Epub ahead of print]

Metabolic immunity against microbes.

Sebastian Kreimendahl, Lena Pernas.

  Pathogens, including viruses, bacteria, fungi, and parasites, remodel the metabolism of their host to acquire the nutrients they need to proliferate. Thus, host cells are often perceived as mere exploitable nutrient pools during infection. Mounting reports challenge this perception and instead suggest that host cells can actively reprogram their metabolism to the detriment of the microbial invader. In this review, we present metabolic mechanisms that host cells use to defend against pathogens. We highlight the contribution of domesticated microbes to host defenses and discuss examples of host-pathogen arms races that are derived from metabolic conflict.

Keywords:  infection; metabolic defenses; metabolic immunity; metabolism; microbiota; mitochondria; pathogens

DOI:  https://doi.org/10.1016/j.tcb.2023.10.013
Annu Rev Physiol. 2023 Nov 27.

Metabolic Rewiring and Communication: An Integrative View of Kidney Proximal Tubule Function.

Maria Chrysopoulou, Markus M Rinschen.

The kidney proximal tubule is a key organ for human metabolism. The kidney responds to stress with altered metabolite transformation and perturbed metabolic pathways, an ultimate cause for kidney disease. Here, we review the proximal tubule's metabolic function through an integrative view of transport, metabolism, and function, and embed it in the context of metabolome-wide data-driven research. Function (filtration, transport, secretion, and reabsorption), metabolite transformation, and metabolite signaling determine kidney metabolic rewiring in disease. Energy metabolism and substrates for key metabolic pathways are orchestrated by metabolite sensors. Given the importance of renal function for the inner milieu, we also review metabolic communication routes with other organs. Exciting research opportunities exist to understand metabolic perturbation of kidney and proximal tubule function, for example, in hypertension-associated kidney disease. We argue that, based on the integrative view outlined here, kidney diseases without genetic cause should be approached scientifically as metabolic diseases. Expected final online publication date for the Annual Review of Physiology, Volume 86 is February 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-physiol-042222-024724
Cell Metab. 2023 Nov 16. pii: S1550-4131(23)00411-4. [Epub ahead of print]

PRMT1 orchestrates with SAMTOR to govern mTORC1 methionine sensing via Arg-methylation of NPRL2.

Cong Jiang, Jing Liu, Shaohui He, Wei Xu, Runzhi Huang, Weijuan Pan, Xiaolong Li, Xiaoming Dai, Jianping Guo, Tao Zhang, Hiroyuki Inuzuka, Ping Wang, John M Asara, Jianru Xiao, Wenyi Wei.

  Methionine is an essential branch of diverse nutrient inputs that dictate mTORC1 activation. In the absence of methionine, SAMTOR binds to GATOR1 and inhibits mTORC1 signaling. However, how mTORC1 is activated upon methionine stimulation remains largely elusive. Here, we report that PRMT1 senses methionine/SAM by utilizing SAM as a cofactor for an enzymatic activity-based regulation of mTORC1 signaling. Under methionine-sufficient conditions, elevated cytosolic SAM releases SAMTOR from GATOR1, which confers the association of PRMT1 with GATOR1. Subsequently, SAM-loaded PRMT1 methylates NPRL2, the catalytic subunit of GATOR1, thereby suppressing its GAP activity and leading to mTORC1 activation. Notably, genetic or pharmacological inhibition of PRMT1 impedes hepatic methionine sensing by mTORC1 and improves insulin sensitivity in aged mice, establishing the role of PRMT1-mediated methionine sensing at physiological levels. Thus, PRMT1 coordinates with SAMTOR to form the methionine-sensing apparatus of mTORC1 signaling.

Keywords:  GATOR1; NPRL2; PRMT1; arginine methylation; mTOR; methionine sensing; nutrient sensing

DOI:  https://doi.org/10.1016/j.cmet.2023.11.001
Eur J Clin Invest. 2023 Dec 01. e14138

Metabolic control of mitophagy.

Andreas Zimmermann, Frank Madeo, Abhinav Diwan, Junichi Sadoshima, Simon Sedej, Guido Kroemer, Mahmoud Abdellatif.

  Mitochondrial dysfunction is a major hallmark of ageing and related chronic disorders. Controlled removal of damaged mitochondria by the autophagic machinery, a process known as mitophagy, is vital for mitochondrial homeostasis and cell survival. The central role of mitochondria in cellular metabolism places mitochondrial removal at the interface of key metabolic pathways affecting the biosynthesis or catabolism of acetyl-coenzyme A, nicotinamide adenine dinucleotide, polyamines, as well as fatty acids and amino acids. Molecular switches that integrate the metabolic status of the cell, like AMP-dependent protein kinase, protein kinase A, mechanistic target of rapamycin and sirtuins, have also emerged as important regulators of mitophagy. In this review, we discuss how metabolic regulation intersects with mitophagy. We place special emphasis on the metabolic regulatory circuits that may be therapeutically targeted to delay ageing and mitochondria-associated chronic diseases. Moreover, we identify outstanding knowledge gaps, such as the ill-defined distinction between basal and damage-induced mitophagy, which must be resolved to boost progress in this area.

Keywords:  AMPK; NAD; acetyl-CoA; ageing; ageing-related disease; metabolism; mitophagy; spermidine

DOI:  https://doi.org/10.1111/eci.14138
bioRxiv. 2023 Nov 13. pii: 2023.11.08.566310. [Epub ahead of print]

Hypermetabolic state is associated with circadian rhythm disruption in mouse and human cancer cells.

Daniel Maxim Iascone, Xue Zhang, Patricia Bafford, Clementina Mesaros, Yogev Sela, Samuel Hofbauer, Shirley L Zhang, Kieona Cook, Pavel Pivarshev, Ben Z Stanger, Stewart Anderson, Chi V Dang, Amita Sehgal.

Crosstalk between cellular metabolism and circadian rhythms is a fundamental building block of multicellular life, and disruption of this reciprocal communication could be relevant to degenerative disease, including cancer. Here, we investigated whether maintenance of circadian rhythms depends upon specific metabolic pathways, particularly in the context of cancer. We found that in adult mouse fibroblasts, ATP levels were a major contributor to overall levels of a clock gene luciferase reporter, although not necessarily to the strength of circadian cycling. In contrast, we identified significant metabolic control of circadian function in an in vitro mouse model of pancreatic adenocarcinoma. Metabolic profiling of a library of congenic tumor cell clones revealed significant differences in levels of lactate, pyruvate, ATP, and other crucial metabolites that we used to identify candidate clones with which to generate circadian reporter lines. Despite the shared genetic background of the clones, we observed diverse circadian profiles among these lines that varied with their metabolic phenotype: the most hypometabolic line had the strongest circadian rhythms while the most hypermetabolic line had the weakest rhythms. Treatment of these tumor cell lines with bezafibrate, a peroxisome proliferator-activated receptor (PPAR) agonist shown to increase OxPhos, decreased the amplitude of circadian oscillation in a subset of tumor cell lines. Strikingly, treatment with the Complex I antagonist rotenone enhanced circadian rhythms only in the tumor cell line in which glycolysis was also low, thereby establishing a hypometabolic state. We further analyzed metabolic and circadian phenotypes across a panel of human patient-derived melanoma cell lines and observed a significant negative association between metabolic activity and circadian cycling strength. Together, these findings suggest that metabolic heterogeneity in cancer directly contributes to circadian function, and that high levels of glycolysis or OxPhos independently disrupt circadian rhythms in these cells.

DOI: https://doi.org/10.1101/2023.11.08.566310
Nat Immunol. 2023 Dec;24(12): 2008-2020

The immunometabolic ecosystem in cancer.

Glenn R Bantug, Christoph Hess.

Our increased understanding of how key metabolic pathways are activated and regulated in malignant cells has identified metabolic vulnerabilities of cancers. Translating this insight to the clinics, however, has proved challenging. Roadblocks limiting efficacy of drugs targeting cancer metabolism may lie in the nature of the metabolic ecosystem of tumors. The exchange of metabolites and growth factors between cancer cells and nonmalignant tumor-resident cells is essential for tumor growth and evolution, as well as the development of an immunosuppressive microenvironment. In this Review, we will examine the metabolic interplay between tumor-resident cells and how targeted inhibition of specific metabolic enzymes in malignant cells could elicit pro-tumorigenic effects in non-transformed tumor-resident cells and inhibit the function of tumor-specific T cells. To improve the efficacy of metabolism-targeted anticancer strategies, a holistic approach that considers the effect of metabolic inhibitors on major tumor-resident cell populations is needed.

DOI: https://doi.org/10.1038/s41590-023-01675-y
Cell Biochem Funct. 2023 Nov 28.

Metabolic signals influence cell-fate decisions in Dictyostelium discoideum.

Tasneem Fatima, Ibanylla Kynjai Hynniewta Hadem, Shweta Saran.

  Nutrient-sensing plays a crucial role in maintaining cellular energy and metabolic homeostasis. Perturbations in sensing pathways are associated with a wide variety of pathologies, especially metabolic diseases. Very little is understood about sensing fluctuations in nutrients and how this information is integrated into physiological and metabolic adaptation that could further affect cell-fate decisions during differentiation in Dictyostelium discoideum (henceafter, Dictyostelium). Glucose is the primary metabolic fuel among all nutrients. Carbohydrates, lipids and proteins ultimately breakdown into glucose, which is further used for providing energy. The maintenance of optimum glucose levels is important for efficient cell-survival. Glucose is not only a nutrient, but also a signaling molecule influencing cell growth and differentiation in Dictyostelium. Modulation of endogenous glucose levels either by varying exogenous glucose levels or genetic overexpression or deletion of genes involved in glucose signaling lead to changes in endogenous metabolite levels such as ADP/ATP ratio, NAD+ /NADH ratio, cAMP and ROS levels which further influence cell-fate decisions. Here, we show that AMPKα and Sir2D are components of glucose-signaling pathway in Dictyostelium which adjust cell metabolism interdependently in response to nutrient-status and promote cell-fate decisions.

Keywords:  AMPKα; Dictyostelium; ROS; Sir2D; differentiation; glucose; metabolites

DOI:  https://doi.org/10.1002/cbf.3892
Nat Commun. 2023 Nov 28. 14(1): 7814

MicroRNA-mediated attenuation of branched-chain amino acid catabolism promotes ferroptosis in chronic kidney disease.

Hisakatsu Sone, Tae Jin Lee, Byung Rho Lee, Dan Heo, Sekyung Oh, Sang-Ho Kwon.

Chronic kidney disease can develop from kidney injury incident to chemotherapy with cisplatin, which complicates the prognosis of cancer patients. MicroRNAs regulate gene expression by pairing with specific sets of messenger RNAs. Therefore, elucidating direct physical interactions between microRNAs and their target messenger RNAs can help decipher crucial biological processes associated with cisplatin-induced kidney injury. Through intermolecular ligation and transcriptome-wide sequencing, we here identify direct pairs of microRNAs and their target messenger RNAs in the kidney of male mice injured by cisplatin. We find that a group of cisplatin-induced microRNAs can target select messenger RNAs that affect the mitochondrial metabolic pathways in the injured kidney. Specifically, a cisplatin-induced microRNA, miR-429-3p, suppresses the pathway that catabolizes branched-chain amino acids in the proximal tubule, leading to cell death dependent on lipid peroxidation, called ferroptosis. Identification of miRNA-429-3p-mediated ferroptosis stimulation suggests therapeutic potential for modulating the branched-chain amino acid pathway in ameliorating cisplatin-induced kidney injury.

DOI: https://doi.org/10.1038/s41467-023-43529-z
Nat Commun. 2023 Dec 01. 14(1): 7762

SMARCB1 loss activates patient-specific distal oncogenic enhancers in malignant rhabdoid tumors.

Ning Qing Liu, Irene Paassen, Lars Custers, Peter Zeller, Hans Teunissen, Dilara Ayyildiz, Jiayou He, Juliane Laura Buhl, Eelco Wieger Hoving, Alexander van Oudenaarden, Elzo de Wit, Jarno Drost.

Malignant rhabdoid tumor (MRT) is a highly malignant and often lethal childhood cancer. MRTs are genetically defined by bi-allelic inactivating mutations in SMARCB1, a member of the BRG1/BRM-associated factors (BAF) chromatin remodeling complex. Mutations in BAF complex members are common in human cancer, yet their contribution to tumorigenesis remains in many cases poorly understood. Here, we study derailed regulatory landscapes as a consequence of SMARCB1 loss in the context of MRT. Our multi-omics approach on patient-derived MRT organoids reveals a dramatic reshaping of the regulatory landscape upon SMARCB1 reconstitution. Chromosome conformation capture experiments subsequently reveal patient-specific looping of distal enhancer regions with the promoter of the MYC oncogene. This intertumoral heterogeneity in MYC enhancer utilization is also present in patient MRT tissues as shown by combined single-cell RNA-seq and ATAC-seq. We show that loss of SMARCB1 activates patient-specific epigenetic reprogramming underlying MRT tumorigenesis.

DOI: https://doi.org/10.1038/s41467-023-43498-3
Mol Cell. 2023 Nov 20. pii: S1097-2765(23)00918-8. [Epub ahead of print]

Boveri and beyond: Chromothripsis and genomic instability from mitotic errors.

Alice Mazzagatti, Justin L Engel, Peter Ly.

  Mitotic cell division is tightly monitored by checkpoints that safeguard the genome from instability. Failures in accurate chromosome segregation during mitosis can cause numerical aneuploidy, which was hypothesized by Theodor Boveri over a century ago to promote tumorigenesis. Recent interrogation of pan-cancer genomes has identified unexpected classes of chromosomal abnormalities, including complex rearrangements arising through chromothripsis. This process is driven by mitotic errors that generate abnormal nuclear structures that provoke extensive yet localized shattering of mis-segregated chromosomes. Here, we discuss emerging mechanisms underlying chromothripsis from micronuclei and chromatin bridges, as well as highlight how this mutational cascade converges on the DNA damage response. A fundamental understanding of these catastrophic processes will provide insight into how initial errors in mitosis can precipitate rapid cancer genome evolution.

Keywords:  DNA repair; aneuploidy; cancer evolution; cell cycle; chromatin bridge; chromosome segregation; chromothripsis; genome rearrangements; micronuclei; mitosis

DOI:  https://doi.org/10.1016/j.molcel.2023.11.002
Trends Endocrinol Metab. 2023 Nov 28. pii: S1043-2760(23)00240-0. [Epub ahead of print]

Methylmalonic acid in aging and disease.

Joanne Tejero, Felicia Lazure, Ana P Gomes.

  Metabolic byproducts have conventionally been disregarded as waste products without functions. In this opinion article, we bring to light the multifaceted role of methylmalonic acid (MMA), a byproduct of the propionate metabolism pathway mostly commonly known as a clinical biomarker of vitamin B12 deficiency. MMA is normally present at low levels in the body, but increased levels can come from different sources, such as vitamin B12 deficiency, genetic mutations in enzymes related to the propionate pathway, the gut microbiota, and aggressive cancers. Here, we describe the diverse metabolic and signaling functions of MMA and discuss the consequences of increased MMA levels, such as during the aging process, for several age-related human pathologies.

Keywords:  aging; disease; metabolism; methylmalonic acid

DOI:  https://doi.org/10.1016/j.tem.2023.11.001
bioRxiv. 2023 Nov 16. pii: 2023.11.14.566937. [Epub ahead of print]

Telomerase reverse transcriptase induces targetable alterations in glutathione and nucleotide biosynthesis in glioblastomas.

Suresh Udutha, Céline Taglang, Georgios Batsios, Anne Marie Gillespie, Meryssa Tran, Sabrina M Ronen, Johanna Ten Hoeve, Thomas G Graeber, Pavithra Viswanath.

Telomerase reverse transcriptase (TERT) is essential for glioblastoma (GBM) proliferation. Delineating metabolic vulnerabilities induced by TERT can lead to novel GBM therapies. We previously showed that TERT upregulates glutathione (GSH) pool size in GBMs. Here, we show that TERT acts via the FOXO1 transcription factor to upregulate expression of the catalytic subunit of glutamate-cysteine ligase (GCLC), the rate-limiting enzyme of de novo GSH synthesis. Inhibiting GCLC using siRNA or buthionine sulfoximine (BSO) reduces synthesis of 13 C-GSH from [U- 13 C]-glutamine and inhibits clonogenicity. However, GCLC inhibition does not induce cell death, an effect that is associated with elevated [U- 13 C]-glutamine metabolism to glutamate and pyrimidine nucleotide biosynthesis. Mechanistically, GCLC inhibition activates MYC and leads to compensatory upregulation of two key glutamine-utilizing enzymes i.e., glutaminase (GLS), which generates glutamate from glutamine, and CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotatase), the enzyme that converts glutamine to the pyrimidine nucleotide precursor dihydroorotate. We then examined the therapeutic potential of inhibiting GLS and CAD in combination with GCLC. 6-diazo-5-oxy-L-norleucin (DON) is a potent inhibitor of glutamine-utilizing enzymes including GLS and CAD. The combination of BSO and DON suppresses GSH and pyrimidine nucleotide biosynthesis and is synergistically lethal in GBM cells. Importantly, in vivo stable isotope tracing indicates that combined treatment with JHU-083 (a brain-penetrant prodrug of DON) and BSO abrogates synthesis of GSH and pyrimidine nucleotides from [U- 13 C]-glutamine and induces tumor shrinkage in mice bearing intracranial GBM xenografts. Collectively, our studies exploit a mechanistic understanding of TERT biology to identify synthetically lethal metabolic vulnerabilities in GBMs.SIGNIFICANCE: Using in vivo stable isotope tracing, metabolomics, and loss-of-function studies, we demonstrate that TERT expression is associated with metabolic alterations that can be synergistically targeted for therapy in glioblastomas.

DOI: https://doi.org/10.1101/2023.11.14.566937
Semin Diagn Pathol. 2023 Nov 17. pii: S0740-2570(23)00095-3. [Epub ahead of print]

Kidney cancer: Links between hereditary syndromes and sporadic tumorigenesis.

Michel Alchoueiry, Kristine Cornejo, Elizabeth P Henske.

  Multiple hereditary syndromes predispose to kidney cancer, including Von Hippel-Lindau syndrome, BAP1-Tumor Predisposition Syndrome, Hereditary Papillary Renal Cell Carcinoma, Tuberous Sclerosis Complex, Birt-Hogg-Dubé syndrome, Hereditary Paraganglioma-Pheochromocytoma Syndrome, Fumarate Hydratase Tumor Predisposition Syndrome, and Cowden syndrome. In some cases, mutations in the genes that cause hereditary kidney cancer are tightly linked to similar histologic features in sporadic RCC. For example, clear cell RCC occurs in the hereditary syndrome VHL, and sporadic ccRCC usually has inactivation of the VHL gene. In contrast, mutations in FLCN, the causative gene for Birt-Hogg-Dube syndrome, are rarely found in sporadic RCC. Here, we focus on the genes and pathways that link hereditary and sporadic RCC.

Keywords:  Cancer; Hereditary syndromes; Kidney; Sporadic

DOI:  https://doi.org/10.1053/j.semdp.2023.11.002
Nat Commun. 2023 Nov 30. 14(1): 7889

The poxvirus F17 protein counteracts mitochondrially orchestrated antiviral responses.

Nathan Meade, Helen K Toreev, Ram P Chakrabarty, Charles R Hesser, Chorong Park, Navdeep S Chandel, Derek Walsh.

Poxviruses are unusual DNA viruses that replicate in the cytoplasm. To do so, they encode approximately 100 immunomodulatory proteins that counteract cytosolic nucleic acid sensors such as cGAMP synthase (cGAS) along with several other antiviral response pathways. Yet most of these immunomodulators are expressed very early in infection while many are variable host range determinants, and significant gaps remain in our understanding of poxvirus sensing and evasion strategies. Here, we show that after infection is established, subsequent progression of the viral lifecycle is sensed through specific changes to mitochondria that coordinate distinct aspects of the antiviral response. Unlike other viruses that cause extensive mitochondrial damage, poxviruses sustain key mitochondrial functions including membrane potential and respiration while reducing reactive oxygen species that drive inflammation. However, poxvirus replication induces mitochondrial hyperfusion that independently controls the release of mitochondrial DNA (mtDNA) to prime nucleic acid sensors and enables an increase in glycolysis that is necessary to support interferon stimulated gene (ISG) production. To counter this, the poxvirus F17 protein localizes to mitochondria and dysregulates mTOR to simultaneously destabilize cGAS and block increases in glycolysis. Our findings reveal how the poxvirus F17 protein disarms specific mitochondrially orchestrated responses to later stages of poxvirus replication.

DOI: https://doi.org/10.1038/s41467-023-43635-y
bioRxiv. 2023 Nov 16. pii: 2023.11.14.567048. [Epub ahead of print]

Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.

Kristen E Kay, Juyeun Lee, Ellen S Hong, Julia Beilis, Sahil Dayal, Emily Wesley, Sofia Mitchell, Sabrina Z Wang, Daniel J Silver, Josephine Volovetz, Sadie Johnson, Mary McGraw, Matthew M Grabowski, Tianyao Lu, Lutz Freytag, Vinod Narayana, Saskia Freytag, Sarah A Best, James R Whittle, Zeneng Wang, Ofer Reizes, Jennifer S Yu, Stanley L Hazen, J Mark Brown, Defne Bayik, Justin D Lathia.

The glioblastoma microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly impact the immune system, but the mechanisms driving these interactions are not completely clear. Here we demonstrate that the polyamine metabolite spermidine is elevated in the glioblastoma tumor microenvironment. Exogenous administration of spermidine drives tumor aggressiveness in an immune-dependent manner in pre-clinical mouse models via reduction of CD8+ T cell frequency and phenotype. Knockdown of ornithine decarboxylase, the rate-limiting enzyme in spermidine synthesis, did not impact cancer cell growth in vitro but did result in extended survival. Furthermore, glioblastoma patients with a more favorable outcome had a significant reduction in spermidine compared to patients with a poor prognosis. Our results demonstrate that spermidine functions as a cancer cell-derived metabolite that drives tumor progression by reducing CD8+T cell number and function.

DOI: https://doi.org/10.1101/2023.11.14.567048
Cell Death Dis. 2023 Nov 25. 14(11): 772

Negative modulation of mitochondrial calcium uniporter complex protects neurons against ferroptosis.

Alejandro Marmolejo-Garza, Inge E Krabbendam, Minh Danh Anh Luu, Famke Brouwer, Marina Trombetta-Lima, Osman Unal, Shane J O'Connor, Naďa Majerníková, Carolina R S Elzinga, Cristina Mammucari, Martina Schmidt, Muniswamy Madesh, Erik Boddeke, Amalia M Dolga.

Ferroptosis is an iron- and reactive oxygen species (ROS)-dependent form of regulated cell death, that has been implicated in Alzheimer's disease and Parkinson's disease. Inhibition of cystine/glutamate antiporter could lead to mitochondrial fragmentation, mitochondrial calcium ([Ca2+]m) overload, increased mitochondrial ROS production, disruption of the mitochondrial membrane potential (ΔΨm), and ferroptotic cell death. The observation that mitochondrial dysfunction is a characteristic of ferroptosis makes preservation of mitochondrial function a potential therapeutic option for diseases associated with ferroptotic cell death. Mitochondrial calcium levels are controlled via the mitochondrial calcium uniporter (MCU), the main entry point of Ca2+ into the mitochondrial matrix. Therefore, we have hypothesized that negative modulation of MCU complex may confer protection against ferroptosis. Here we evaluated whether the known negative modulators of MCU complex, ruthenium red (RR), its derivative Ru265, mitoxantrone (MX), and MCU-i4 can prevent mitochondrial dysfunction and ferroptotic cell death. These compounds mediated protection in HT22 cells, in human dopaminergic neurons and mouse primary cortical neurons against ferroptotic cell death. Depletion of MICU1, a [Ca2+]m gatekeeper, demonstrated that MICU is protective against ferroptosis. Taken together, our results reveal that negative modulation of MCU complex represents a therapeutic option to prevent degenerative conditions, in which ferroptosis is central to the progression of these pathologies.

DOI: https://doi.org/10.1038/s41419-023-06290-1
Semin Cancer Biol. 2023 Nov 27. pii: S1044-579X(23)00146-3. [Epub ahead of print]

Epigenetic remodelling under hypoxia.

Roxane Verdikt, Bernard Thienpont.

  Hypoxia is intrinsic to tumours and contributes to malignancy and metastasis while hindering the efficiency of existing treatments. Epigenetic mechanisms play a crucial role in the regulation of hypoxic cancer cell programs, both in the initial phases of sensing the decrease in oxygen levels and during adaptation to chronic lack of oxygen. During the latter, the epigenetic regulation of tumour biology intersects with hypoxia-sensitive transcription factors in a complex network of gene regulation that also involves metabolic reprogramming. Here, we review the current literature on the epigenetic control of gene programs in hypoxic cancer cells. We highlight common themes and features of such epigenetic remodelling and discuss their relevance for the development of therapeutic strategies.

Keywords:  Cancer programs; Epigenetics; Tumour hypoxia

DOI:  https://doi.org/10.1016/j.semcancer.2023.10.005
FASEB J. 2023 Dec;37(12): e23319

Lysine-372-dependent SUMOylation inhibits the enzymatic activity of glutamine synthases.

Ting Ling, Siyi Li, Huan Chen, Qiuping Wang, Jing Shi, Yirong Li, Wenjun Bao, Kunming Liang, Hai-Long Piao.

Glutamine synthetase (GS) is a crucial enzyme involved in de novo synthesis of glutamine and participates in several biological processes, including nitrogen metabolism, nucleotide synthesis, and amino acid synthesis. Post-translational modification makes GS more adaptable to the needs of cells, and acetylation modification of GS at double sites has attracted considerable attention. Despite very intensive research, how SUMOylation affects GS activity at a molecular level remains unclear. Here, we report that previously undiscovered GS SUMOylation which is deficient mutant K372R of GS exhibits more bluntness under glutamine starvation. Mechanistically, glutamine deprivation triggers the GS SUMOylation, and this SUMOylation impaired the protein stability of GS, within a concomitant decrease in enzymatic activity. In addition, we identified SAE1, Ubc9, and PIAS1 as the assembly enzymes of GS SUMOylation respectively. Furthermore, Senp1/2 functions as a SUMO-specific protease to reverse the SUMOylation of GS. This study provides the first evidence that SUMOylation serves as a regulatory mechanism for determining the GS enzymatic activity, contributing to understanding the GS regulation roles in various cellular and pathophysiological processes.

DOI: https://doi.org/10.1096/fj.202301462RR
bioRxiv. 2023 Nov 16. pii: 2023.11.15.567241. [Epub ahead of print]

Mitochondria possess a large, non-selective ionic current that is enhanced during cardiac injury.

Enrique Balderas, Sandra H J Lee, Thirupura S Shankar, Xue Yin, Anthony M Balynas, Christos P Kyriakopoulos, Craig H Selzman, Stavros G Drakos, Dipayan Chaudhuri.

Mitochondrial ion channels are essential for energy production and cell survival. To avoid depleting the electrochemical gradient used for ATP synthesis, channels so far described in the mitochondrial inner membrane open only briefly, are highly ion-selective, have restricted tissue distributions, or have small currents. Here, we identify a mitochondrial inner membrane conductance that has strikingly different behavior from previously described channels. It is expressed ubiquitously, and transports cations non-selectively, producing a large, up to nanoampere-level, current. The channel does not lead to inner membrane uncoupling during normal physiology because it only becomes active at depolarized voltages. It is inhibited by external Ca 2+ , corresponding to the intermembrane space, as well as amiloride. This large, ubiquitous, non-selective, amiloride-sensitive (LUNA) current appears most active when expression of the mitochondrial calcium uniporter is minimal, such as in the heart. In this organ, we find that LUNA current magnitude increases two- to threefold in multiple mouse models of injury, an effect also seen in cardiac mitochondria from human patients with heart failure with reduced ejection fraction. Taken together, these features lead us to speculate that LUNA current may arise from an essential protein that acts as a transporter under physiological conditions, but becomes a channel under conditions of mitochondrial stress and depolarization.

DOI: https://doi.org/10.1101/2023.11.15.567241
Nat Biomed Eng. 2023 Nov 27.

Tachycardia-induced metabolic rewiring as a driver of contractile dysfunction.

Chengyi Tu, Arianne Caudal, Yu Liu, Nikoloz Gorgodze, Hao Zhang, Chi Keung Lam, Yuqin Dai, Angela Zhang, Alexa Wnorowski, Matthew A Wu, Huaxiao Yang, Oscar J Abilez, Xuchao Lyu, Sanjiv M Narayan, Luisa Mestroni, Matthew R G Taylor, Fabio A Recchia, Joseph C Wu.

Prolonged tachycardia-a risk factor for cardiovascular morbidity and mortality-can induce cardiomyopathy in the absence of structural disease in the heart. Here, by leveraging human patient data, a canine model of tachycardia and engineered heart tissue generated from human induced pluripotent stem cells, we show that metabolic rewiring during tachycardia drives contractile dysfunction by promoting tissue hypoxia, elevated glucose utilization and the suppression of oxidative phosphorylation. Mechanistically, a metabolic shift towards anaerobic glycolysis disrupts the redox balance of nicotinamide adenine dinucleotide (NAD), resulting in increased global protein acetylation (and in particular the acetylation of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase), a molecular signature of heart failure. Restoration of NAD redox by NAD+ supplementation reduced sarcoplasmic/endoplasmic reticulum Ca2+-ATPase acetylation and accelerated the functional recovery of the engineered heart tissue after tachycardia. Understanding how metabolic rewiring drives tachycardia-induced cardiomyopathy opens up opportunities for therapeutic intervention.

DOI: https://doi.org/10.1038/s41551-023-01134-x
J Biochem. 2023 Nov 28. pii: mvad098. [Epub ahead of print]

Review title: Mechanisms of mitochondrial reorganization.

Tatsuro Maruyama, Yutaro Hama, Nobuo N Noda.

  The cytoplasm of eukaryotes is dynamically zoned by membrane-bound and membraneless organelles. Cytoplasmic zoning allows various biochemical reactions to take place at the right time and place. Mitochondrion is a membrane-bound organelle that provides a zone for intracellular energy production and metabolism of lipids and iron. A key feature of mitochondria is their high dynamics: mitochondria constantly undergo fusion and fission, and excess or damaged mitochondria are selectively eliminated by mitophagy. Therefore, mitochondria are appropriate model systems to understand dynamic cytoplasmic zoning by membrane organelles. In this review, we summarize the molecular mechanisms of mitochondrial fusion and fission as well as mitophagy unveiled through studies using yeast and mammalian models.

Keywords:  cytoplasmic zoning; mitochondria; mitochondrial fission; mitochondrial fusion; mitophagy

DOI:  https://doi.org/10.1093/jb/mvad098
Biochem Biophys Res Commun. 2023 Nov 18. pii: S0006-291X(23)01367-0. [Epub ahead of print]691 149273

Fatty acid elongation regulates mitochondrial β-oxidation and cell viability in prostate cancer by controlling malonyl-CoA levels.

Julia S Scott, Lake-Ee Quek, Andrew J Hoy, Johannes V Swinnen, Zeyad D Nassar, Lisa M Butler.

  Recently, the fatty acid elongation enzyme ELOVL5 was identified as a critical pro-metastatic factor in prostate cancer, required for cell growth and mitochondrial homeostasis. The fatty acid elongation reaction catalyzed by ELOVL5 utilizes malonyl-CoA as the carbon donor. Here, we demonstrate that ELOVL5 knockdown causes malonyl-CoA accumulation. Malonyl-CoA is a cellular substrate that can inhibit fatty acid β-oxidation in the mitochondria through allosteric inhibition of carnitine palmitoyltransferase 1A (CPT1A), the enzyme that controls the rate-limiting step of the long chain fatty acid β-oxidation cycle. We hypothesized that changes in malonyl-CoA abundance following ELOVL5 knockdown could influence mitochondrial β-oxidation rates in prostate cancer cells, and regulate cell viability. Accordingly, we find that ELOVL5 knockdown is associated with decreased mitochondrial β-oxidation in prostate cancer cells. Combining ELOVL5 knockdown with FASN inhibition to increase malonyl-CoA abundance endogenously enhances the effect of ELOVL5 knockdown on prostate cancer cell viability, while preventing malonyl-CoA production rescues the cells from the effect of ELOVL5 knockdown. Our findings indicate an additional role for fatty acid elongation, in the control of malonyl-CoA homeostasis, alongside its established role in the production of long-chain fatty acid species, to explain the importance of fatty acid elongation for cell viability.

Keywords:  Fatty acid elongation; Fatty acid oxidation; Malonyl-CoA; Prostate cancer

DOI:  https://doi.org/10.1016/j.bbrc.2023.149273
Trends Cell Biol. 2023 Nov 25. pii: S0962-8924(23)00234-9. [Epub ahead of print]

Olfaction: an emerging regulator of longevity and metabolism.

Maximillian A Thompson, Evandro A De-Souza.

  Ageing is a malleable process influenced by the environment. Recent research reveals that neurons interact with peripheral organs to regulate metabolism and longevity by responding to olfactory cues through specific pathways, such as the unfolded protein response (UPR) and microRNAs. Here, we examine the significance of these findings.

Keywords:  environmental cues; longevity; odorants; proteostasis; stress responses

DOI:  https://doi.org/10.1016/j.tcb.2023.11.001
Nat Commun. 2023 Nov 29. 14(1): 7824

CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice.

Philipp Hammerschmidt, Sophie M Steculorum, Cécile L Bandet, Almudena Del Río-Martín, Lukas Steuernagel, Vivien Kohlhaas, Marvin Feldmann, Luis Varela, Adam Majcher, Marta Quatorze Correia, Rhena F U Klar, Corinna A Bauder, Ecem Kaya, Marta Porniece, Nasim Biglari, Anna Sieben, Tamas L Horvath, Thorsten Hornemann, Susanne Brodesser, Jens C Brüning.

Dysregulation of hypothalamic ceramides has been associated with disrupted neuronal pathways in control of energy and glucose homeostasis. However, the specific ceramide species promoting neuronal lipotoxicity in obesity have remained obscure. Here, we find increased expression of the C16:0 ceramide-producing ceramide synthase (CerS)6 in cultured hypothalamic neurons exposed to palmitate in vitro and in the hypothalamus of obese mice. Conditional deletion of CerS6 in hypothalamic neurons attenuates high-fat diet (HFD)-dependent weight gain and improves glucose metabolism. Specifically, CerS6 deficiency in neurons expressing pro-opiomelanocortin (POMC) or steroidogenic factor 1 (SF-1) alters feeding behavior and alleviates the adverse metabolic effects of HFD feeding on insulin sensitivity and glucose tolerance. POMC-expressing cell-selective deletion of CerS6 prevents the diet-induced alterations of mitochondrial morphology and improves cellular leptin sensitivity. Our experiments reveal functions of CerS6-derived ceramides in hypothalamic lipotoxicity, altered mitochondrial dynamics, and ER/mitochondrial stress in the deregulation of food intake and glucose metabolism in obesity.

DOI: https://doi.org/10.1038/s41467-023-42595-7
Redox Biol. 2023 Nov 20. pii: S2213-2317(23)00363-4. [Epub ahead of print]68 102962

Organic Selenium induces ferroptosis in pancreatic cancer cells.

Roberta Noè, Noemi Inglese, Patrizia Romani, Thauan Serafini, Carlotta Paoli, Beatrice Calciolari, Marco Fantuz, Agata Zamborlin, Nicoletta C Surdo, Vittoria Spada, Martina Spacci, Sara Volta, Maria Laura Ermini, Giulietta Di Benedetto, Valentina Frusca, Claudio Santi, Konstantinos Lefkimmiatis, Sirio Dupont, Valerio Voliani, Luca Sancineto, Alessandro Carrer.

  Pancreatic ductal adenocarcinoma (PDA) cells reprogram both mitochondrial and lysosomal functions to support growth. At the same time, this causes significant dishomeostasis of free radicals. While this is compensated by the upregulation of detoxification mechanisms, it also represents a potential vulnerability. Here we demonstrate that PDA cells are sensitive to the inhibition of the mevalonate pathway (MVP), which supports the biosynthesis of critical antioxidant intermediates and protect from ferroptosis. We attacked the susceptibility of PDA cells to ferroptotic death with selenorganic compounds, including dibenzyl diselenide (DBDS) that exhibits potent pro-oxidant properties and inhibits tumor growth in vitro and in vivo. DBDS treatment induces the mobilization of iron from mitochondria enabling uncontrolled lipid peroxidation. Finally, we showed that DBDS and statins act synergistically to promote ferroptosis and provide evidence that combined treatment is a viable strategy to combat PDA.

Keywords:  Dibenzyl diselenide (DBDS); Ferroptosis; Mevalonate pathway (MVP); Pancreatic cancer; Selenorganic compounds

DOI:  https://doi.org/10.1016/j.redox.2023.102962
Cell Death Dis. 2023 Dec 01. 14(12): 788

Mitochondrial E3 ligase MARCH5 is a safeguard against DNA-PKcs-mediated immune signaling in mitochondria-damaged cells.

June Heo, Yeon-Ji Park, Yonghyeon Kim, Ho-Soo Lee, Jeongah Kim, Soon-Hwan Kwon, Myeong-Gyun Kang, Hyun-Woo Rhee, Woong Sun, Jae-Ho Lee, Hyeseong Cho.

Mitochondrial dysfunction is important in various chronic degenerative disorders, and aberrant immune responses elicited by cytoplasmic mitochondrial DNA (mtDNA) may be related. Here, we developed mtDNA-targeted MTERF1-FokI and TFAM-FokI endonuclease systems to induce mitochondrial DNA double-strand breaks (mtDSBs). In these cells, the mtDNA copy number was significantly reduced upon mtDSB induction. Interestingly, in cGAS knockout cells, synthesis of interferon β1 and interferon-stimulated gene was increased upon mtDSB induction. We found that mtDSBs activated DNA-PKcs and HSPA8 in a VDAC1-dependent manner. Importantly, the mitochondrial E3 ligase MARCH5 bound active DNA-PKcs in cells with mtDSBs and reduced the type І interferon response through the degradation of DNA-PKcs. Likewise, mitochondrial damage caused by LPS treatment in RAW264.7 macrophage cells increased phospho-HSPA8 levels and the synthesis of mIFNB1 mRNA in a DNA-PKcs-dependent manner. Accordingly, in March5 knockout macrophages, phospho-HSPA8 levels and the synthesis of mIFNB1 mRNA were prolonged after LPS stimulation. Together, cytoplasmic mtDNA elicits a cellular immune response through DNA-PKcs, and mitochondrial MARCH5 may be a safeguard to prevent persistent inflammatory reactions.

DOI: https://doi.org/10.1038/s41419-023-06315-9
Nat Aging. 2023 Nov 27.

In vivo reprogramming leads to premature death linked to hepatic and intestinal failure.

Alberto Parras, Alba Vílchez-Acosta, Gabriela Desdín-Micó, Sara Picó, Calida Mrabti, Elena Montenegro-Borbolla, Céline Yacoub Maroun, Amin Haghani, Robert Brooke, María Del Carmen Maza, Cheyenne Rechsteiner, Fabrice Battiston, Clémence Branchina, Kevin Perez, Steve Horvath, Claire Bertelli, Christine Sempoux, Alejandro Ocampo.

The induction of cellular reprogramming via expression of the transcription factors Oct4, Sox2, Klf4 and c-Myc (OSKM) can drive dedifferentiation of somatic cells and ameliorate age-associated phenotypes in multiple tissues and organs. However, the benefits of long-term in vivo reprogramming are limited by detrimental side-effects. Here, using complementary genetic approaches, we demonstrated that continuous induction of the reprogramming factors in vivo leads to hepatic and intestinal dysfunction resulting in decreased body weight and contributing to premature death (within 1 week). By generating a transgenic reprogrammable mouse strain, avoiding OSKM expression in both liver and intestine, we reduced the early lethality and adverse effects associated with in vivo reprogramming and induced a decrease in organismal biological age. This reprogramming mouse strain, which allows longer-term continuous induction of OSKM with attenuated toxicity, can help better understand rejuvenation, regeneration and toxicity during in vivo reprogramming.

DOI: https://doi.org/10.1038/s43587-023-00528-5
J Immunol. 2023 Dec 01. pii: ji2200835. [Epub ahead of print]

Cutting Edge: STING Induces ACLY Activation and Metabolic Adaptations in Human Macrophages through TBK1.

Maximilian Nickenig, Matthew S J Mangan, Hye Eun Lee, Konstantinos Symeonidis, Antonia Henne, Romina Kaiser, Eike Geißmar, Hendrikus Garritsen, Zeinab Abdullah, Karsten Hiller, Eicke Latz, Mario A Lauterbach.

The 2'3'-cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of IFN genes (STING) pathway can sense infection and cellular stress by detecting cytosolic DNA. Upon ligand binding, cGAS produces the cyclic dinucleotide messenger cGAMP, which triggers its receptor STING. Active STING initiates gene transcription through the transcription factors IFN regulatory factor 3 (IRF3) and NF-κB and induces autophagy, but whether STING can cause changes in the metabolism of macrophages is unknown. In this study, we report that STING signaling activates ATP-citrate lyase (ACLY) by phosphorylation in human macrophages. Using genetic and pharmacologic perturbation, we show that STING targets ACLY via its prime downstream signaling effector TANK (TRAF family member-associated NF-κB activator)-binding kinase 1 (TBK1). We further identify that TBK1 alters cellular metabolism upon cGAMP treatment. Our results suggest that STING-mediated metabolic reprogramming adjusts the cellular response to DNA sensing in addition to transcription factor activation and autophagy induction.

DOI: https://doi.org/10.4049/jimmunol.2200835
Cancer Res. 2023 Dec 01.

Adipose triglyceride lipase is a therapeutic target in advanced prostate cancer that promotes metabolic plasticity.

Dominik Awad, Pham Hong Anh Cao, Thomas L Pulliam, Meredith Spradlin, Elavarasan Subramani, Tristen V Tellman, Caroline F Ribeiro, Riccardo Muzzioli, Brittany E Jewell, Hubert Pakula, Jeffrey J Ackroyd, Mollianne M Murray, Jenny J Han, Mei Leng, Antrix Jain, Badrajee Piyarathna, JIngjing Liu, Xingzhi Song, Jianhua Zhang, Albert R Klekers, Justin M Drake, Michael M Ittmann, Cristian Coarfa, David Piwnica-Worms, Mary C Farach-Carson, Massimo Loda, Livia S Eberlin, Daniel E Frigo.

Lipid metabolism plays a central role in prostate cancer. To date, the major focus has centered on de novo lipogenesis and lipid uptake in prostate cancer, but inhibitors of these processes have not benefited patients. Better understanding of how cancer cells access lipids once they are created or taken up and stored could uncover more effective strategies to perturb lipid metabolism and treat patients. Here, we identified that expression of adipose triglyceride lipase (ATGL), an enzyme that controls lipid droplet homeostasis and a previously suspected tumor suppressor, correlates with worse overall survival in men with advanced, castration-resistant prostate cancer (CRPC). Molecular, genetic, or pharmacological inhibition of ATGL impaired human and murine prostate cancer growth in vivo and in cell culture or organoids under conditions mimicking the tumor microenvironment. Mass spectrometry imaging demonstrated ATGL profoundly regulates lipid metabolism in vivo, remodeling membrane composition. ATGL inhibition induced metabolic plasticity, causing a glycolytic shift that could be exploited therapeutically by co-targeting both metabolic pathways. Patient-derived phosphoproteomics identified ATGL serine 404 as a target of CAMKK2-AMPK signaling in CRPC cells. Mutation of serine 404 did not alter the lipolytic activity of ATGL but did decrease CRPC growth, migration, and invasion, indicating that non-canonical ATGL activity also contributes to disease progression. Unbiased immunoprecipitation/mass spectrometry suggested that mutation of serine 404 not only disrupts existing ATGL protein interactions but also leads to new protein-protein interactions. Together, these data nominate ATGL as a therapeutic target for CRPC and provide insights for future drug development and combination therapies.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-0555
PLoS One. 2023 ;18(11): e0294312

Trehalose enhances mitochondria deficits in human NPC1 mutant fibroblasts but disrupts mouse Purkinje cell dendritic growth ex vivo.

Collin M MacLeod, Fawad A K Yousufzai, Liam T Spencer, Sarah Kim, Lucianne A Rivera-Rosario, Zerian D Barrera, Lindsay Walsh, Claude Krummenacher, Benjamin Carone, Ileana Soto.

Lysosomes play important roles in catabolism, nutrient sensing, metabolic signaling, and homeostasis. NPC1 deficiency disrupts lysosomal function by inducing cholesterol accumulation that leads to early neurodegeneration in Niemann-Pick type C (NPC) disease. Mitochondria pathology and deficits in NPC1 deficient cells are associated with impaired lysosomal proteolysis and metabolic signaling. It is thought that activation of the transcription factor TFEB, an inducer of lysosome biogenesis, restores lysosomal-autophagy activity in lysosomal storage disorders. Here, we investigated the effect of trehalose, a TFEB activator, in the mitochondria pathology of NPC1 mutant fibroblasts in vitro and in mouse developmental Purkinje cells ex vivo. We found that in NPC1 mutant fibroblasts, serum starvation or/and trehalose treatment, both activators of TFEB, reversed mitochondria fragmentation to a more tubular mitochondrion. Trehalose treatment also decreased the accumulation of Filipin+ cholesterol in NPC1 mutant fibroblasts. However, trehalose treatment in cerebellar organotypic slices (COSCs) from wild-type and Npc1nmf164 mice caused mitochondria fragmentation and lack of dendritic growth and degeneration in developmental Purkinje cells. Our data suggest, that although trehalose successfully restores mitochondria length and decreases cholesterol accumulation in NPC1 mutant fibroblasts, in COSCs, Purkinje cells mitochondria and dendritic growth are negatively affected possibly through the overactivation of the TFEB-lysosomal-autophagy pathway.

DOI: https://doi.org/10.1371/journal.pone.0294312
EMBO J. 2023 Nov 27. e112348

Bidirectional interplay between metabolism and epigenetics in hematopoietic stem cells and leukemia.

Yu Wei Zhang, Katharina Schönberger, Nina Cabezas-Wallscheid.

  During the last decades, remarkable progress has been made in further understanding the complex molecular regulatory networks that maintain hematopoietic stem cell (HSC) function. Cellular and organismal metabolisms have been shown to directly instruct epigenetic alterations, and thereby dictate stem cell fate, in the bone marrow. Epigenetic regulatory enzymes are dependent on the availability of metabolites to facilitate DNA- and histone-modifying reactions. The metabolic and epigenetic features of HSCs and their downstream progenitors can be significantly altered by environmental perturbations, dietary habits, and hematological diseases. Therefore, understanding metabolic and epigenetic mechanisms that regulate healthy HSCs can contribute to the discovery of novel metabolic therapeutic targets that specifically eliminate leukemia stem cells while sparing healthy HSCs. Here, we provide an in-depth review of the metabolic and epigenetic interplay regulating hematopoietic stem cell fate. We discuss the influence of metabolic stress stimuli, as well as alterations occurring during leukemic development. Additionally, we highlight recent therapeutic advancements toward eradicating acute myeloid leukemia cells by intervening in metabolic and epigenetic pathways.

Keywords:  acute myeloid leukemia; epigenetics; hematopoietic stem cells; leukemia stem cells; metabolism

DOI:  https://doi.org/10.15252/embj.2022112348
Nat Commun. 2023 Nov 25. 14(1): 7733

Acetyl-CoA is a key molecule for nephron progenitor cell pool maintenance.

Fabiola Diniz, Nguyen Yen Nhi Ngo, Mariel Colon-Leyva, Francesca Edgington-Giordano, Sylvia Hilliard, Kevin Zwezdaryk, Jiao Liu, Samir S El-Dahr, Giovane G Tortelote.

Nephron endowment at birth impacts long-term renal and cardiovascular health, and it is contingent on the nephron progenitor cell (NPC) pool. Glycolysis modulation is essential for determining NPC fate, but the underlying mechanism is unclear. Combining RNA sequencing and quantitative proteomics we identify 267 genes commonly targeted by Wnt activation or glycolysis inhibition in NPCs. Several of the impacted pathways converge at Acetyl-CoA, a co-product of glucose metabolism. Notably, glycolysis inhibition downregulates key genes of the Mevalonate/cholesterol pathway and stimulates NPC differentiation. Sodium acetate supplementation rescues glycolysis inhibition effects and favors NPC maintenance without hindering nephrogenesis. Six2Cre-mediated removal of ATP-citrate lyase (Acly), an enzyme that converts citrate to acetyl-CoA, leads to NPC pool depletion, glomeruli count reduction, and increases Wnt4 expression at birth. Sodium acetate supplementation counters the effects of Acly deletion on cap-mesenchyme. Our findings show a pivotal role of acetyl-CoA metabolism in kidney development and uncover new avenues for manipulating nephrogenesis and preventing adult kidney disease.

DOI: https://doi.org/10.1038/s41467-023-43513-7
Nat Commun. 2023 Nov 29. 14(1): 7827

Contribution of pks+ E. coli mutations to colorectal carcinogenesis.

Bingjie Chen, Daniele Ramazzotti, Timon Heide, Inmaculada Spiteri, Javier Fernandez-Mateos, Chela James, Luca Magnani, Trevor A Graham, Andrea Sottoriva.

The dominant mutational signature in colorectal cancer genomes is C > T deamination (COSMIC Signature 1) and, in a small subgroup, mismatch repair signature (COSMIC signatures 6 and 44). Mutations in common colorectal cancer driver genes are often not consistent with those signatures. Here we perform whole-genome sequencing of normal colon crypts from cancer patients, matched to a previous multi-omic tumour dataset. We analyse normal crypts that were distant vs adjacent to the cancer. In contrast to healthy individuals, normal crypts of colon cancer patients have a high incidence of pks + (polyketide synthases) E.coli (Escherichia coli) mutational and indel signatures, and this is confirmed by metagenomics. These signatures are compatible with many clonal driver mutations detected in the corresponding cancer samples, including in chromatin modifier genes, supporting their role in early tumourigenesis. These results provide evidence that pks + E.coli is a potential driver of carcinogenesis in the human gut.

DOI: https://doi.org/10.1038/s41467-023-43329-5
EMBO Mol Med. 2023 Nov 27. e18028

Tumor endothelial cell autophagy is a key vascular-immune checkpoint in melanoma.

Jelle Verhoeven, Kathryn A Jacobs, Francesca Rizzollo, Francesca Lodi, Yichao Hua, Joanna Poźniak, Adhithya Narayanan Srinivasan, Diede Houbaert, Gautam Shankar, Sanket More, Marco B Schaaf, Nikolina Dubroja Lakic, Maarten Ganne, Jochen Lamote, Johan Van Weyenbergh, Louis Boon, Oliver Bechter, Francesca Bosisio, Yasuo Uchiyama, Mathieu Jm Bertrand, Jean Christophe Marine, Diether Lambrechts, Gabriele Bergers, Madhur Agrawal, Patrizia Agostinis.

  Tumor endothelial cells (TECs) actively repress inflammatory responses and maintain an immune-excluded tumor phenotype. However, the molecular mechanisms that sustain TEC-mediated immunosuppression remain largely elusive. Here, we show that autophagy ablation in TECs boosts antitumor immunity by supporting infiltration and effector function of T-cells, thereby restricting melanoma growth. In melanoma-bearing mice, loss of TEC autophagy leads to the transcriptional expression of an immunostimulatory/inflammatory TEC phenotype driven by heightened NF-kB and STING signaling. In line, single-cell transcriptomic datasets from melanoma patients disclose an enriched InflammatoryHigh /AutophagyLow TEC phenotype in correlation with clinical responses to immunotherapy, and responders exhibit an increased presence of inflamed vessels interfacing with infiltrating CD8+ T-cells. Mechanistically, STING-dependent immunity in TECs is not critical for the immunomodulatory effects of autophagy ablation, since NF-kB-driven inflammation remains functional in STING/ATG5 double knockout TECs. Hence, our study identifies autophagy as a principal tumor vascular anti-inflammatory mechanism dampening melanoma antitumor immunity.

Keywords:  autophagy; cancer; immunotherapy; inflammation; tumor endothelial cells

DOI:  https://doi.org/10.15252/emmm.202318028
Methodist Debakey Cardiovasc J. 2023 ;19(5): 26-36

Metabolic Control of Cardiomyocyte Cell Cycle.

Ivan Menendez-Montes, Daniel J Garry, Jianyi Jay Zhang, Hesham A Sadek.

  Current therapies for heart failure aim to prevent the deleterious remodeling that occurs after MI injury, but currently no therapies are available to replace lost cardiomyocytes. Several organisms now being studied are capable of regenerating their myocardium by the proliferation of existing cardiomyocytes. In this review, we summarize the main metabolic pathways of the mammalian heart and how modulation of these metabolic pathways through genetic and pharmacological approaches influences cardiomyocyte proliferation and heart regeneration.

Keywords:  cardiac regeneration; cardiomyocyte proliferation; glycolysis; oxidative phosphorylation; reactive oxygen species; uridine diphosphate N-acetylglucosamine (UDP GlycNAC)

DOI:  https://doi.org/10.14797/mdcvj.1309
Sci Immunol. 2023 Dec;8(90): eadf4919

Noncanonical MAVS signaling restrains dendritic cell-driven antitumor immunity by inhibiting IL-12.

Lingling Wu, Xiaochuan Hong, Chao Yang, Yuanqin Yang, Wenwen Li, Lu Lu, Meichun Cai, Dongqing Cao, Guanglei Zhuang, Liufu Deng.

Mitochondrial antiviral signaling protein (MAVS)-mediated cytosolic RNA sensing plays a central role in tumor immunogenicity. However, the effects of host MAVS signaling on antitumor immunity remain unclear. Here, we demonstrate that the host MAVS pathway supports tumor growth and impairs antitumor immunity, whereas MAVS deficiency in dendritic cells (DCs) promotes tumor-reactive CD8+ T cell responses. Specifically, CD8+ T cell priming capacity was enhanced by MAVS ablation in a type I interferon-independent, but IL-12-dependent, manner. Mechanistically, loss of the RIG-I/MAVS cascade activated the noncanonical NF-κB pathway and in turn induced IL-12 production by DCs. MAVS-restrained IL-12 promoted cross-talk between CD8+ T cells and DCs, which was licensed by IFN-γ. Moreover, ablation of host MAVS sensitized tumors to immunotherapy and attenuated radiation resistance, thereby facilitating the maintenance of effector CD8+ T cells. These findings demonstrate that the host MAVS pathway acts as an immune regulator of DC-driven antitumor immunity and support the development of immunotherapies that antagonize MAVS signaling in DCs.

DOI: https://doi.org/10.1126/sciimmunol.adf4919
Immun Ageing. 2023 Dec 02. 20(1): 70

Impact of NAD+ metabolism on ovarian aging.

Jinghui Liang, Feiling Huang, Zhaoqi Song, Ruiyi Tang, Peng Zhang, Rong Chen.

  Nicotinamide adenine dinucleotide (NAD+), a crucial coenzyme in cellular redox reactions, is closely associated with age-related functional degeneration and metabolic diseases. NAD exerts direct and indirect influences on many crucial cellular functions, including metabolic pathways, DNA repair, chromatin remodeling, cellular senescence, and immune cell functionality. These cellular processes and functions are essential for maintaining tissue and metabolic homeostasis, as well as healthy aging. Causality has been elucidated between a decline in NAD levels and multiple age-related diseases, which has been confirmed by various strategies aimed at increasing NAD levels in the preclinical setting. Ovarian aging is recognized as a natural process characterized by a decline in follicle number and function, resulting in decreased estrogen production and menopause. In this regard, it is necessary to address the many factors involved in this complicated procedure, which could improve fertility in women of advanced maternal age. Concerning the decrease in NAD+ levels as ovarian aging progresses, promising and exciting results are presented for strategies using NAD+ precursors to promote NAD+ biosynthesis, which could substantially improve oocyte quality and alleviate ovarian aging. Hence, to acquire further insights into NAD+ metabolism and biology, this review aims to probe the factors affecting ovarian aging, the characteristics of NAD+ precursors, and the current research status of NAD+ supplementation in ovarian aging. Specifically, by gaining a comprehensive understanding of these aspects, we are optimistic about the prominent progress that will be made in both research and therapy related to ovarian aging.

Keywords:  Infertility; Metabolic homeostasis; NAD+ metabolism; Ovary aging

DOI:  https://doi.org/10.1186/s12979-023-00398-w
Mitochondrion. 2023 Nov 29. pii: S1567-7249(23)00093-4. [Epub ahead of print]

Understanding differential aspects of microdiffusion (channeling) in the Coenzyme Q and Cytochrome c regions of the mitochondrial respiratory system.

Giorgio Lenaz, Salvatore Nesci, Maria Luisa Genova.

  Over the past decades, models of the organization of mitochondrial respiratory system have been controversial. The goal of this perspective is to assess this "conflict of models" by focusing on specific kinetic evidence in the two distinct segments of Coenzyme Q- and Cytochrome c-mediated electron transfer. Respiratory supercomplexes provide kinetic advantage by allowing a restricted diffusion of Coenzyme Q and Cytochrome c, and short-range interaction with their partner enzymes. In particular, electron transfer from NADH is compartmentalized by channeling of Coenzyme Q within supercomplexes, whereas succinate oxidation proceeds separately using the free Coenzyme Q pool. Previous evidence favoring Coenzyme Q random diffusion in the NADH-dependent electron transfer is due to downstream flux interference and misinterpretation of results. Indeed, electron transfer by complexes III and IV via Cytochrome c is less strictly dependent on substrate channeling in mammalian mitochondria. We briefly describe these differences and their physiological implications.

Keywords:  Coenzyme Q or ubiquinone; Cytochrome c; channeling; diffusion; respiratory supercomplex

DOI:  https://doi.org/10.1016/j.mito.2023.11.005
bioRxiv. 2023 Nov 19. pii: 2023.11.19.567663. [Epub ahead of print]

Disruption of redox balance in glutaminolytic triple negative breast cancer by inhibition of glutamate export and glutaminase.

Hoon Choi, Mamta Gupta, Christopher Hensley, Hsiaoju Lee, Yu-Ting Lu, Austin Pantel, David Mankoff, Rong Zhou.

In triple-negative breast cancer (TNBC) that relies on catabolism of amino acid glutamine, glutaminase (GLS) converts glutamine to glutamate, which facilitates glutathione synthesis by mediating the enrichment of intracellular cystine via xCT antiporter activity. To overcome chemo resistant TNBC, we have tested a strategy of disrupting cellular redox balance by inhibition of GLS and xCT by CB839 and Erastin, respectively. Key findings of our study include: 1. Dual metabolic inhibition (CB839+Erastin) led to significant increases of cellular superoxide level in both parent and chemo resistant TNBC cells, but superoxide level was distinctly lower in resistant cells. 2. Dual metabolic inhibition combined with doxorubicin or cisplatin induced significant apoptosis in TNBC cells and is associated with high degrees of GSH depletion. In vivo , dual metabolic inhibition plus cisplatin led to significant growth delay of chemo resistant human TNBC xenografts. 3. Ferroptosis is induced by doxorubicin (DOX) but not by cisplatin or paclitaxel. Addition of dual metabolic inhibition to DOX chemotherapy significantly enhanced ferroptotic cell death. 4. Significant changes in cellular metabolites concentration preceded transcriptome changes revealed by single cell RNA sequencing, underscoring the potential of capturing early changes in metabolites as pharmacodynamic markers of metabolic inhibitors. Here we demonstrated that 4-(3-[ 18 F]fluoropropyl)-L-glutamic acid ([ 18 F]FSPG) PET detected xCT blockade by Erastin or its analog in mice bearing human TNBC xenografts. In summary, our study provides compelling evidence for the therapeutic benefit and feasibility of non-invasive monitoring of dual metabolic blockade as a translational strategy to sensitize chemo resistant TNBC to cytotoxic chemotherapy.

DOI: https://doi.org/10.1101/2023.11.19.567663
Proc Natl Acad Sci U S A. 2023 Dec 05. 120(49): e2314857120

Expression of the vesicular GABA transporter within neuromedin S+ neurons sustains behavioral circadian rhythms.

Ivana L Bussi, Alexandra F Neitz, Raymond E A Sanchez, Leandro P Casiraghi, Michael Moldavan, Divya Kunda, Charles N Allen, Jennifer A Evans, Horacio O de la Iglesia.

  The suprachiasmatic nucleus (SCN) of the hypothalamus is the site of a central circadian clock that orchestrates overt rhythms of physiology and behavior. Circadian timekeeping requires intercellular communication among SCN neurons, and multiple signaling pathways contribute to SCN network coupling. Gamma-aminobutyric acid (GABA) is produced by virtually all SCN neurons, and previous work demonstrates that this transmitter regulates coupling in the adult SCN but is not essential for the nucleus to sustain overt circadian rhythms. Here, we show that the deletion of the gene that codes for the GABA vesicular transporter Vgat from neuromedin-S (NMS)+ neurons-a subset of neurons critical for SCN function-causes arrhythmia of locomotor activity and sleep. Further, NMS-Vgat deletion impairs intrinsic clock gene rhythms in SCN explants cultured ex vivo. Although vasoactive intestinal polypeptide (VIP) is critical for SCN function, Vgat deletion from VIP-expressing neurons did not lead to circadian arrhythmia in locomotor activity rhythms. Likewise, adult SCN-specific deletion of Vgat led to mild impairment of behavioral rhythms. Our results suggest that while the removal of GABA release from the adult SCN does not affect the pacemaker's ability to sustain overt circadian rhythms, its removal from a critical subset of neurons within the SCN throughout development removes the nucleus ability to sustain circadian rhythms. Our findings support a model in which SCN GABA release is critical for the developmental establishment of intercellular network properties that define the SCN as a central pacemaker.

Keywords:  GABA; Vgat; sleep; suprachiasmatic

DOI:  https://doi.org/10.1073/pnas.2314857120
Anal Biochem. 2023 Nov 26. pii: S0003-2697(23)00370-6. [Epub ahead of print]685 115405

Comparison of colorimetric, fluorometric, and liquid chromatography-mass spectrometry assays for acetyl-coenzyme A.

Daniel S Kantner, Emily Megill, Anna Bostwick, Vicky Yang, Carmen Bekeova, Alexandria Van Scoyk, Erin L Seifert, Michael W Deininger, Nathaniel W Snyder.

  Acetyl-Coenzyme A is a central metabolite in catabolic and anabolic pathways as well as the acyl donor for acetylation reactions. Multiple quantitative measurement techniques for acetyl-CoA have been reported, including commercially available kits. Comparisons between techniques for acetyl-CoA measurement have not been reported. This lack of comparability between assays makes context-specific assay selection and interpretation of results reporting changes in acetyl-CoA metabolism difficult. We compared commercially available colorimetric ELISA and fluorometric enzymatic-based kits to liquid chromatography-mass spectrometry-based assays using tandem mass spectrometry (LC-MS/MS) and high-resolution mass spectrometry (LC-HRMS). The colorimetric ELISA kit did not produce interpretable results even with commercially available pure standards. The fluorometric enzymatic kit produced comparable results to the LC-MS-based assays depending on matrix and extraction. LC-MS/MS and LC-HRMS assays produced well-aligned results, especially when incorporating stable isotope-labeled internal standards. In addition, we demonstrated the multiplexing capability of the LC-HRMS assay by measuring a suite of short-chain acyl-CoAs in a variety of acute myeloid leukemia cell lines and patient cells.

Keywords:  Acetyl-CoA; Mass spectrometry; Metabolite; Method comparison

DOI:  https://doi.org/10.1016/j.ab.2023.115405
Ageing Res Rev. 2023 Nov 27. pii: S1568-1637(23)00304-5. [Epub ahead of print] 102145

Mitochondria as a sensor, a central hub and a biological clock in psychological stress-accelerated aging.

Xuyun Liu, Xing Zhang, Lin Zhao, Jiangang Long, Zhihui Feng, Jiacan Su, Feng Gao, Jiankang Liu.

  The theory that oxidative damage caused by mitochondrial free radicals leads to aging has brought mitochondria into the forefront of aging research. Psychological stress that encompasses many different experiences and exposures across the lifespan has been identified as a catalyst for accelerated aging. Mitochondria, known for their dynamic nature and adaptability, function as a highly sensitive stress sensor and central hub in the process of accelerated aging. In this review, we explore how mitochondria as sensors respond to psychological stress and contribute to the molecular processes in accelerated aging by viewing mitochondria as hormonal, mechanosensitive and immune suborganelles. This understanding of the key role played by mitochondria and their close association with accelerated aging helps us to distinguish normal aging from accelerated aging, correct misconceptions in aging studies, and develop strategies such as exercise and mitochondria-targeted nutrients and drugs for slowing down accelerated aging, and also hold promise for prevention and treatment of age-related diseases.

Keywords:  Accelerated aging; Hormonal sensor; Inflammation; Mechanosensor; Mitochondria; Psychological stress

DOI:  https://doi.org/10.1016/j.arr.2023.102145
Dis Model Mech. 2023 Nov 01. pii: dmm050404. [Epub ahead of print]16(11):

Membrane transporters in cell physiology, cancer metabolism and drug response.

Sara Alam, Emily Doherty, Paula Ortega-Prieto, Julia Arizanova, Louise Fets.

  By controlling the passage of small molecules across lipid bilayers, membrane transporters influence not only the uptake and efflux of nutrients, but also the metabolic state of the cell. With more than 450 members, the Solute Carriers (SLCs) are the largest transporter super-family, clustering into families with different substrate specificities and regulatory properties. Cells of different types are, therefore, able to tailor their transporter expression signatures depending on their metabolic requirements, and the physiological importance of these proteins is illustrated by their mis-regulation in a number of disease states. In cancer, transporter expression is heterogeneous, and the SLC family has been shown to facilitate the accumulation of biomass, influence redox homeostasis, and also mediate metabolic crosstalk with other cell types within the tumour microenvironment. This Review explores the roles of membrane transporters in physiological and malignant settings, and how these roles can affect drug response, through either indirect modulation of sensitivity or the direct transport of small-molecule therapeutic compounds into cells.

Keywords:  Cancer Metabolism; Drug Uptake; Pharmacology; Transporters

DOI:  https://doi.org/10.1242/dmm.050404