bims-camemi 2024-12-29 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2024–12–29
34 papers selected by
Christian Frezza, Universität zu Köln

Preventing excessive autophagy protects from the pathology of mtDNA mutations in Drosophila melanogaster.
Effects of Aging on Glucose and Lipid Metabolism in Mice.
Optimized MALDI2-Mass Spectrometry Imaging for Stable Isotope Tracing of Tissue-Specific Metabolic Pathways in Mice.
Mitochondrial DNA mutations in human oocytes undergo frequency-dependent selection but do not increase with age.
Functionally conserved inner mitochondrial membrane proteins CCDC51 and Mdm33 demarcate a subset of fission events.
Metabolic Adaptations To Acute Glucose Uptake Inhibition Converge Upon Mitochondrial Respiration For Leukemia Cell Survival.
Similar deficiencies, different outcomes: succinate dehydrogenase loss in adrenal medulla vs. fibroblast cell culture models of paraganglioma.
Genome-scale modeling identifies dynamic metabolic vulnerabilities during the epithelial to mesenchymal transition.
Limiting serine availability during tumor progression promotes muscle wasting in cancer cachexia.
Aging through the lens of mitochondrial DNA mutations and inheritance paradoxes.
Targeted degradation of oncogenic KRASG12V triggers antitumor immunity in lung cancer models.
RNA sensing induced by chromosome missegregation augments anti-tumor immunity.
Metabolic profiling of patient-derived organoids reveals nucleotide synthesis as a metabolic vulnerability in malignant rhabdoid tumors.
Senolysis by ABT-263 is associated with inherent apoptotic dependence of cancer cells derived from the non-senescent state.
Different effects of fatty acid oxidation on hematopoietic stem cells based on age and diet.
Age-associated changes in transcriptional elongation and their effects on homeostasis.
Mitonuclear Communication in Stem Cell Function.
The many paths ascending to ferroptosis.
Pyrimidine synthesis enzyme CTP synthetase 1 suppresses antiviral interferon induction by deamidating IRF3.
Impairment of lipid homeostasis causes lysosomal accumulation of endogenous protein aggregates through ESCRT disruption.
'Ozempic, you're able': a festive parody song from the Nature Podcast.
LDB1 establishes multi-enhancer networks to regulate gene expression.
Deafness-associated mitochondrial 12S rRNA mutation reshapes mitochondrial and cellular homeostasis.
3D chromatin hubs as regulatory units of identity and survival in human acute leukemia.
Epstein-Barr virus hijacks B cell metabolism to establish persistent infection and drive pathogenesis.
Dura immunity configures leptomeningeal metastasis immunosuppression for cerebrospinal fluid barrier invasion.
Mutations in tumor suppressor genes Vhl and Rassf1a cause DNA damage, chromosomal instability and induce gene expression changes characteristic of clear cell renal cell carcinoma.
ZNF143 is a transcriptional regulator of nuclear-encoded mitochondrial genes that acts independently of looping and CTCF.
The N-degron pathway mediates the autophagic degradation of cytosolic mitochondrial DNA during sterile innate immune responses.
The Mitochondrial Lactate Oxidation Complex: endpoint for carbohydrate carbon disposal.
Perception of a pathogenic signature initiates intergenerational protection.
Restoring Mitochondrial Quantity and Quality to Reverse Warburg Effect and Drive Tumor Differentiation.
Immunometabolism in the Aging Heart.
De novo discovery of bicycles.

Nat Commun. 2024 Dec 23. 15(1): 10719

Preventing excessive autophagy protects from the pathology of mtDNA mutations in Drosophila melanogaster.

Najla El Fissi, Florian A Rosenberger, Kai Chang, Alissa Wilhalm, Tom Barton-Owen, Fynn M Hansen, Zoe Golder, David Alsina, Anna Wedell, Matthias Mann, Patrick F Chinnery, Christoph Freyer, Anna Wredenberg.

Aberration of mitochondrial function is a shared feature of many human pathologies, characterised by changes in metabolic flux, cellular energetics, morphology, composition, and dynamics of the mitochondrial network. While some of these changes serve as compensatory mechanisms to maintain cellular homeostasis, their chronic activation can permanently affect cellular metabolism and signalling, ultimately impairing cell function. Here, we use a Drosophila melanogaster model expressing a proofreading-deficient mtDNA polymerase (POLγexo-) in a genetic screen to find genes that mitigate the harmful accumulation of mtDNA mutations. We identify critical pathways associated with nutrient sensing, insulin signalling, mitochondrial protein import, and autophagy that can rescue the lethal phenotype of the POLγexo- flies. Rescued flies, hemizygous for dilp1, atg2, tim14 or melted, normalise their autophagic flux and proteasome function and adapt their metabolism. Mutation frequencies remain high with the exception of melted-rescued flies, suggesting that melted may act early in development. Treating POLγexo- larvae with the autophagy activator rapamycin aggravates their lethal phenotype, highlighting that excessive autophagy can significantly contribute to the pathophysiology of mitochondrial diseases. Moreover, we show that the nucleation process of autophagy is a critical target for intervention.

DOI: https://doi.org/10.1038/s41467-024-55559-2
Aging Cell. 2024 Dec 27. e14462

Effects of Aging on Glucose and Lipid Metabolism in Mice.

Evan C Lien, Ngoc Vu, Anna M Westermark, Laura V Danai, Allison N Lau, Yetiş Gültekin, Matthew A Kukurugya, Bryson D Bennett, Matthew G Vander Heiden.

  Aging is accompanied by multiple molecular changes that contribute to aging associated pathologies, such as accumulation of cellular damage and mitochondrial dysfunction. Tissue metabolism can also change with age, in part, because mitochondria are central to cellular metabolism. Moreover, the cofactor NAD+, which is reported to decline across multiple tissues during aging, plays a central role in metabolic pathways such as glycolysis, the tricarboxylic acid cycle, and the oxidative synthesis of nucleotides, amino acids, and lipids. To further characterize how tissue metabolism changes with age, we intravenously infused [U-13C]-glucose into young and old C57BL/6J, WSB/EiJ, and diversity outbred mice to trace glucose fate into downstream metabolites within plasma, liver, gastrocnemius muscle, and brain tissues. We found that glucose incorporation into central carbon and amino acid metabolism was robust during healthy aging across these different strains of mice. We also observed that levels of NAD+, NADH, and the NAD+/NADH ratio were unchanged in these tissues with healthy aging. However, aging tissues, particularly brain, exhibited evidence of upregulated fatty acid and sphingolipid metabolism reactions that regenerate NAD+ from NADH. These data suggest that NAD+-generating lipid metabolism reactions may help to maintain the NAD+/NADH ratio during healthy aging.

Keywords:  NAD; aging; metabolic rate; mice

DOI:  https://doi.org/10.1111/acel.14462
Anal Chem. 2024 Dec 27.

Optimized MALDI2-Mass Spectrometry Imaging for Stable Isotope Tracing of Tissue-Specific Metabolic Pathways in Mice.

Yanyan Chen, Yuanyuan Song, Zhu Yang, Yi Ru, Peisi Xie, Jing Han, Xuyang Chai, Jianing Wang, Zongwei Cai.

Spatial stable isotope tracing metabolic imaging is a cutting-edge technique designed to investigate tissue-specific metabolic functions and heterogeneity. Traditional matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) techniques often struggle with low coverage of low-molecular-weight (LMW) metabolites, which are often crucial for spatial metabolic studies. To address this, we developed a high-coverage spatial isotope tracing metabolic method that incorporates optimized matrix selection, sample preparation protocols, and enhanced post-ionization (MALDI2) techniques. We employed this approach to mouse kidney, brain, and breast tumors to visualize the spatial dynamics of metabolic flow. Our results revealed diverse regional distributions of nine labeled intermediates derived from 13C6-glucose across glycolysis, glycogen metabolism, and the tricarboxylic acid (TCA) cycle in kidney tissues. In brain sections, we successfully mapped six intermediates from the TCA cycle and glutamate-glutamine (Glu-Gln) cycle simultaneously in distinct neurological regions. Furthermore, in breast cancer tumor tissues, our approach facilitated the mapping of nine metabolic intermediates in multiple pathways, including glycolysis, the pentose phosphate pathway (PPP), and the TCA cycle, illustrating metabolic heterogeneity within the tumor microenvironment. This methodology enhances metabolite coverage, enabling more comprehensive imaging of isotope-labeled metabolites and opening new avenues for exploring the metabolic landscape in various biological contexts.

DOI: https://doi.org/10.1021/acs.analchem.4c04600
bioRxiv. 2024 Dec 12. pii: 2024.12.09.627454. [Epub ahead of print]

Mitochondrial DNA mutations in human oocytes undergo frequency-dependent selection but do not increase with age.

Barbara Arbeithuber, Kate Anthony, Bonnie Higgins, Peter Oppelt, Omar Shebl, Irene Tiemann-Boege, Francesca Chiaromonte, Thomas Ebner, Kateryna D Makova.

Mitochondria, cellular powerhouses, harbor DNA (mtDNA) inherited from the mothers. MtDNA mutations can cause diseases, yet whether they increase with age in human germline cells-oocytes-remains understudied. Here, using highly accurate duplex sequencing of full-length mtDNA, we detected de novo mutations in single oocytes, blood, and saliva in women between 20 and 42 years of age. We found that, with age, mutations increased in blood and saliva but not in oocytes. In oocytes, mutations with high allele frequencies (≥1%) were less prevalent in coding than non-coding regions, whereas mutations with low allele frequencies (<1%) were more uniformly distributed along mtDNA, suggesting frequency-dependent purifying selection. In somatic tissues, mutations caused elevated amino acid changes in protein-coding regions, suggesting positive or destructive selection. Thus, mtDNA in human oocytes is protected against accumulation of mutations having functional consequences and with aging. These findings are particularly timely as humans tend to reproduce later in life.

DOI: https://doi.org/10.1101/2024.12.09.627454
J Cell Biol. 2025 Mar 03. pii: e202403140. [Epub ahead of print]224(3):

Functionally conserved inner mitochondrial membrane proteins CCDC51 and Mdm33 demarcate a subset of fission events.

Alia R Edington, Olivia M Connor, Abigail C Love, Madeleine Marlar-Pavey, Jonathan R Friedman.

While extensive work has examined the mechanisms of mitochondrial fission, it remains unclear whether internal mitochondrial proteins in metazoans play a direct role in the process. Previously, the yeast inner membrane protein Mdm33 was shown to be required for normal mitochondrial morphology and has been hypothesized to be involved in mitochondrial fission. However, it is unknown whether Mdm33 plays a direct role, and it is not thought to have a mammalian homolog. Here, we use a bioinformatic approach to identify a structural ortholog of Mdm33 in humans, CCDC51 (also called MITOK), whose depletion phenocopies loss of Mdm33. We find that knockdown of CCDC51 also leads to reduced rates of mitochondrial fission. Further, we spatially and temporally resolve Mdm33 and CCDC51 to a subset of mitochondrial fission events. Finally, we show that CCDC51 overexpression promotes its spatial association with Drp1 and induces mitochondrial fragmentation, suggesting it is a positive effector of mitochondrial fission. Together, our data reveal that Mdm33 and CCDC51 are functionally conserved and suggest that internal mitochondrial proteins are directly involved in at least a subset of mitochondrial fission events in human cells.

DOI: https://doi.org/10.1083/jcb.202403140
bioRxiv. 2024 Nov 22. pii: 2024.11.20.624567. [Epub ahead of print]

Metabolic Adaptations To Acute Glucose Uptake Inhibition Converge Upon Mitochondrial Respiration For Leukemia Cell Survival.

Monika Komza, Jesminara Khatun, Jesse D Gelles, Andrew P Trotta, Ioana Abraham-Enachescu, Juan Henao, Ahmed Elsaadi, Andriana G Kotini, Cara Clementelli, JoAnn Arandela, Sebastian El Ghaity-Beckley, Agneesh Barua, Yiyang Chen, Bridget K Marcellino, Eirini P Papapetrou, Masha V Poyurovsky, Jerry Edward Chipuk.

One hallmark of cancer is the upregulation and dependency on glucose metabolism to fuel macromolecule biosynthesis and rapid proliferation. Despite significant pre-clinical effort to exploit this pathway, additional mechanistic insights are necessary to prioritize the diversity of metabolic adaptations upon acute loss of glucose metabolism. Here, we investigated a potent small molecule inhibitor to Class I glucose transporters, KL-11743, using glycolytic leukemia cell lines and patient-based model systems. Our results reveal that while several metabolic adaptations occur in response to acute glucose uptake inhibition, the most critical is increased mitochondrial oxidative phosphorylation. KL-11743 treatment efficiently blocks the majority of glucose uptake and glycolysis, yet markedly increases mitochondrial respiration via enhanced Complex I function. Compared to partial glucose uptake inhibition, dependency on mitochondrial respiration is less apparent suggesting robust blockage of glucose uptake is essential to create a metabolic vulnerability. When wild-type and oncogenic RAS patient-derived induced pluripotent stem cell acute myeloid leukemia (AML) models were examined, KL-11743 mediated induction of mitochondrial respiration and dependency for survival associated with oncogenic RAS. Furthermore, we examined the therapeutic potential of these observations by treating a cohort of primary AML patient samples with KL-11743 and witnessed similar dependency on mitochondrial respiration for sustained cellular survival. Together, these data highlight conserved adaptations to acute glucose uptake inhibition in diverse leukemic models and AML patient samples, and position mitochondrial respiration as a key determinant of treatment success.

DOI: https://doi.org/10.1101/2024.11.20.624567
Cancer Metab. 2024 Dec 23. 12(1): 39

Similar deficiencies, different outcomes: succinate dehydrogenase loss in adrenal medulla vs. fibroblast cell culture models of paraganglioma.

Fatimah J Al Khazal, Sanjana Mahadev Bhat, Yuxiang Zhu, Cristina M de Araujo Correia, Sherry X Zhou, Brandon A Wilbanks, Clifford D Folmes, Gary C Sieck, Judith Favier, L James Maher.

  Heterozygosity for loss-of-function alleles of the genes encoding the four subunits of succinate dehydrogenase (SDHA, SDHB, SDHC, SDHD), as well as the SDHAF2 assembly factor predispose affected individuals to pheochromocytoma and paraganglioma (PPGL), two rare neuroendocrine tumors that arise from neural crest-derived paraganglia. Tumorigenesis results from loss of the remaining functional SDHx gene copy, leading to a cell with no functional SDH and a defective tricarboxylic acid (TCA) cycle. It is believed that the subsequent accumulation of succinate competitively inhibits multiple dioxygenase enzymes that normally suppress hypoxic signaling and demethylate histones and DNA, ultimately leading to increased expression of genes involved in angiogenesis and cell proliferation. Why SDH loss is selectively tumorigenic in neuroendocrine cells remains poorly understood. In the absence of SDH-loss tumor-derived cell models, the cellular burden of SDH loss and succinate accumulation have been investigated through conditional knockouts of SDH subunits in pre-existing murine or human cell lines with varying degrees of clinical relevance. Here we characterize two available murine SDH-loss cell lines, immortalized adrenally-derived premature chromaffin cells vs. immortalized fibroblasts, at a level of detail beyond that currently reported in the literature and with the intention of laying the foundation for future investigations into adaptive pathways and vulnerabilities in SDH-loss cells. We report different mechanistic and phenotypic manifestations of SDH subunit loss in the presented cellular contexts. These findings highlight similarities and differences in the cellular response to SDH loss between the two cell models. We show that adrenally-derived cells display more severe morphological cellular and mitochondrial alterations, yet are unique in preserving residual Complex I function, perhaps allowing them to better tolerate SDH loss, thus making them a closer model to SDH-loss PPGL relative to fibroblasts.(281 words).

Keywords:  Complex I; Hypoxia; Paraganglioma; Pheochromocytoma; Succinate dehydrogenase; Tricarboxylic acid cycle

DOI:  https://doi.org/10.1186/s40170-024-00369-9
Commun Biol. 2024 Dec 27. 7(1): 1704

Genome-scale modeling identifies dynamic metabolic vulnerabilities during the epithelial to mesenchymal transition.

Rupa Bhowmick, Scott Campit, Shiva Krishna Katkam, Venkateshwar G Keshamouni, Sriram Chandrasekaran.

Epithelial-to-mesenchymal transition (EMT) is a conserved cellular process critical for embryogenesis, wound healing, and cancer metastasis. During EMT, cells undergo large-scale metabolic reprogramming that supports multiple functional phenotypes including migration, invasion, survival, chemo-resistance and stemness. However, the extent of metabolic network rewiring during EMT is unclear. In this work, using genome-scale metabolic modeling, we perform a meta-analysis of time-course transcriptomics, time-course proteomics, and single-cell transcriptomics EMT datasets from cell culture models stimulated with TGF-β. We uncovered temporal metabolic dependencies in glycolysis and glutamine metabolism, and experimentally validated isoform-specific dependency on Enolase3 for cell survival during EMT. We derived a prioritized list of metabolic dependencies based on model predictions, literature mining, and CRISPR-Cas9 essentiality screens. Notably, enolase and triose phosphate isomerase reaction fluxes significantly correlate with survival of lung adenocarcinoma patients. Our study illustrates how integration of heterogeneous datasets using a mechanistic computational model can uncover temporal and cell-state-specific metabolic dependencies.

DOI: https://doi.org/10.1038/s42003-024-07408-7
Cell Death Discov. 2024 Dec 21. 10(1): 510

Limiting serine availability during tumor progression promotes muscle wasting in cancer cachexia.

Erica Pranzini, Livio Muccillo, Ilaria Nesi, Alice Santi, Caterina Mancini, Giulia Lori, Massimo Genovese, Tiziano Lottini, Giuseppina Comito, Anna Caselli, Annarosa Arcangeli, Lina Sabatino, Vittorio Colantuoni, Maria Letizia Taddei, Paolo Cirri, Paolo Paoli.

Cancer cachexia is a multifactorial syndrome characterized by a progressive loss of body weight occurring in about 80% of cancer patients, frequently representing the leading cause of death. Dietary intervention is emerging as a promising therapeutic strategy to counteract cancer-induced wasting. Serine is the second most-consumed amino acid (AA) by cancer cells and has emerged to be strictly necessary to preserve skeletal muscle structure and functionality. Here, we demonstrate that decreased serine availability during tumor progression promotes myotubes diameter reduction in vitro and induces muscle wasting in in vivo mice models. By investigating the metabolic crosstalk between colorectal cancer cells and muscle cells, we found that incubating myotubes with conditioned media from tumor cells relying on exogenous serine consumption triggers pronounced myotubes diameter reduction. Accordingly, culturing myotubes in a serine-free medium induces fibers width reduction and suppresses the activation of the AKT-mTORC1 pathway with consequent impairment in protein synthesis, increased protein degradation, and enhanced expression of the muscle atrophy-related genes Atrogin1 and MuRF1. In addition, serine-starved conditions affect myoblast differentiation and mitochondrial oxidative metabolism, finally inducing oxidative stress in myotubes. Consistently, serine dietary deprivation strongly strengthens cancer-associated weight loss and muscle atrophy in mice models. These findings uncover serine consumption by tumor cells as a previously undisclosed driver in cancer cachexia, opening new routes for possible therapeutic approaches.

DOI: https://doi.org/10.1038/s41420-024-02271-1
Biogerontology. 2024 Dec 27. 26(1): 33

Aging through the lens of mitochondrial DNA mutations and inheritance paradoxes.

Jia Chen, Hongyu Li, Runyu Liang, Yongyin Huang, Qiang Tang.

  Mitochondrial DNA encodes essential components of the respiratory chain complexes, serving as the foundation of mitochondrial respiratory function. Mutations in mtDNA primarily impair energy metabolism, exerting far-reaching effects on cellular physiology, particularly in the context of aging. The intrinsic vulnerability of mtDNA is increasingly recognized as a key driver in the initiation of aging and the progression of its related diseases. In the field of aging research, it is critical to unravel the intricate mechanisms underpinning mtDNA mutations in living organisms and to elucidate the pathological consequences they trigger. Interestingly, certain effects, such as oxidative stress and apoptosis, may not universally accelerate aging as traditionally perceived. These phenomena demand deeper investigation and a more nuanced reinterpretation of current findings to address persistent scientific uncertainties. By synthesizing recent insights, this review seeks to clarify how pathogenic mtDNA mutations drive cellular senescence and systemic health deterioration, while also exploring the complex dynamics of mtDNA inheritance that may propagate these mutations. Such a comprehensive understanding could ultimately inform the development of innovative therapeutic strategies to counteract mitochondrial dysfunctions associated with aging.

Keywords:  Aging; Evolutionary selection; Genetic bottleneck; Mitochondrial DNA mutations; Mother’s curse

DOI:  https://doi.org/10.1007/s10522-024-10175-x
J Clin Invest. 2024 Dec 24. pii: e174249. [Epub ahead of print]

Targeted degradation of oncogenic KRASG12V triggers antitumor immunity in lung cancer models.

Dezhi Li, Ke Geng, Yuan Hao, Jiajia Gu, Saurav Kumar, Annabel T Olson, Christina C Kuismi, Hye Mi Kim, Yuanwang Pan, Fiona Sherman, Asia M Williams, Yiting Li, Fei Li, Ting Chen, Cassandra Thakurdin, Michela Ranieri, Mary Meynardie, Daniel S Levin, Janaye Stephens, Alison Chafitz, Joy Chen, Mia S Donald-Paladino, Jaylen M Powell, Ze-Yan Zhang, Wei Chen, Magdalena Ploszaj, Han Han, Shengqing Gu, Tinghu Zhang, Baoli Hu, Benjamin A Nacev, Medard Ernest Kaiza, Alice H Berger, Xuerui Wang, Jing Li, Xuejiao Sun, Yang Liu, Xiaoyang Zhang, Tullia C Bruno, Nathanael S Gray, Behnam Nabet, Kwok-Kin Wong, Hua Zhang.

  KRAS is the most frequently mutated oncogene in lung adenocarcinoma, with G12C and G12V being the most predominant forms. Recent breakthroughs in KRASG12C inhibitors have transformed the clinical management of patients with G12C mutation and advanced our understanding of its function. However, little is known about the targeted disruption of KRASG12V, partly due to a lack of specific inhibitors. Here, we leverage the degradation tag (dTAG) system to develop a KRASG12V transgenic mouse model. We explore the therapeutic potential of KRASG12V degradation and characterize its impact on the tumor microenvironment (TME). Our study reveals that degrading KRASG12V abolishes lung and pancreatic tumors in mice and causes a robust inhibition of KRAS-regulated cancer intrinsic signaling. Importantly, targeted degradation of KRASG12V reprograms the TME towards a stimulatory milieu and drives antitumor immunity, elicited mainly by effector and cytotoxic CD8+ T cells. Our work provides important insights into the impact of degrading KRASG12V on both tumor progression and immune response, highlighting degraders as a powerful strategy for targeting KRAS mutant cancers.

Keywords:  Immunology; Lung cancer; Oncology

DOI:  https://doi.org/10.1172/JCI174249
Mol Cell. 2024 Dec 10. pii: S1097-2765(24)00950-X. [Epub ahead of print]

RNA sensing induced by chromosome missegregation augments anti-tumor immunity.

Nobunari Sasaki, Mizuki Homme, Takahiko Murayama, Tatsuya Osaki, Toshiyuki Tenma, Tadaichi An, Yujiro Takegami, Tetsuo Tani, Patrick C Gedeon, Yoshihisa Kobayashi, Israel Cañadas, David A Barbie, Ryoji Yao, Shunsuke Kitajima.

  Viral mimicry driven by endogenous double-stranded RNA (dsRNA) stimulates innate and adaptive immune responses. However, the mechanisms that regulate dsRNA-forming transcripts during cancer therapy remain unclear. Here, we demonstrate that dsRNA is significantly accumulated in cancer cells following pharmacologic induction of micronuclei, stimulating mitochondrial antiviral signaling (MAVS)-mediated dsRNA sensing in conjunction with the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway. Activation of cytosolic dsRNA sensing cooperates with double-stranded DNA (dsDNA) sensing to upregulate immune cell migration and antigen-presenting machinery. Tracing of dsRNA-sequences reveals that dsRNA-forming transcripts are predominantly generated from non-exonic regions, particularly in locations proximal to genes exhibiting high chromatin accessibility. Activation of this pathway by pulsed monopolar spindle 1 (MPS1) inhibitor treatment, which potently induces micronuclei formation, upregulates cytoplasmic dsRNA sensing and thus promotes anti-tumor immunity mediated by cytotoxic lymphocyte activation in vivo. Collectively, our findings uncover a mechanism in which dsRNA sensing cooperates with dsDNA sensing to boost immune responses, offering an approach to enhance the efficacy of cancer therapies targeting genomic instability.

Keywords:  MAVS; Mps1; STING; cGAS; chromosome missegregation; dsRNA; micronuclei; tumor immunity; type I interferon

DOI:  https://doi.org/10.1016/j.molcel.2024.11.025
Cell Rep Med. 2024 Dec 11. pii: S2666-3791(24)00649-9. [Epub ahead of print] 101878

Metabolic profiling of patient-derived organoids reveals nucleotide synthesis as a metabolic vulnerability in malignant rhabdoid tumors.

Marjolein M G Kes, Francisco Morales-Rodriguez, Esther A Zaal, Terezinha de Souza, Natalie Proost, Marieke van de Ven, Marry M van den Heuvel-Eibrink, Jeroen W A Jansen, Celia R Berkers, Jarno Drost.

  Malignant rhabdoid tumor (MRT) is one of the most aggressive childhood cancers for which no effective treatment options are available. Reprogramming of cellular metabolism is an important hallmark of cancer, with various metabolism-based drugs being approved as a cancer treatment. In this study, we use patient-derived tumor organoids (tumoroids) to map the metabolic landscape of several pediatric cancers. Combining gene expression analyses and metabolite profiling using mass spectrometry, we find nucleotide biosynthesis to be a particular vulnerability of MRT. Treatment of MRT tumoroids with de novo nucleotide synthesis inhibitors methotrexate (MTX) and BAY-2402234 lowers nucleotide levels in MRT tumoroids and induces apoptosis. Lastly, we demonstrate in vivo efficacy of MTX in MRT patient-derived xenograft (PDX) mouse models. Our study reveals nucleotide biosynthesis as an MRT-specific metabolic vulnerability, which can ultimately lead to better treatment options for children suffering from this lethal pediatric malignancy.

Keywords:  DHODH inhibitor; Methotrexate; cancer metabolism; isotope tracing; malignant rhabdoid tumors; metabolomics; nucleotide synthesis; pediatric kidney cancer

DOI:  https://doi.org/10.1016/j.xcrm.2024.101878
Cell Death Differ. 2024 Dec 21.

Senolysis by ABT-263 is associated with inherent apoptotic dependence of cancer cells derived from the non-senescent state.

Fleur Jochems, Chrysiida Baltira, Julie A MacDonald, Veerle Daniels, Abhijeet Mathur, Mark C de Gooijer, Olaf van Tellingen, Anthony Letai, René Bernards.

Cellular senescence is a stress response that cells can employ to resist cell death. Senescent cells rely on anti-apoptotic signaling for their survival, which can be targeted by senolytic agents, like the BCL-XL, BCL-2, BCL-W inhibitor ABT-263. However, the response to ABT-263 of senescent cancer cells ranges from highly sensitive to refractory. Using BH3 profiling, we identify here apoptotic blocks in cancer cells that are resistant to this senolytic treatment and discover a correlation between mitochondrial apoptotic priming and cellular sensitivity to ABT-263 in senescence. Intriguingly, ABT-263 sensitivity correlates with overall mitochondrial apoptotic priming, not only in senescence but also in the parental state. Moreover, we confirm that ABT-263 exposure increases dependency on MCL-1, which is most enhanced in ABT-263 sensitive cells. ABT-263 resistant cells however upregulate MCL-1, while sensitive cells exhibit low levels of this anti-apoptotic protein. Overall, our data indicate that the response of senescent cells to ABT-263 is predetermined by the mitochondrial apoptotic priming state of the parental cells, which could serve as a predictive biomarker for response to senolytic therapy.

DOI: https://doi.org/10.1038/s41418-024-01439-7
Cell Stem Cell. 2024 Dec 12. pii: S1934-5909(24)00413-2. [Epub ahead of print]

Different effects of fatty acid oxidation on hematopoietic stem cells based on age and diet.

Salma Merchant, Animesh Paul, Amanda Reyes, Daniel Cassidy, Ashley Leach, Dohun Kim, Sarah Muh, Gerik Grabowski, Gerta Hoxhaj, Zhiyu Zhao, Sean J Morrison.

  Fatty acid oxidation is of uncertain importance in most stem cells. We show by 14C-palmitate tracing and metabolomic analysis that hematopoietic stem/progenitor cells (HSPCs) engage in long-chain fatty acid oxidation that depends upon carnitine palmitoyltransferase 1a (CPT1a) and hydroxyacyl-CoA dehydrogenase (HADHA) enzymes. CPT1a or HADHA deficiency had little or no effect on HSPCs or hematopoiesis in young adult mice. Young HSPCs had the plasticity to oxidize other substrates, including glutamine, and compensated for loss of fatty acid oxidation by decreasing pyruvate dehydrogenase phosphorylation, which should increase function. This metabolic plasticity declined as mice aged, when CPT1a or HADHA deficiency altered hematopoiesis and impaired hematopoietic stem cell (HSC) function upon serial transplantation. A high-fat diet increased fatty acid oxidation and reduced HSC function. This was rescued by CPT1a or HADHA deficiency, demonstrating that increased fatty acid oxidation can undermine HSC function. Long-chain fatty acid oxidation is thus dispensable in young HSCs but necessary during aging and deleterious with a high-fat diet.

Keywords:  aging; fatty acid; hematopoiesis; high-fat diet; metabolic plasticity; metabolism; mitochondria; β-oxidation

DOI:  https://doi.org/10.1016/j.stem.2024.11.014
Trends Cell Biol. 2024 Dec 19. pii: S0962-8924(24)00247-2. [Epub ahead of print]

Age-associated changes in transcriptional elongation and their effects on homeostasis.

Argyris Papantonis, Adam Antebi, Linda Partridge, Andreas Beyer.

  Cellular homeostasis declines with age due to the declining fidelity of biosynthetic processes and the accumulation of molecular damage. Yet, it remains largely elusive how individual processes are affected during aging and what their specific contribution to age-related functional decline is. This review discusses a series of recent publications that has shown that transcription elongation is compromised during aging due to increasing DNA damage, stalling of RNA polymerase II (RNAPII), erroneous transcription initiation in gene bodies, and accelerated RNAPII elongation. Importantly, several of these perturbations likely arise from changes in chromatin organization with age. Thus, taken together, this work establishes a network of interlinked processes contributing to age-related decline in the quantity and quality of RNA production.

Keywords:  RNA polymerase; RNA processing; chromatin organization; genome integrity; organismal aging; senescence

DOI:  https://doi.org/10.1016/j.tcb.2024.11.005
Cell Prolif. 2024 Dec 26. e13796

Mitonuclear Communication in Stem Cell Function.

Baozhou Peng, Yaning Wang, Hongbo Zhang.

  Mitochondria perform multiple functions within the cell, including the production of ATP and a great deal of metabolic intermediates, while also contributing to the cellular stress response. The majority of mitochondrial proteins are encoded by nuclear genomes, highlighting the importance of mitonuclear communication for sustaining mitochondrial homeostasis and functional. As a crucial part of the intracellular signalling network, mitochondria can impact stem cell fate determinations. Considering the essential function of stem cells in tissue maintenance, regeneration and aging, it is important to understand how mitochondria influence stem cell fate. This review explores the significant roles of mitonuclear communication and mitochondrial proteostasis, highlighting their influence on stem cells. We also examine how mitonuclear interactions contribute to cellular homeostasis, stem cell therapies, and the potential for extending lifespan.

Keywords:  aging; fate determination; metabolism; mitochondria; mitochondrial stress; mitonuclear communication; stem cell

DOI:  https://doi.org/10.1111/cpr.13796
Nat Chem Biol. 2025 Jan;21(1): 18-19

The many paths ascending to ferroptosis.

Marcus Conrad, Adam Wahida.

DOI: https://doi.org/10.1038/s41589-024-01794-z
Immunity. 2024 Dec 13. pii: S1074-7613(24)00535-1. [Epub ahead of print]

Pyrimidine synthesis enzyme CTP synthetase 1 suppresses antiviral interferon induction by deamidating IRF3.

Youliang Rao, Chao Qin, Ali Can Savas, Qizhi Liu, Shu Feng, Guoli Hou, Taolin Xie, Pinghui Feng.

  Metabolism is typically contextualized in conjunction with proliferation and growth. The roles of metabolic enzymes beyond metabolism-such as in innate immune responses-are underexplored. Using a focused short hairpin RNA (shRNA)-mediated screen, we identified CTP synthetase 1 (CTPS1), a rate-limiting enzyme of pyrimidine synthesis, as a negative regulator of interferon induction. Mechanistically, CTPS1 interacts with and deamidates interferon regulatory factor 3 (IRF3). Deamidation at N85 impairs IRF3 binding to promoters containing IRF3-responsive elements, thus muting interferon (IFN) induction. Employing CTPS1 conditional deletion and IRF3 deamidated or deamidation-resistant knockin mice, we demonstrated that CTPS1-driven IRF3 deamidation restricts IFN induction in response to viral infection in vivo. However, during immune activation, IRF3 deamidation by CTPS1 is inhibited by glycogen synthase kinase 3 beta (GSK3β) to promote IFN induction. This work demonstrates how CTPS1 tames innate immunity independent of its role in pyrimidine synthesis, thus expanding the functional repertoire of metabolic enzymes into immune regulation.

Keywords:  CTP synthetase; RNA and DNA viruses; interferon production; interferon regulatory factor; protein deamidation; pyrimidine synthesis enzyme

DOI:  https://doi.org/10.1016/j.immuni.2024.11.020
Elife. 2024 Dec 23. pii: RP86194. [Epub ahead of print]12

Impairment of lipid homeostasis causes lysosomal accumulation of endogenous protein aggregates through ESCRT disruption.

John Yong, Jacqueline E Villalta, Ngoc Vu, Matthew A Kukurugya, Niclas Olsson, Magdalena Preciado López, Julia R Lazzari-Dean, Kayley Hake, Fiona E McAllister, Bryson D Bennett, Calvin H Jan.

  Protein aggregation increases during aging and is a pathological hallmark of many age-related diseases. Protein homeostasis (proteostasis) depends on a core network of factors directly influencing protein production, folding, trafficking, and degradation. Cellular proteostasis also depends on the overall composition of the proteome and numerous environmental variables. Modulating this cellular proteostasis state can influence the stability of multiple endogenous proteins, yet the factors contributing to this state remain incompletely characterized. Here, we performed genome-wide CRISPRi screens to elucidate the modulators of proteostasis state in mammalian cells, using a fluorescent dye to monitor endogenous protein aggregation. These screens identified known components of the proteostasis network and uncovered a novel link between protein and lipid homeostasis. Increasing lipid uptake and/or disrupting lipid metabolism promotes the accumulation of sphingomyelins and cholesterol esters and drives the formation of detergent-insoluble protein aggregates at the lysosome. Proteome profiling of lysosomes revealed ESCRT accumulation, suggesting disruption of ESCRT disassembly, lysosomal membrane repair, and microautophagy. Lipid dysregulation leads to lysosomal membrane permeabilization but does not otherwise impact fundamental aspects of lysosomal and proteasomal functions. Together, these results demonstrate that lipid dysregulation disrupts ESCRT function and impairs proteostasis.

Keywords:  CRISPR; ESCRT; aggregation; cell biology; human; lipid dysregulation; lysosome; proteostasis

DOI:  https://doi.org/10.7554/eLife.86194
Nature. 2024 Dec 24.

'Ozempic, you're able': a festive parody song from the Nature Podcast.

Noah Baker.



Keywords:  Medical research; Metabolism

DOI:  https://doi.org/10.1038/d41586-024-04239-8
Mol Cell. 2024 Dec 18. pii: S1097-2765(24)00992-4. [Epub ahead of print]

LDB1 establishes multi-enhancer networks to regulate gene expression.

Nicholas G Aboreden, Jessica C Lam, Viraat Y Goel, Siqing Wang, Xiaokang Wang, Susannah C Midla, Alma Quijano, Cheryl A Keller, Belinda M Giardine, Ross C Hardison, Haoyue Zhang, Anders S Hansen, Gerd A Blobel.

  How specific enhancer-promoter pairing is established remains mostly unclear. Besides the CTCF/cohesin machinery, few nuclear factors have been studied for a direct role in physically connecting regulatory elements. Using a murine erythroid cell model, we show via acute degradation experiments that LDB1 directly and broadly promotes connectivity among regulatory elements. Most LDB1-mediated contacts, even those spanning hundreds of kb, can form in the absence of CTCF, cohesin, or YY1 as determined using multiple degron systems. Moreover, an engineered LDB1-driven chromatin loop is cohesin independent. Cohesin-driven loop extrusion does not stall at LDB1-occupied sites but aids the formation of a subset of LDB1-anchored loops. Leveraging the dynamic reorganization of nuclear architecture during the transition from mitosis to G1 phase, we observe that loop formation and de novo LDB1 occupancy correlate and can occur independently of structural loops. Tri-C and Region Capture Micro-C reveal that LDB1 organizes multi-enhancer networks to activate transcription. These findings establish LDB1 as a driver of spatial connectivity.

Keywords:  chromatin architecture, enhancer, LDB1, looping, CTCF, cohesin, YY1, cell cycle, hub, LMO2

DOI:  https://doi.org/10.1016/j.molcel.2024.11.037
J Biol Chem. 2024 Dec 21. pii: S0021-9258(24)02626-7. [Epub ahead of print] 108124

Deafness-associated mitochondrial 12S rRNA mutation reshapes mitochondrial and cellular homeostasis.

Yunfan He, Zhining Tang, Gao Zhu, Luhang Cai, Chao Chen, Min-Xin Guan.

Human mitochondrial 12S ribosomal RNA (rRNA) 1555A>G mutation has been associated with aminoglycoside-induced and nonsyndromic deafness in many families worldwide. Our previous investigation revealed that the m.1555A>G mutation impaired mitochondrial translation and oxidative phosphorylation (OXPHOS). However, the mechanisms by which mitochondrial dysfunctions induced by m.1555A>G mutation regulate intracellular signaling for mitochondrial and cellular integrity remain poorly understood. Here, we demonstrated that the m.1555A>G mutation downregulated the expression of nuclear-encoded subunits of complexes I and IV but upregulated the expression of assemble factors for OXPHOS complexes, using cybrids derived from one hearing-impaired Chinese subject bearing the m.1555A>G mutation and from one hearing normal control lacking the mutation. These alterations resulted in the aberrant assembly, instability and reduced activities of respiratory chain enzyme complexes I, IV and V, rate of oxygen consumption, and diminished ATP production. Furthermore, the mutant cell lines carrying the m.1555A>G mutation exhibited decreased membrane potential and increased the production of reactive oxygen species. The aberrant assembly and biogenesis of OXPHOS impacted mitochondrial quality controls, including the imbalance of mitochondrial dynamics via increasing fission with abnormal mitochondrial morphology and impaired mitophagy. Strikingly, the cells bearing the m.1555A>G mutation revealed the upregulation of both ubiquitin-dependent and independent mitophagy pathways, evidenced by increasing the levels of Parkin, Pink, BNIP3L and NIX. The m.1555A>G mutation-induced deficiencies ameliorate the cell homeostasis via elevating the autophagy process and upregulating apoptotic pathways. Our findings provide new insights into pathophysiology of mitochondrial deafness arising from reshaping mitochondrial and cellular homeostasis due to 12S rRNA 1555A>G mutation.

DOI: https://doi.org/10.1016/j.jbc.2024.108124
Mol Cell. 2024 Dec 17. pii: S1097-2765(24)00995-X. [Epub ahead of print]

3D chromatin hubs as regulatory units of identity and survival in human acute leukemia.

Giovanni Gambi, Francesco Boccalatte, Javier Rodriguez Hernaez, Ziyan Lin, Bettina Nadorp, Alexander Polyzos, Jimin Tan, Kleopatra Avrampou, Giorgio Inghirami, Alex Kentsis, Effie Apostolou, Iannis Aifantis, Aristotelis Tsirigos.

  Cancer progression involves genetic and epigenetic changes that disrupt chromatin 3D organization, affecting enhancer-promoter interactions and promoting growth. Here, we provide an integrative approach, combining chromatin conformation, accessibility, and transcription analysis, validated by in silico and CRISPR-interference screens, to identify relevant 3D topologies in pediatric T cell leukemia (T-ALL and ETP-ALL). We characterize 3D hubs as regulatory centers for oncogenes and disease markers, linking them to biological processes like cell division, inflammation, and stress response. Single-cell mapping reveals heterogeneous gene activation in discrete epigenetic clones, aiding in patient stratification for relapse risk after chemotherapy. Finally, we identify MYB as a 3D hub regulator in leukemia cells and show that the targeting of key regulators leads to hub dissolution, thereby providing a novel and effective anti-leukemic strategy. Overall, our work demonstrates the relevance of studying oncogenic 3D hubs to better understand cancer biology and tumor heterogeneity and to propose novel therapeutic strategies.

Keywords:  HiChIP; MYB; chromatin structure; heterogeneity; hubs; leukemia; modules; scATAC

DOI:  https://doi.org/10.1016/j.molcel.2024.11.040
Trends Immunol. 2024 Dec 20. pii: S1471-4906(24)00296-5. [Epub ahead of print]

Epstein-Barr virus hijacks B cell metabolism to establish persistent infection and drive pathogenesis.

Bojana Müller-Durovic, Jessica Jäger, Glenn R Bantug, Christoph Hess.

  When B cells engage in an immune response, metabolic reprogramming is key to meeting cellular energetic and biosynthetic demands. Epstein-Barr virus (EBV) is a highly prevalent gamma-herpesvirus, latently infecting B cells for the human host's lifetime. By hijacking signaling pathways of T cell-dependent humoral immunity, EBV activates B cells in a T cell-independent manner, forcing lymphoblastoid transformation. Interlinked with this coercion of signaling pathways, EBV has also evolved strategies to manipulate B cell metabolism. In this opinion article we integrate recent findings from studies of B cell metabolic reprogramming after EBV infection and during antigen-specific activation, respectively. We hypothesize that defining EBV host-cell metabolic vulnerabilities that differ from pathways required for B cell immunity might uncover novel therapeutic targets against EBV-related diseases.

Keywords:  B cells; Epstein–Barr virus; IDO1; NAD; cellular metabolism; glycolysis; oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.it.2024.11.011
Nat Cancer. 2024 Dec;5(12): 1940-1961

Dura immunity configures leptomeningeal metastasis immunosuppression for cerebrospinal fluid barrier invasion.

Jiaxu Zhao, Rui Zeng, Xiaohui Li, Ying Lu, Zuoyun Wang, Haibao Peng, Hao Chen, Minjie Fu, Ye Zhang, Yang Huang, Wenhan Chen, Xin Wang, Yun Guan, Wei Han, Ruofan Huang, Chengjun Yao, Zhiyong Qin, Lingchao Chen, Liang Chen, Xue Feng, Hanting Yang, Patrícia M R Pereira, Xuemei Tong, Bin Li, Qiangqiang Zhang, Yudan Chi.

The cerebrospinal fluid (CSF) border accommodates diverse immune cells that permit peripheral cell immunosurveillance. However, the intricate interactions between CSF immune cells and infiltrating cancer cells remain poorly understood. Here we use fate mapping, longitudinal time-lapse imaging and multiomics technologies to investigate the precise origin, cellular crosstalk and molecular landscape of macrophages that contribute to leptomeningeal metastasis (LM) progression. Mechanically, we find that dura-derived LM-associated macrophages (dLAMs) migrate into the CSF in a matrix metalloproteinase 14 (MMP14)-dependent manner. Furthermore, we identify that dLAMs critically require the presence of secreted phosphoprotein 1 (SPP1) in cancer cells for their recruitment, fostering an immunosuppressed microenvironment characterized by T cell exhaustion and inactivation. Conversely, inhibition of the SPP1-MMP14 axis can impede macrophages from bypassing the border barrier, prevent cancer cell growth and improve survival in LM mouse models. Our findings reveal an unexpectedly private source of innate immunity within the meningeal space, shed light on CSF barrier dysfunction dynamics and supply potential targets of clinical immunotherapy.

DOI: https://doi.org/10.1038/s43018-024-00858-2
Kidney Int. 2024 Dec 24. pii: S0085-2538(24)00912-8. [Epub ahead of print]

Mutations in tumor suppressor genes Vhl and Rassf1a cause DNA damage, chromosomal instability and induce gene expression changes characteristic of clear cell renal cell carcinoma.

Antonella Catalano, Laura S Haas, Kyra Zodel, Mojca Adlesic, Francesca Cuomo, Asin Peighambari, Patrick Metzger, Hsin Huang, Stefan Haug, Anna Köttgen, Natalie Köhler, Melanie Boerries, Ian J Frew.

  RASSF1A is frequently biallelically inactivated in clear cell renal cell carcinoma (ccRCC) due to loss of chromosome 3p and promoter hypermethylation. Here we investigated the cellular and molecular consequences of single and combined deletion of the Rassf1a and Vhl tumor suppressor genes to model the common ccRCC genotype of combined loss of function of RASSF1A and VHL. In mouse embryonic fibroblasts and in primary kidney epithelial cells, double deletion of Rassf1a and Vhl caused chromosomal segregation defects and increased formation of micronuclei, demonstrating that pVHL and RASSF1A function to maintain genomic integrity. Combined Rassf1a and Vhl deletion in kidney epithelial cells in vivo increased proliferation and caused mild tubular disorganization, but did not lead to the development of kidney tumors. Single cell RNA-sequencing unexpectedly revealed that Rassf1a or Vhl deletion both induce the expression of an overlapping set of genes in a sub-population of proximal tubule cells. Many of these genes are also upregulated in the Vhl/Trp53/Rb1 deficient mouse model of ccRCC. In other subsets of proximal tubule cells, combined Vhl/Rassf1a deletion induced the expression of additional genes that were not upregulated in each of the single knockouts. The expression of the human homologues of Rassf1a-regulated genes correlate negatively with RASSF1 expression levels in human ccRCC. Our results suggest that the loss of RASSF1A function establishes a ccRCC-characteristic gene expression pattern.

Keywords:  Clear cell renal cell carcinoma; DNA damage; chromosome 3p; chromosome segregation; proximal tubule; replication stress; single-cell RNA sequencing

DOI:  https://doi.org/10.1016/j.kint.2024.12.003
Mol Cell. 2024 Dec 12. pii: S1097-2765(24)00956-0. [Epub ahead of print]

ZNF143 is a transcriptional regulator of nuclear-encoded mitochondrial genes that acts independently of looping and CTCF.

Mikhail D Magnitov, Michela Maresca, Noemí Alonso Saiz, Hans Teunissen, Jinhong Dong, Kizhakke M Sathyan, Luca Braccioli, Michael J Guertin, Elzo de Wit.

  Gene expression is orchestrated by transcription factors, which function within the context of a three-dimensional genome. Zinc-finger protein 143 (ZNF143/ZFP143) is a transcription factor that has been implicated in both gene activation and chromatin looping. To study the direct consequences of ZNF143/ZFP143 loss, we generated a ZNF143/ZFP143 depletion system in mouse embryonic stem cells. Our results show that ZNF143/ZFP143 degradation has no effect on chromatin looping. Systematic analysis of ZNF143/ZFP143 occupancy data revealed that a commonly used antibody cross-reacts with CTCF, leading to its incorrect association with chromatin loops. Nevertheless, ZNF143/ZFP143 specifically activates nuclear-encoded mitochondrial genes, and its loss leads to severe mitochondrial dysfunction. Using an in vitro embryo model, we find that ZNF143/ZFP143 is an essential regulator of organismal development. Our results establish ZNF143/ZFP143 as a conserved transcriptional regulator of cell proliferation and differentiation by safeguarding mitochondrial activity.

Keywords:  3D genome; chromatin looping; development; differentiation; gene regulation; mitochondria; transcription

DOI:  https://doi.org/10.1016/j.molcel.2024.11.031
Cell Rep. 2024 Dec 21. pii: S2211-1247(24)01445-1. [Epub ahead of print]44(1): 115094

The N-degron pathway mediates the autophagic degradation of cytosolic mitochondrial DNA during sterile innate immune responses.

Chan Hoon Jung, Yoon Jee Lee, Eun Hye Cho, Gee Eun Lee, Sung Tae Kim, Ki Sa Sung, Daeho Kim, Dong Hyun Kim, Yeon Sung Son, Jin-Hyun Ahn, Dohyun Han, Yong Tae Kwon.

  The human body reacts to tissue damage by generating damage-associated molecular patterns (DAMPs) that activate sterile immune responses. To date, little is known about how DAMPs are removed to avoid excessive immune responses. Here, we show that proteasomal dysfunction induces the release of mitochondrial DNA (mtDNA) as a DAMP that activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway and is subsequently degraded through the N-degron pathway. In the resolution phase of sterile immune responses, DNA-dependent protein kinase (DNA-PK) senses cytosolic mtDNA and activates N-terminal (Nt-) arginylation by ATE1 R-transferases. The substrates of Nt-arginylation include the molecular chaperone BiP/GRP78 retrotranslocated from the endoplasmic reticulum (ER). R-BiP, the Nt-arginylated species of BiP, is associated with cytosolic mtDNA to accelerate its targeting to autophagic membranes for lysosomal degradation. Thus, cytosolic mtDNA activates the N-degron pathway to facilitate its own degradation and form a negative feedback loop, by which the cell can turn off sterile immune responses at the right time.

Keywords:  ATE1; CP: Immunology; DNA-PK; KU70; R-BiP; autophagy; mitochondrial DNA; proteasomal dysfunction; sterile immune response; the N-degron pathway; type I interferon

DOI:  https://doi.org/10.1016/j.celrep.2024.115094
Am J Physiol Endocrinol Metab. 2024 Dec 23.

The Mitochondrial Lactate Oxidation Complex: endpoint for carbohydrate carbon disposal.

Robert G Leija, Jose A Arevalo, Dianna Xing, José Pablo Vázquez-Medina, George A Brooks.

  The Lactate Shuttle concept has revolutionized our understanding and study of metabolism in physiology, biochemistry, metabolism, nutrition, and medicine. Seminal findings of the Mitochondrial Lactate Oxidation Complex (mLOC) elucidated the architectural structure of its components. Here, we report that the mitochondrial pyruvate carrier (mPC) is an additional member of the mLOC in mouse muscle and C2C12 myoblasts and myotubes. Immunoblots, mass spectrometry, and co-immunoprecipitation experiments of mitochondrial preparations revealed abundant amounts of mitochondrial lactate dehydrogenase (mLDH), monocarboxylate transporter (mMCT), basigin (CD147), cytochrome oxidase (COx), and pyruvate carriers 1 and 2 (mPC1 and 2). Additionally, using confocal laser scanning microscopy (CLSM) and in situ proximity ligation, we also demonstrated planar and 3D colocalization of pyruvate and lactate transporters with COx in fixed skeletal muscle sections, myotubes, and C2C12 myoblasts. This work serves as a landmark for configuring the final pathway of carbohydrate oxidation.

Keywords:  Lactate; Lactate Shuttle; Mitochondral Reticulum; Pyruvate; Skeletal Muscle

DOI:  https://doi.org/10.1152/ajpendo.00306.2024
Cell. 2024 Dec 24. pii: S0092-8674(24)01342-4. [Epub ahead of print]

Perception of a pathogenic signature initiates intergenerational protection.

Corinne L Pender, Julian G Dishart, Holly K Gildea, Kelsie M Nauta, Emily M Page, Talha F Siddiqi, Shannon S Cheung, Larry Joe, Nicholas O Burton, Andrew Dillin.

  Transmission of immune responses from one generation to the next represents a powerful adaptive mechanism to protect an organism's descendants. Parental infection by the natural C. elegans pathogen Pseudomonas vranovensis induces a protective response in progeny, but the bacterial cues and intergenerational signal driving this response were previously unknown. Here, we find that animals activate a protective stress response program upon exposure to P. vranovensis-derived cyanide and that a metabolic byproduct of cyanide detoxification, β-cyanoalanine, acts as an intergenerational signal to protect progeny from infection. Remarkably, this mechanism does not require direct parental infection; rather, exposure to pathogen-derived volatiles is sufficient to enhance the survival of the next generation, indicating that parental surveillance of environmental cues can activate a protective intergenerational response. Therefore, the mere perception of a pathogen-derived toxin, in this case cyanide, can protect an animal's progeny from future pathogenic challenges.

Keywords:  C. elegans; CYSL-2; MDT-15; Pseudomonas; SKN-1; cyanide; intergenerational inheritance; pathogen sensing; volatile response; β-cyanoalanine

DOI:  https://doi.org/10.1016/j.cell.2024.11.026
Res Sq. 2024 Dec 13. pii: rs.3.rs-5494402. [Epub ahead of print]

Restoring Mitochondrial Quantity and Quality to Reverse Warburg Effect and Drive Tumor Differentiation.

Jiangbin Ye, Haowen Jiang, Sarah Tiche, Clifford He, Junyan Liu, Fuyun Bian, Mohamed Jedoui, Balint Forgo, Md Tauhidul Islam, Meng Zhao, Pamela Emengo, Bo He, Yang Li, Albert Li, Anh Truong, Jestine Ho, Cathyrin Simmermaker, Yanan Yang, Meng-Ning Zhou, Zhen Hu, Katrin Svensson, Daniel Cuthbertson, Florette Hazard, Lei Xing, Hiroyuki Shimada, Bill Chiu.

Reduced mitochondrial quality and quantity in tumors is associated with dedifferentiation and increased malignancy. However, it remains unclear how to restore mitochondrial quantity and quality in tumors, and whether mitochondrial restoration can drive tumor differentiation. Our study shows that restoring mitochondrial function using retinoic acid (RA) to boost mitochondrial biogenesis and a mitochondrial uncoupler to enhance respiration synergistically drives neuroblastoma differentiation and inhibits proliferation. U-13C-glucose/glutamine isotope tracing revealed a metabolic shift from the pentose phosphate pathway to oxidative phosphorylation, accelerating the TCA cycle and switching substrate preference from glutamine to glucose. These effects were reversed by ETC inhibitors or in ρ0 cells lacking mtDNA, emphasizing the necessity of mitochondrial function for differentiation. Dietary RA and uncoupler treatment promoted tumor differentiation in an orthotopic neuroblastoma xenograft model, evidenced by neuropil production and Schwann cell recruitment. Single-cell RNA sequencing analysis of the orthotopic xenografts revealed that this strategy effectively eliminated the stem cell population, promoted differentiation, and increased mitochondrial gene signatures along the differentiation trajectory, which could potentially significantly improve patient outcomes. Collectively, our findings establish a mitochondria-centric therapeutic strategy for inducing tumor differentiation, suggesting that maintaining/driving differentiation in tumor requires not only ATP production but also continuous ATP consumption and sustained ETC activity.

DOI: https://doi.org/10.21203/rs.3.rs-5494402/v1
J Am Heart Assoc. 2024 Dec 24. e039216

Immunometabolism in the Aging Heart.

Kranti A Mapuskar, Barry London, Zeb R Zacharias, Jon C D Houtman, Bryan G Allen.

  Structural, functional, and molecular-level changes in the aging heart are influenced by a dynamic interplay between immune signaling and cellular metabolism that is referred to as immunometabolism. This review explores the crosstalk between cellular metabolic pathways including glycolysis, oxidative phosphorylation, fatty acid metabolism, and the immune processes that govern cardiac aging. With a rapidly aging population that coincides with increased cardiovascular risk and cancer incidence rates, understanding the immunometabolic underpinnings of cardiac aging provides a foundation for identifying therapeutic targets to mitigate cardiac dysfunction. Aging alters the immune environment of the heart by concomitantly driving the changes in immune cell metabolism, mitochondrial dysfunction, and redox signaling. Shifts in these metabolic pathways exacerbate inflammation and impair tissue repair, creating a vicious cycle that accelerates cardiac functional decline. Treatment with cancer therapy further complicates this landscape, as aging-associated immunometabolic disruptions augment the susceptibility to cardiotoxicity. The current review highlights therapeutic strategies that target the immunometabolic axis to alleviate cardiac aging pathologies. Interventions include modulating metabolic intermediates, improving mitochondrial function, and leveraging immune signaling pathways to restore cardiac health. Advances in immunometabolism thus hold significant potential for translating preclinical findings into therapies that improve the quality of life for the aging population and underscore the need for approaches that address the immunometabolic mechanisms of cardiac aging, providing a framework for future research.

Keywords:  cardiac aging; immunometabolism; inflammaging; oxidative phosphorylation

DOI:  https://doi.org/10.1161/JAHA.124.039216
Nat Chem Biol. 2025 Jan;21(1): 29-31

De novo discovery of bicycles.

Xu-Dong Kong, Changlin Tian.

DOI: https://doi.org/10.1038/s41589-024-01798-9