bims-camemi 2024-10-13 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2024‒10‒13
forty-five papers selected by
Christian Frezza, Universität zu Köln

The intricacies of mitochondrial calcium and enzyme regulation in liver metabolism.
Spatial and functional separation of mTORC1 signalling in response to different amino acid sources.
Dietary restriction can extend lifespan - but genetics matters more.
A germline-to-soma signal triggers an age-related decline of mitochondrial stress response.
Robust estimation of cancer and immune cell-type proportions from bulk tumor ATAC-Seq data.
Evidence for a hydrogen sulfide-sensing E3 ligase in yeast.
A platform to map the mind-mitochondria connection and the hallmarks of psychobiology: the MiSBIE study.
Compensatory activity of the PC-ME1 metabolic axis underlies differential sensitivity to mitochondrial complex I inhibition.
Generation of transmitochondrial cybrids in cancer cells.
Histone lactylation drives CD8+ T cell metabolism and function.
Transcriptional repression by HDAC3 mediates T cell exclusion from Kras mutant lung tumors.
Ribosomes hibernate on mitochondria during cellular stress.
CD38 and the mitochondrial calcium uniporter contribute to age-related hematopoietic stem cell dysfunction.
Failure of metabolic checkpoint control during late-stage granulopoiesis drives neutropenia in reticular dysgenesis.
Cancer-induced systemic pre-conditioning of distant organs: building a niche for metastatic cells.
Effect of alternative oxidase (AOX) expression on mouse cerebral mitochondria bioenergetics.
DELE1 maintains muscle proteostasis to promote growth and survival in mitochondrial myopathy.
Metabolic regulation of mitochondrial morphologies in pancreatic beta cells: coupling of bioenergetics and mitochondrial dynamics.
Dynamic death decisions: How mitochondrial dynamics shape cellular commitment to apoptosis and ferroptosis.
Metabolite regulation of epigenetics in cancer.
Male melanoma comes of age.
GLUT1 overexpression in CAR-T cells induces metabolic reprogramming and enhances potency.
The membrane curvature-inducing REEP1-4 proteins generate an ER-derived vesicular compartment.
Eating less can lead to a longer life: massive study in mice shows why.
Lactylation in cancer: Current understanding and challenges.
Metabolic modelling reveals distinct roles of sugars and carboxylic acids in stomatal opening and uncovers unexpected carbon fluxes.
The interplay of mutagenesis and ecDNA shapes urothelial cancer evolution.
TRAF7 determines circadian period through ubiquitination and degradation of DBP.
Detecting Rhythmic Gene Expression in Single-cell Transcriptomics.
Calcium signaling in mitochondrial intermembrane space.
Coordinating BNIP3/NIX-mediated mitophagy in space and time.
Mitochondrial RNA maturation.
Disruption of cellular plasticity by repeat RNAs in human pancreatic cancer.
The hallmarks of cancer immune evasion.
Epigenetic regulators of clonal hematopoiesis control CD8 T cell stemness during immunotherapy.
Mitochondrial Extracellular Vesicles (mitoEVs): Emerging mediators of cell-to-cell communication in health, aging and age-related diseases.
Human DNA polymerase ε is a source of C>T mutations at CpG dinucleotides.
Contextualizing aging clocks and properly describing biological age.
Selection promotes age-dependent degeneration of the mitochondrial genome.
Germline loss diminishes somatic mitochondria but confers preservation of respiratory function during aging and hypothermia.
The brain-body energy conservation model of aging.
Single cell atlas reveals multilayered metabolic heterogeneity across tumour types.
Nuclear compensatory evolution driven by mito-nuclear incompatibilities.
Endocrine persistence in ER+ breast cancer is accompanied by metabolic vulnerability in oxidative phosphorylation.
An automated network-based tool to search for metabolic vulnerabilities in cancer.

Cell Calcium. 2024 Oct 05. pii: S0143-4160(24)00116-7. [Epub ahead of print]124 102958

The intricacies of mitochondrial calcium and enzyme regulation in liver metabolism.

Cristina Mammucari.

  Mitochondrial Ca2+ plays a positive role in regulating pyruvate dehydrogenase, as well as the TCA cycle enzymes isocitrate dehydrogenase and α-ketoglutarate dehydrogenase. This regulation boosts the production of reducing equivalents that fuel the electron transport chain, ultimately driving ATP production. The Mitochondrial Calcium Uniporter (MCU) is the highly selective channel responsible for mitochondrial Ca2+ uptake when local Ca2+ levels reach the threshold for channel activation. In a recent study, LaMoia et al. used an innovative [13C5]glutamine-based metabolic flux analysis method (Q-flux) to measure in vivo hepatic metabolic fluxes in liver-specific MCU-/- mice. Surprisingly, they observed increased flux through isocitrate dehydrogenase and α-ketoglutarate dehydrogenase. Metabolic pathways are continuously reorganized in response to intrinsic cellular signals, as well as hormonal and nutritional inputs. Integrating metabolic flux analysis into complex systems can provide deeper insights into how metabolic adaptations occur under different conditions.

Keywords:  Calcium; Metabolic flux; Mitochondrial calcium uniporter; TCA cycle

DOI:  https://doi.org/10.1016/j.ceca.2024.102958
Nat Cell Biol. 2024 Oct 09.

Spatial and functional separation of mTORC1 signalling in response to different amino acid sources.

Stephanie A Fernandes, Danai-Dimitra Angelidaki, Julian Nüchel, Jiyoung Pan, Peter Gollwitzer, Yoav Elkis, Filippo Artoni, Sabine Wilhelm, Marija Kovacevic-Sarmiento, Constantinos Demetriades.

Amino acid (AA) availability is a robust determinant of cell growth through controlling mechanistic/mammalian target of rapamycin complex 1 (mTORC1) activity. According to the predominant model in the field, AA sufficiency drives the recruitment and activation of mTORC1 on the lysosomal surface by the heterodimeric Rag GTPases, from where it coordinates the majority of cellular processes. Importantly, however, the teleonomy of the proposed lysosomal regulation of mTORC1 and where mTORC1 acts on its effector proteins remain enigmatic. Here, by using multiple pharmacological and genetic means to perturb the lysosomal AA-sensing and protein recycling machineries, we describe the spatial separation of mTORC1 regulation and downstream functions in mammalian cells, with lysosomal and non-lysosomal mTORC1 phosphorylating distinct substrates in response to different AA sources. Moreover, we reveal that a fraction of mTOR localizes at lysosomes owing to basal lysosomal proteolysis that locally supplies new AAs, even in cells grown in the presence of extracellular nutrients, whereas cytoplasmic mTORC1 is regulated by exogenous AAs. Overall, our study substantially expands our knowledge about the topology of mTORC1 regulation by AAs and hints at the existence of distinct, Rag- and lysosome-independent mechanisms that control its activity at other subcellular locations. Given the importance of mTORC1 signalling and AA sensing for human ageing and disease, our findings will probably pave the way towards the identification of function-specific mTORC1 regulators and thus highlight more effective targets for drug discovery against conditions with dysregulated mTORC1 activity in the future.

DOI: https://doi.org/10.1038/s41556-024-01523-7
Nature. 2024 Oct 09.

Dietary restriction can extend lifespan - but genetics matters more.

Nicholas J Schork.



Keywords:  Ageing; Immunology; Metabolism; Nutrition

DOI:  https://doi.org/10.1038/d41586-024-03055-4
Nat Commun. 2024 Oct 08. 15(1): 8723

A germline-to-soma signal triggers an age-related decline of mitochondrial stress response.

Liankui Zhou, Liu Jiang, Lan Li, Chengchuan Ma, Peixue Xia, Wanqiu Ding, Ying Liu.

The abilities of an organism to cope with extrinsic stresses and activate cellular stress responses decline during aging. The signals that modulate stress responses in aged animals remain to be elucidated. Here, we discover that feeding Caenorhabditis elegans (C. elegans) embryo lysates to adult worms enabled the animals to activate the mitochondrial unfolded protein response (UPRmt) upon mitochondrial perturbations. This discovery led to subsequent investigations that unveil a hedgehog-like signal that is transmitted from the germline to the soma in adults to inhibit UPRmt in somatic tissues. Additionally, we find that the levels of germline-expressed piRNAs in adult animals markedly decreased. This reduction in piRNA levels coincides with the production and secretion of a hedgehog-like signal and suppression of the UPRmt in somatic cells. Building upon existing research, our study further elucidates the intricate mechanisms of germline-to-soma signaling and its role in modulating the trade-offs between reproduction and somatic maintenance within the context of organismal aging.

DOI: https://doi.org/10.1038/s41467-024-53064-0
Elife. 2024 Oct 09. pii: RP94833. [Epub ahead of print]13

Robust estimation of cancer and immune cell-type proportions from bulk tumor ATAC-Seq data.

Aurélie Anne-Gaëlle Gabriel, Julien Racle, Maryline Falquet, Camilla Jandus, David Gfeller.

  Assay for Transposase-Accessible Chromatin sequencing (ATAC-Seq) is a widely used technique to explore gene regulatory mechanisms. For most ATAC-Seq data from healthy and diseased tissues such as tumors, chromatin accessibility measurement represents a mixed signal from multiple cell types. In this work, we derive reliable chromatin accessibility marker peaks and reference profiles for most non-malignant cell types frequently observed in the microenvironment of human tumors. We then integrate these data into the EPIC deconvolution framework (Racle et al., 2017) to quantify cell-type heterogeneity in bulk ATAC-Seq data. Our EPIC-ATAC tool accurately predicts non-malignant and malignant cell fractions in tumor samples. When applied to a human breast cancer cohort, EPIC-ATAC accurately infers the immune contexture of the main breast cancer subtypes.

Keywords:  ATAC-Seq; bulk deconvolution; cancer biology; chromatin accessibility; computational biology; human; systems biology; tumor microenvironment

DOI:  https://doi.org/10.7554/eLife.94833
Genetics. 2024 Oct 08. pii: iyae154. [Epub ahead of print]

Evidence for a hydrogen sulfide-sensing E3 ligase in yeast.

Zane Johnson, Yun Wang, Benjamin M Sutter, Benjamin P Tu.

  In yeast, control of sulfur amino acid metabolism relies upon Met4, a transcription factor that activates the expression of a network of enzymes responsible for the biosynthesis of cysteine and methionine. In times of sulfur abundance, the activity of Met4 is repressed via ubiquitination by the SCFMet30 E3 ubiquitin ligase, but the mechanism by which the F-box protein Met30 senses sulfur status to tune its E3 ligase activity remains unresolved. Herein, we show that Met30 responds to flux through the trans-sulfuration pathway to regulate the MET gene transcriptional program. In particular, Met30 is responsive to the biological gas hydrogen sulfide, which is sufficient to induce ubiquitination of Met4 in vivo. Additionally, we identify important cysteine residues in Met30's WD-40 repeat region that sense the availability of sulfur in the cell. Our findings reveal how SCFMet30 dynamically senses the flow of sulfur metabolites through the trans-sulfuration pathway to regulate the synthesis of these special amino acids.

Keywords:  E3 ubiquitin ligase; amino acid; metabolism; nutrients; sensor; sulfur; yeast

DOI:  https://doi.org/10.1093/genetics/iyae154
Trends Endocrinol Metab. 2024 Oct 09. pii: S1043-2760(24)00225-X. [Epub ahead of print]

A platform to map the mind-mitochondria connection and the hallmarks of psychobiology: the MiSBIE study.

MiSBIE Study Group

  Health emerges from coordinated psychobiological processes powered by mitochondrial energy transformation. But how do mitochondria regulate the multisystem responses that shape resilience and disease risk across the lifespan? The Mitochondrial Stress, Brain Imaging, and Epigenetics (MiSBIE) study was established to address this question and determine how mitochondria influence the interconnected neuroendocrine, immune, metabolic, cardiovascular, cognitive, and emotional systems among individuals spanning the spectrum of mitochondrial energy transformation capacity, including participants with rare mitochondrial DNA (mtDNA) lesions causing mitochondrial diseases (MitoDs). This interdisciplinary effort is expected to generate new insights into the pathophysiology of MitoDs, provide a foundation to develop novel biomarkers of human health, and integrate our fragmented knowledge of bioenergetic, brain-body, and mind-mitochondria processes relevant to medicine and public health.

Keywords:  allostasis; metabolism; mitochondrial disorders; mtDNA; psychobiology; stress

DOI:  https://doi.org/10.1016/j.tem.2024.08.006
Nat Commun. 2024 Oct 07. 15(1): 8682

Compensatory activity of the PC-ME1 metabolic axis underlies differential sensitivity to mitochondrial complex I inhibition.

Lucia Del Prado, Myriam Jaraíz-Rodríguez, Mauro Agro, Marcos Zamora-Dorta, Natalia Azpiazu, Manuel Calleja, Mario Lopez-Manzaneda, Jaime de Juan-Sanz, Alba Fernández-Rodrigo, José A Esteban, Mònica Girona, Albert Quintana, Eduardo Balsa.

Deficiencies in the electron transport chain (ETC) lead to mitochondrial diseases. While mutations are distributed across the organism, cell and tissue sensitivity to ETC disruption varies, and the molecular mechanisms underlying this variability remain poorly understood. Here we show that, upon ETC inhibition, a non-canonical tricarboxylic acid (TCA) cycle upregulates to maintain malate levels and concomitant production of NADPH. Our findings indicate that the adverse effects observed upon CI inhibition primarily stem from reduced NADPH levels, rather than ATP depletion. Furthermore, we find that Pyruvate carboxylase (PC) and ME1, the key mediators orchestrating this metabolic reprogramming, are selectively expressed in astrocytes compared to neurons and underlie their differential sensitivity to ETC inhibition. Augmenting ME1 levels in the brain alleviates neuroinflammation and corrects motor function and coordination in a preclinical mouse model of CI deficiency. These studies may explain why different brain cells vary in their sensitivity to ETC inhibition, which could impact mitochondrial disease management.

DOI: https://doi.org/10.1038/s41467-024-52968-1
Methods Cell Biol. 2024 ;pii: S0091-679X(24)00152-3. [Epub ahead of print]189 23-40

Generation of transmitochondrial cybrids in cancer cells.

Ruth Soler-Agesta, Cristina Ripollés-Yuba, Joaquín Marco-Brualla, Raquel Moreno-Loshuertos, Ai Sato, Manuel Beltrán-Visiedo, Lorenzo Galluzzi, Alberto Anel.

  At odds with historical views suggesting that mitochondrial functions are largely dispensable for cancer cells, it is now clear that mitochondria have a major impact on malignant transformation, tumor progression and response to treatment. Mitochondria are indeed critical for neoplastic cells not only as an abundant source of ATP and other metabolic intermediates, but also as gatekeepers of apoptotic cell death and inflammation. Interestingly, while mitochondrial components are mostly encoded by nuclear genes, mitochondria contain a small, circular genome that codes for a few mitochondrial proteins, ribosomal RNAs and transfer RNAs. Here, we describe a straightforward method to generate transmitochondrial cybrids, i.e., cancer cells depleted of their mitochondrial DNA and reconstituted with intact mitochondria from another cellular source. Once established, transmitochondrial cybrids can be stably propagated and are valuable to dissect the specific impact of the mitochondrial genome on cancer cell functions.

Keywords:  22Rv1 cells; Cancer metabolism; DU-145 cells; Immunity; mtDNA; rho(0) cells

DOI:  https://doi.org/10.1016/bs.mcb.2024.05.010
Nat Immunol. 2024 Oct 07.

Histone lactylation drives CD8+ T cell metabolism and function.

Deblina Raychaudhuri, Pratishtha Singh, Bidisha Chakraborty, Mercedes Hennessey, Aminah J Tannir, Shrinidhi Byregowda, Seanu Meena Natarajan, Abel Trujillo-Ocampo, Jin Seon Im, Sangeeta Goswami.

The activation and functional differentiation of CD8+ T cells are linked to metabolic pathways that result in the production of lactate. Lactylation is a lactate-derived histone post-translational modification; however, the relevance of histone lactylation in the context of CD8+ T cell activation and function is not known. Here, we show the enrichment of H3K18 lactylation (H3K18la) and H3K9 lactylation (H3K9la) in human and mouse CD8+ T cells, which act as transcription initiators of key genes regulating CD8+ T cell function. Further, we note distinct patterns of H3K18la and H3K9la in CD8+ T cell subsets linked to their specific metabolic profiles. Additionally, we find that modulation of H3K18la and H3K9la by targeting metabolic and epigenetic pathways influence CD8+ T cell effector function, including antitumor immunity, in preclinical models. Overall, our study uncovers the potential roles of H3K18la and H3K9la in CD8+ T cells.

DOI: https://doi.org/10.1038/s41590-024-01985-9
Proc Natl Acad Sci U S A. 2024 Oct 15. 121(42): e2317694121

Transcriptional repression by HDAC3 mediates T cell exclusion from Kras mutant lung tumors.

Caroline K McGuire, Ambryn S Meehan, Evan Couser, Lois Bull, Allegra C Minor, Alexandra Kuhlmann-Hogan, Susan M Kaech, Reuben J Shaw, Lillian J Eichner.

  Histone Deacetylase 3 (HDAC3) function in vivo is nuanced and directed in a tissue-specific fashion. The importance of HDAC3 in Kras mutant lung tumors has recently been identified, but HDAC3 function in this context remains to be fully elucidated. Here, we identified HDAC3 as a lung tumor cell-intrinsic transcriptional regulator of the tumor immune microenvironment. In Kras mutant lung cancer cells, we found that HDAC3 is a direct transcriptional repressor of a cassette of secreted chemokines, including Cxcl10. Genetic and pharmacological inhibition of HDAC3 robustly up-regulated this gene set in human and mouse Kras, LKB1 (KL) and Kras, p53 (KP) mutant lung cancer cells through an NF-κB/p65-dependent mechanism. Using genetically engineered mouse models, we found that HDAC3 inactivation in vivo induced expression of this gene set selectively in lung tumors and resulted in enhanced T cell recruitment at least in part via Cxcl10. Furthermore, we found that inhibition of HDAC3 in the presence of Kras pathway inhibitors dissociated Cxcl10 expression from that of immunosuppressive chemokines and that combination treatment of entinostat with trametinib enhanced T cell recruitment into lung tumors in vivo. Finally, we showed that T cells contribute to in vivo tumor growth control in the presence of entinostat and trametinib combination treatment. Together, our findings reveal that HDAC3 is a druggable endogenous repressor of T cell recruitment into Kras mutant lung tumors.

Keywords:  Histone Deacetylase 3; KRAS mutant lung cancer; NF-κB p65; T cell recruitment; tumor immune microenvironment

DOI:  https://doi.org/10.1073/pnas.2317694121
Nat Commun. 2024 Oct 08. 15(1): 8666

Ribosomes hibernate on mitochondria during cellular stress.

Olivier Gemin, Maciej Gluc, Higor Rosa, Michael Purdy, Moritz Niemann, Yelena Peskova, Simone Mattei, Ahmad Jomaa.

Cell survival under nutrient-deprived conditions relies on cells' ability to adapt their organelles and rewire their metabolic pathways. In yeast, glucose depletion induces a stress response mediated by mitochondrial fragmentation and sequestration of cytosolic ribosomes on mitochondria. This cellular adaptation promotes survival under harsh environmental conditions; however, the underlying mechanism of this response remains unknown. Here, we demonstrate that upon glucose depletion protein synthesis is halted. Cryo-electron microscopy structure of the ribosomes show that they are devoid of both tRNA and mRNA, and a subset of the particles depicted a conformational change in rRNA H69 that could prevent tRNA binding. Our in situ structural analyses reveal that the hibernating ribosomes tether to fragmented mitochondria and establish eukaryotic-specific, higher-order storage structures by assembling into oligomeric arrays on the mitochondrial surface. Notably, we show that hibernating ribosomes exclusively bind to the outer mitochondrial membrane via the small ribosomal subunit during cellular stress. We identify the ribosomal protein Cpc2/RACK1 as the molecule mediating ribosomal tethering to mitochondria. This study unveils the molecular mechanism connecting mitochondrial stress with the shutdown of protein synthesis and broadens our understanding of cellular responses to nutrient scarcity and cell quiescence.

DOI: https://doi.org/10.1038/s41467-024-52911-4
Immunometabolism (Cobham). 2024 Oct;6(4): e00048

CD38 and the mitochondrial calcium uniporter contribute to age-related hematopoietic stem cell dysfunction.

Connor S R Jankowski, Thomas Weichhart.

  Hematopoietic stem cells (HSCs) are the multipotent progenitors of all immune cells. During aging, their regenerative capacity decreases for reasons that are not well understood. Recently, Song et al investigated the roles of two metabolic proteins in age-related HSC dysfunction: CD38 (a membrane-bound NADase) and the mitochondrial calcium uniporter that transports calcium into the mitochondrial matrix. They found that the interplay between these proteins is deranged in aged HSCs, contributing to their diminished renewal capacity. These findings implicate compromised nicotinamide adenine dinucleotide metabolism as underlying HSC dysfunction in aging.

Keywords:  CD38; aging; hematopoiesis; mitochondria; mitochondrial calcium uniporter; nicotinamide adenine dinucleotide metabolism

DOI:  https://doi.org/10.1097/IN9.0000000000000048
Blood. 2024 Oct 08. pii: blood.2024024123. [Epub ahead of print]

Failure of metabolic checkpoint control during late-stage granulopoiesis drives neutropenia in reticular dysgenesis.

Wenqing Wang, Martin Arreola, Thomas Mathews, Andrew W DeVilbiss, Zhiyu Zhao, Misty Martin-Sandoval, Abdulvasey Mohammed, Giorgia Benegiamo, Avni Awani, Ludger J E Goeminne, Daniel Patrick Dever, Yusuke Nakauchi, Matthew H Porteus, Mara Pavel-Dinu, Waleed Al Herz, Johan Auwerx, Sean J Morrison, Katja G Weinacht.

Cellular metabolism is highly dynamic during hematopoiesis, yet the regulatory networks that maintain metabolic homeostasis during differentiation are incompletely understood. Here, we have studied the grave immunodeficiency syndrome reticular dysgenesis caused by loss of mitochondrial adenylate kinase 2 (AK2) function. By coupling single-cell transcriptomics in reticular dysgenesis patient samples with a CRISPR model of this disorder in primary human hematopoietic stem cells, we found that the consequences of AK2 deficiency for the hematopoietic system are contingent on the effective engagement of metabolic checkpoints. In hematopoietic stem and progenitor cells, including early granulocyte precursors, AK2 deficiency reduced mechanistic target of rapamycin (mTOR) signaling and anabolic pathway activation. This conserved nutrient homeostasis and maintained cell survival and proliferation. In contrast, during late-stage granulopoiesis, metabolic checkpoints were ineffective, leading to a paradoxical upregulation of mTOR activity and energy-consuming anabolic pathways such as ribonucleoprotein synthesis in AK2-deficient cells. This caused nucleotide imbalance, including highly elevated AMP and IMP levels, the depletion of essential substrates such as NAD+ and aspartate, and ultimately resulted in proliferation arrest and demise of the granulocyte lineage. Our findings suggest that even severe metabolic defects can be tolerated with the help of metabolic checkpoints but that the failure of such checkpoints in differentiated cells results in a catastrophic loss of homeostasis.

DOI: https://doi.org/10.1182/blood.2024024123
Nat Rev Cancer. 2024 Oct 10.

Cancer-induced systemic pre-conditioning of distant organs: building a niche for metastatic cells.

Nicolas Rabas, Rute M M Ferreira, Stefania Di Blasio, Ilaria Malanchi.

From their early genesis, tumour cells integrate with the surrounding normal cells to form an abnormal structure that is tightly integrated with the host organism via blood and lymphatic vessels and even neural associations. Using these connections, emerging cancers send a plethora of mediators that efficiently perturb the entire organism and induce changes in distant tissues. These perturbations serendipitously favour early metastatic establishment by promoting a more favourable tissue environment (niche) that supports the persistence of disseminated tumour cells within a foreign tissue. Because the establishment of early metastatic niches represents a key limiting step for metastasis, the creation of a more suitable pre-conditioned tissue strongly enhances metastatic success. In this Review, we provide an updated view of the mechanisms and mediators of primary tumours described so far that induce a pro-metastatic conditioning of distant organs, which favours early metastatic niche formation. We reflect on the nature of cancer-induced systemic conditioning, considering that non-cancer-dependent perturbations of tissue homeostasis are also able to trigger pro-metastatic conditioning. We argue that a more holistic view of the processes catalysing metastatic progression is needed to identify preventive or therapeutic opportunities.

DOI: https://doi.org/10.1038/s41568-024-00752-0
Redox Biol. 2024 Oct 01. pii: S2213-2317(24)00356-2. [Epub ahead of print]77 103378

Effect of alternative oxidase (AOX) expression on mouse cerebral mitochondria bioenergetics.

Belem Yoval-Sánchez, Ivan Guerrero, Fariha Ansari, Zoya Niatsetskaya, Max Siragusa, Jordi Magrane, Vadim Ten, Csaba Konrad, Marten Szibor, Alexander Galkin.

  Alternative oxidase (AOX) is an enzyme that transfers electrons from reduced quinone directly to oxygen without proton translocation. When AOX from Ciona intestinalis is xenotopically expressed in mice, it can substitute the combined electron-transferring activity of mitochondrial complexes III/IV. Here, we used brain mitochondria from AOX-expressing mice with such a chimeric respiratory chain to study respiratory control bioenergetic mechanisms. AOX expression did not compromise the function of the mammalian respiratory chain at physiological conditions, however the complex IV inhibitor cyanide only partially blocked respiration by AOX-containing mitochondria. The relative fraction of cyanide-insensitive respiration increased at lower temperatures, indicative of a temperature-controlled attenuation of mammalian respiratory enzyme activity. As AOX does not translocate protons, the mitochondrial transmembrane potential in AOX-containing mitochondria was more sensitive to cyanide during succinate oxidation than during malate/pyruvate-supported respiration. High concentrations of cyanide fully collapsed membrane potential during oxidation of either succinate or glycerol 3-phosphate, but not during malate/pyruvate-supported respiration. This confirms AOX's electroneutral redox activity and indicates differences in the proton-translocating capacity of dehydrogenases upstream of the ubiquinone pool. Our respiration data refutes previous proposals for quinone partitioning within the supercomplexes of the respiratory chain, instead supporting the concept of a single homogeneous, freely diffusing quinone pool. Respiration with either succinate or glycerol 3-phosphate promotes reverse electron transfer (RET) towards complex I. AOX expression significantly decreased RET-induced ROS generation, with the effect more pronounced at low temperatures. Inhibitor-sensitivity analysis showed that the AOX-induced decrease in H2O2 release is due to the lower contribution of complex I to net ROS production during RET. Overall, our findings provide new insights into the role of temperature as a mechanism to control respiration and highlight the utility of AOX as a genetic tool to characterize both the distinct pathways of oxygen reduction and the role of redox control in RET.

Keywords:  Alternative quinol oxidase; Complex I; Mitochondria; Mitochondrial membrane potential; ROS generation; Reverse electron transfer

DOI:  https://doi.org/10.1016/j.redox.2024.103378
EMBO J. 2024 Oct 08.

DELE1 maintains muscle proteostasis to promote growth and survival in mitochondrial myopathy.

Hsin-Pin Lin, Jennifer D Petersen, Alexandra J Gilsrud, Angelo Madruga, Theresa M D'Silva, Xiaoping Huang, Mario K Shammas, Nicholas P Randolph, Kory R Johnson, Yan Li, Drew R Jones, Michael E Pacold, Derek P Narendra.

  Mitochondrial dysfunction causes devastating disorders, including mitochondrial myopathy, but how muscle senses and adapts to mitochondrial dysfunction is not well understood. Here, we used diverse mouse models of mitochondrial myopathy to show that the signal for mitochondrial dysfunction originates within mitochondria. The mitochondrial proteins OMA1 and DELE1 sensed disruption of the inner mitochondrial membrane and, in response, activated the mitochondrial integrated stress response (mt-ISR) to increase the building blocks for protein synthesis. In the absence of the mt-ISR, protein synthesis in muscle was dysregulated causing protein misfolding, and mice with early-onset mitochondrial myopathy failed to grow and survive. The mt-ISR was similar following disruptions in mtDNA maintenance (Tfam knockout) and mitochondrial protein misfolding (CHCHD10 G58R and S59L knockin) but heterogenous among mitochondria-rich tissues, with broad gene expression changes observed in heart and skeletal muscle and limited changes observed in liver and brown adipose tissue. Taken together, our findings identify that the DELE1 mt-ISR mediates a similar response to diverse forms of mitochondrial stress and is critical for maintaining growth and survival in early-onset mitochondrial myopathy.

Keywords:  Mitochondria Unfolded Protein Response (mt-UPR); Mitochondrial Disorders; Mitohormesis; Mitonuclear Communication; Mitophagy

DOI:  https://doi.org/10.1038/s44318-024-00242-x
Commun Biol. 2024 Oct 05. 7(1): 1267

Metabolic regulation of mitochondrial morphologies in pancreatic beta cells: coupling of bioenergetics and mitochondrial dynamics.

Wen-Wei Tseng, Ching-Hsiang Chu, Yi-Ju Lee, Shirui Zhao, Chen Chang, Yi-Ping Ho, An-Chi Wei.

Cellular bioenergetics and mitochondrial dynamics are crucial for the secretion of insulin by pancreatic beta cells in response to elevated levels of blood glucose. To elucidate the interactions between energy production and mitochondrial fission/fusion dynamics, we combine live-cell mitochondria imaging with biophysical-based modeling and graph-based network analysis. The aim is to determine the mechanism that regulates mitochondrial morphology and balances metabolic demands in pancreatic beta cells. A minimalistic differential equation-based model for beta cells is constructed that includes glycolysis, oxidative phosphorylation, calcium dynamics, and fission/fusion dynamics, with ATP synthase flux and proton leak flux as main regulators of mitochondrial dynamics. The model shows that mitochondrial fission occurs in response to hyperglycemia, starvation, ATP synthase inhibition, uncoupling, and diabetic conditions, in which the rate of proton leakage exceeds the rate of mitochondrial ATP synthesis. Under these metabolic challenges, the propensities of tip-to-tip fusion events simulated from the microscopy images of the mitochondrial networks are lower than those in the control group and prevent the formation of mitochondrial networks. The study provides a quantitative framework that couples bioenergetic regulation with mitochondrial dynamics, offering insights into how mitochondria adapt to metabolic challenges.

DOI: https://doi.org/10.1038/s42003-024-06955-3
Dev Cell. 2024 Oct 07. pii: S1534-5807(24)00532-X. [Epub ahead of print]59(19): 2549-2565

Dynamic death decisions: How mitochondrial dynamics shape cellular commitment to apoptosis and ferroptosis.

Jesminara Khatun, Jesse D Gelles, Jerry Edward Chipuk.

  The incorporation of mitochondria into early eukaryotes established organelle-based biochemistry and enabled metazoan development. Diverse mitochondrial biochemistry is essential for life, and its homeostatic control via mitochondrial dynamics supports organelle quality and function. Mitochondrial crosstalk with numerous regulated cell death (RCD) pathways controls the decision to die. In this review, we will focus on apoptosis and ferroptosis, two distinct forms of RCD that utilize divergent signaling to kill a targeted cell. We will highlight how proteins and processes involved in mitochondrial dynamics maintain biochemically diverse subcellular compartments to support apoptosis and ferroptosis machinery, as well as unite disparate RCD pathways through dual control of organelle biochemistry and the decision to die.

Keywords:  apoptosis; cell biology; cell death; ferroptosis; membranes; mitochondria; mitochondrial dynamics; signal transduction

DOI:  https://doi.org/10.1016/j.devcel.2024.09.004
Cell Rep. 2024 Oct 04. pii: S2211-1247(24)01166-5. [Epub ahead of print]43(10): 114815

Metabolite regulation of epigenetics in cancer.

Pu Wang, Lei-Lei Chen, Yue Xiong, Dan Ye.

  The catalytic activity of most epigenetic enzymes requires a metabolite produced by central carbon metabolism as a cofactor or (co-)substrate. The concentrations of these metabolites undergo dynamic changes in response to nutrient levels and environmental conditions, reprogramming metabolic processes and epigenetic landscapes. Abnormal accumulations of epigenetic modulatory metabolites resulting from mutations in metabolic enzymes contribute to tumorigenesis. In this review, we first present the concept that metabolite regulation of gene expression represents an evolutionarily conserved mechanism from prokaryotes to eukaryotes. We then review how individual metabolites affect epigenetic enzymes and cancer development. Lastly, we discuss the advancement of and opportunity for therapeutic targeting of metabolite-epigenetic regulation in cancer therapy.

Keywords:  CP: Cancer; CP: Metabolism

DOI:  https://doi.org/10.1016/j.celrep.2024.114815
Nat Rev Cancer. 2024 Oct 10.

Male melanoma comes of age.

Daniela Senft.

DOI: https://doi.org/10.1038/s41568-024-00766-8
Nat Commun. 2024 Oct 06. 15(1): 8658

GLUT1 overexpression in CAR-T cells induces metabolic reprogramming and enhances potency.

Justin A Guerrero, Dorota D Klysz, Yiyun Chen, Meena Malipatlolla, Jameel Lone, Carley Fowler, Lucille Stuani, Audre May, Malek Bashti, Peng Xu, Jing Huang, Basil Michael, Kévin Contrepois, Shaurya Dhingra, Chris Fisher, Katrin J Svensson, Kara L Davis, Maya Kasowski, Steven A Feldman, Elena Sotillo, Crystal L Mackall.

The intensive nutrient requirements needed to sustain T cell activation and proliferation, combined with competition for nutrients within the tumor microenvironment, raise the prospect that glucose availability may limit CAR-T cell function. Here, we seek to test the hypothesis that stable overexpression (OE) of the glucose transporter GLUT1 in primary human CAR-T cells would improve their function and antitumor potency. We observe that GLUT1OE in CAR-T cells increases glucose consumption, glycolysis, glycolytic reserve, and oxidative phosphorylation, and these effects are associated with decreased T cell exhaustion and increased Th17 differentiation. GLUT1OE also induces broad metabolic reprogramming associated with increased glutathione-mediated resistance to reactive oxygen species, and increased inosine accumulation. When challenged with tumors, GLUT1OE CAR-T cells secrete more proinflammatory cytokines and show enhanced cytotoxicity in vitro, and demonstrate superior tumor control and persistence in mouse models. Our collective findings support a paradigm wherein glucose availability is rate limiting for effector CAR-T cell function and demonstrate that enhancing glucose availability via GLUT1OE could augment antitumor immune function.

DOI: https://doi.org/10.1038/s41467-024-52666-y
Nat Commun. 2024 Oct 05. 15(1): 8655

The membrane curvature-inducing REEP1-4 proteins generate an ER-derived vesicular compartment.

Yoko Shibata, Emily E Mazur, Buyan Pan, Joao A Paulo, Steven P Gygi, Suyog Chavan, L Sebastian Alexis Valerio, Jiuchun Zhang, Tom A Rapoport.

The endoplasmic reticulum (ER) is shaped by abundant membrane curvature-generating proteins that include the REEP family member REEP5. The REEP1 subfamily, consisting of four proteins in mammals (REEP1-4), is less abundant and lack a N-terminal region. Mutations in REEP1 and REEP2 cause Hereditary Spastic Paraplegia, but the function of these four REEP proteins remains enigmatic. Here we show that REEP1-4 reside in a unique vesicular compartment and identify features that determine their localization. Mutations in REEP1-4 that compromise curvature generation, including those causing disease, relocalize the proteins to the bulk ER. These mutants interact with wild-type proteins to retain them in the ER, consistent with their autosomal-dominant disease inheritance. REEP1 vesicles contain the membrane fusogen atlastin-1, but not general ER proteins. We propose that REEP1-4 generate these vesicles themselves by budding from the ER, and that they cycle back to the ER by atlastin-mediated fusion. The vesicles may serve to regulate ER tubule dynamics.

DOI: https://doi.org/10.1038/s41467-024-52901-6
Nature. 2024 Oct 09.

Eating less can lead to a longer life: massive study in mice shows why.

Elie Dolgin.



Keywords:  Ageing; Genetics; Metabolism; Nutrition

DOI:  https://doi.org/10.1038/d41586-024-03277-6
Cancer Cell. 2024 Oct 08. pii: S1535-6108(24)00354-4. [Epub ahead of print]

Lactylation in cancer: Current understanding and challenges.

Hongde Li, Linchong Sun, Ping Gao, Hai Hu.

Lactylation, a recently identified post-translational modification, has initially been linked to gene transcription regulation through epigenetic mechanisms. However, its role in tumorigenesis-whether as a major driver or a minor regulator-remains uncertain. Here, we summarize the current understanding of lactylation and discuss the inherent challenges in definitively attributing specific biological roles to this modification. We emphasize the necessity for precise methodologies to manipulate lactylation levels within pathophysiologically relevant conditions. Further investigation is required to determine whether lactylation plays a critical role in tumor biology or merely reflects secondary metabolic alterations.

DOI: https://doi.org/10.1016/j.ccell.2024.09.006
Plant Cell. 2024 Oct 05. pii: koae252. [Epub ahead of print]

Metabolic modelling reveals distinct roles of sugars and carboxylic acids in stomatal opening and uncovers unexpected carbon fluxes.

Noah Sprent, C Y Maurice Cheung, Sanu Shameer, R George Ratcliffe, J Lee Sweetlove, Nadine Töpfer.

Guard cell metabolism is crucial for stomatal dynamics, but a full understanding of its role is hampered by experimental limitations and the flexible nature of the metabolic network. To tackle this challenge, we constructed a time-resolved stoichiometric model of guard cell metabolism that accounts for energy and osmolyte requirements and which is integrated with the mesophyll. The model resolved distinct roles for starch, sugars, and malate in guard cell metabolism and revealed several unexpected flux patterns in central metabolism. During blue light-mediated stomatal opening, starch breakdown was the most efficient way to generate osmolytes with downregulation of glycolysis allowing starch-derived glucose to accumulate as a cytosolic osmolyte. Maltose couldalso accumulate as a cytosolic osmoticum, although this made the metabolic system marginally less efficient. The metabolic energy for stomatal opening was predicted to be derived independently of starch, using nocturnally accumulated citrate which was metabolised in the tricarboxylic acid cycle to malate to provide mitochondrial reducing power for ATP synthesis. In white light-mediated stomatal opening, malate transferred reducing equivalents from guard cell photosynthesis to mitochondria for ATP production. Depending on the capacity for guard cell photosynthesis, glycolysis showed little flux during the day but was crucial for energy metabolism at night. In summary, our analyses have corroborated recent findings in Arabidopsis guard cell research, resolved conflicting observations by highlighting the flexibility of guard cell metabolism, and proposed new metabolic flux modes for further experimental testing.

DOI: https://doi.org/10.1093/plcell/koae252
Nature. 2024 Oct 09.

The interplay of mutagenesis and ecDNA shapes urothelial cancer evolution.

Duy D Nguyen, William F Hooper, Weisi Liu, Timothy R Chu, Heather Geiger, Jennifer M Shelton, Minita Shah, Zoe R Goldstein, Lara Winterkorn, Adrienne Helland, Michael Sigouros, Jyothi Manohar, Jenna Moyer, Majd Al Assaad, Alissa Semaan, Sandra Cohen, Florencia Madorsky Rowdo, David Wilkes, Mohamed Osman, Rahul R Singh, Andrea Sboner, Henkel L Valentine, Phillip Abbosh, Scott T Tagawa, David M Nanus, Jones T Nauseef, Cora N Sternberg, Ana M Molina, Douglas Scherr, Giorgio Inghirami, Juan Miguel Mosquera, Olivier Elemento, Nicolas Robine, Bishoy M Faltas.

Advanced urothelial cancer is a frequently lethal disease characterized by marked genetic heterogeneity1. In this study, we investigated the evolution of genomic signatures caused by endogenous and external mutagenic processes and their interplay with complex structural variants (SVs). We superimposed mutational signatures and phylogenetic analyses of matched serial tumours from patients with urothelial cancer to define the evolutionary dynamics of these processes. We show that APOBEC3-induced mutations are clonal and early, whereas chemotherapy induces mutational bursts of hundreds of late subclonal mutations. Using a genome graph computational tool2, we observed frequent high copy-number circular amplicons characteristic of extrachromosomal DNA (ecDNA)-forming SVs. We characterized the distinct temporal patterns of APOBEC3-induced and chemotherapy-induced mutations within ecDNA-forming SVs, gaining new insights into the timing of these mutagenic processes relative to ecDNA biogenesis. We discovered that most CCND1 amplifications in urothelial cancer arise within circular ecDNA-forming SVs. ecDNA-forming SVs persisted and increased in complexity, incorporating additional DNA segments and contributing to the evolution of treatment resistance. Oxford Nanopore Technologies long-read whole-genome sequencing followed by de novo assembly mapped out CCND1 ecDNA structure. Experimental modelling of CCND1 ecDNA confirmed its role as a driver of treatment resistance. Our findings define fundamental mechanisms that drive urothelial cancer evolution and have important therapeutic implications.

DOI: https://doi.org/10.1038/s41586-024-07955-3
Commun Biol. 2024 Oct 08. 7(1): 1280

TRAF7 determines circadian period through ubiquitination and degradation of DBP.

Shusaku Masuda, Nobuhiro Kurabayashi, Rina Nunokawa, Yuta Otobe, Hiroko Kozuka-Hata, Masaaki Oyama, Yuri Shibata, Jun-Ichiro Inoue, Michinori Koebis, Atsu Aiba, Hikari Yoshitane, Yoshitaka Fukada.

D-site binding protein, DBP, is a clock-controlled transcription factor and drives daily rhythms of physiological processes through the regulation of an array of genes harboring a DNA binding motif, D-box. DBP protein levels show a circadian oscillation with an extremely robust peak/trough ratio, but it is elusive how the temporal pattern is regulated by post-translational regulation. In this study, we show that DBP protein levels are down-regulated by the ubiquitin-proteasome pathway. Analysis using 19 dominant-negative forms of E2 enzymes have revealed that UBE2G1 and UBE2T mediate the degradation of DBP. A proteomic analysis of DBP-interacting proteins and database screening have identified Tumor necrosis factor Receptor-Associated Factor 7 (TRAF7), a RING-type E3 ligase, that forms a complex with UBE2G1 and/or UBE2T. Ubiquitination analysis have revealed that TRAF7 enhances K48-linked polyubiquitination of DBP in cultured cells. Overexpression of TRAF7 down-regulates DBP protein level, while knockdown of TRAF7 up-regulates DBP in cultured cells. Knockout of TRAF7 in NIH3T3 cells have revealed that TRAF7 mediates the time-of-the-day-dependent regulation of DBP levels. Furthermore, TRAF7 has a period-shortening effect on the cellular clock. Together, TRAF7 plays an important role in circadian clock oscillation through destabilization of DBP.

DOI: https://doi.org/10.1038/s42003-024-07002-x
J Biol Rhythms. 2024 Oct 08. 7487304241273182

Detecting Rhythmic Gene Expression in Single-cell Transcriptomics.

Bingxian Xu, Dingbang Ma, Katharine Abruzzi, Rosemary Braun.

  An autonomous, environmentally synchronizable circadian rhythm is a ubiquitous feature of life on Earth. In multicellular organisms, this rhythm is generated by a transcription-translation feedback loop present in nearly every cell that drives daily expression of thousands of genes in a tissue-dependent manner. Identifying the genes that are under circadian control can elucidate the mechanisms by which physiological processes are coordinated in multicellular organisms. Today, transcriptomic profiling at the single-cell level provides an unprecedented opportunity to understand the function of cell-level clocks. However, while many cycling detection algorithms have been developed to identify genes under circadian control in bulk transcriptomic data, it is not known how best to adapt these algorithms to single-cell RNA seq data. Here, we benchmark commonly used circadian detection methods on their reliability and efficiency when applied to single-cell RNA seq data. Our results provide guidance on adapting existing cycling detection methods to the single-cell domain and elucidate opportunities for more robust and efficient rhythm detection in single-cell data. We also propose a subsampling procedure combined with harmonic regression as an efficient strategy to detect circadian genes in the single-cell setting.

Keywords:  benchmarking; circadian rhythm; cycling detection; reproducibility; single-cell RNA sequencing

DOI:  https://doi.org/10.1177/07487304241273182
Biochem Soc Trans. 2024 Oct 11. pii: BST20240319. [Epub ahead of print]

Calcium signaling in mitochondrial intermembrane space.

Shanikumar Goyani, Shatakshi Shukla, Pooja Jadiya, Dhanendra Tomar.

  The mitochondrial intermembrane space (IMS) is a highly protected compartment, second only to the matrix. It is a crucial bridge, coordinating mitochondrial activities with cellular processes such as metabolites, protein, lipid, and ion exchange. This regulation influences signaling pathways for metabolic activities and cellular homeostasis. The IMS harbors various proteins critical for initiating apoptotic cascades and regulating reactive oxygen species production by controlling the respiratory chain. Calcium (Ca2+), a key intracellular secondary messenger, enter the mitochondrial matrix via the IMS, regulating mitochondrial bioenergetics, ATP production, modulating cell death pathways. IMS acts as a regulatory site for Ca2+ entry due to the presence of different Ca2+ sensors such as MICUs, solute carriers (SLCs); ion exchangers (LETM1/SCaMCs); S100A1, mitochondrial glycerol-3-phosphate dehydrogenase, and EFHD1, each with unique Ca2+ binding motifs and spatial localizations. This review primarily emphasizes the role of these IMS-localized Ca2+ sensors concerning their spatial localization, mechanism, and molecular functions. Additionally, we discuss how these sensors contribute to the progression and pathogenesis of various human health conditions and diseases.

Keywords:  Ca2+ sensors; LETM1; MICU; SCaMs; SLC25A12/13; mitochondrial intermembrane space

DOI:  https://doi.org/10.1042/BST20240319
Biochem Soc Trans. 2024 Oct 08. pii: BST20221364. [Epub ahead of print]

Coordinating BNIP3/NIX-mediated mitophagy in space and time.

Natalie M Niemi, Jonathan R Friedman.

  Mitochondria maintain organellar homeostasis through multiple quality control pathways, including the clearance of defective or unwanted mitochondria by selective autophagy. This removal of mitochondria, mitophagy, is controlled in large part by the outer mitochondrial membrane mitophagy receptors BNIP3 and NIX. While it has long been appreciated that BNIP3 and NIX mediate mitophagy by controlling the recruitment of autophagic machinery to the mitochondrial surface, the requirement for the carefully controlled spatiotemporal regulation of receptor-mediated mitophagy has only recently come to light. Several new factors that regulate the BNIP3/NIX-mediated mitophagy pathway have emerged, and various loss-of-function cell and animal models have revealed the dire consequences of their dysregulation. In this mini-review, we discuss new insights into the mechanisms and roles of the regulation of BNIP3 and NIX and highlight questions that have emerged from the identification of these new regulators.

Keywords:  autophagy; mitochondria; mitophagy

DOI:  https://doi.org/10.1042/BST20221364
RNA Biol. 2024 Jan;21(1): 28-39

Mitochondrial RNA maturation.

Zofia M Chrzanowska-Lightowlers, Robert N Lightowlers.

  The vast majority of oxygen-utilizing eukaryotes need to express their own mitochondrial genome, mtDNA, to survive. In comparison to size of their nuclear genome, mtDNA is minimal, even in the most exceptional examples. Having evolved from bacteria in an endosymbiotic event, it might be expected that the process of mtDNA expression would be relatively simple. The aim of this short review is to illustrate just how wrong this assumption is. The production of functional mitochondrial RNA across species evolved in many directions. Organelles use a dizzying array of RNA processing, modifying, editing, splicing and maturation events that largely require the import of nuclear-encoded proteins from the cytosol. These processes are sometimes driven by the unusual behaviour of the mitochondrial genome from which the RNA is originally transcribed, but in many examples the complex processes that are essential for the production of functional RNA in the organelle, are fascinating and bewildering.

Keywords:  Mitochondrial; maturation; messenger RNA; modifications; processing; translation

DOI:  https://doi.org/10.1080/15476286.2024.2414157
Cell. 2024 Oct 01. pii: S0092-8674(24)01072-9. [Epub ahead of print]

Disruption of cellular plasticity by repeat RNAs in human pancreatic cancer.

Eunae You, Patrick Danaher, Chenyue Lu, Siyu Sun, Luli Zou, Ildiko E Phillips, Alexandra S Rojas, Natalie I Ho, Yuhui Song, Michael J Raabe, Katherine H Xu, Peter M Richieri, Hao Li, Natalie Aston, Rebecca L Porter, Bidish K Patel, Linda T Nieman, Nathan Schurman, Briana M Hudson, Khrystyna North, Sarah E Church, Vikram Deshpande, Andrew S Liss, Tae K Kim, Yi Cui, Youngmi Kim, Benjamin D Greenbaum, Martin J Aryee, David T Ting.

  Aberrant expression of repeat RNAs in pancreatic ductal adenocarcinoma (PDAC) mimics viral-like responses with implications on tumor cell state and the response of the surrounding microenvironment. To better understand the relationship of repeat RNAs in human PDAC, we performed spatial molecular imaging at single-cell resolution in 46 primary tumors, revealing correlations of high repeat RNA expression with alterations in epithelial state in PDAC cells and myofibroblast phenotype in cancer-associated fibroblasts (CAFs). This loss of cellular identity is observed with dosing of extracellular vesicles (EVs) and individual repeat RNAs of PDAC and CAF cell culture models pointing to cell-cell intercommunication of these viral-like elements. Differences in PDAC and CAF responses are driven by distinct innate immune signaling through interferon regulatory factor 3 (IRF3). The cell-context-specific viral-like responses to repeat RNAs provide a mechanism for modulation of cellular plasticity in diverse cell types in the PDAC microenvironment.

Keywords:  cancer-associated fibroblast; cellular plasticity; extracellular vesicles; pancreatic cancer; repeat RNA; spatial transcriptomics; tumor microenvironment

DOI:  https://doi.org/10.1016/j.cell.2024.09.024
Cancer Cell. 2024 Oct 09. pii: S1535-6108(24)00358-1. [Epub ahead of print]

The hallmarks of cancer immune evasion.

Claudia Galassi, Timothy A Chan, Ilio Vitale, Lorenzo Galluzzi.

  According to the widely accepted "three Es" model, the host immune system eliminates malignant cell precursors and contains microscopic neoplasms in a dynamic equilibrium, preventing cancer outgrowth until neoplastic cells acquire genetic or epigenetic alterations that enable immune escape. This immunoevasive phenotype originates from various mechanisms that can be classified under a novel "three Cs" conceptual framework: (1) camouflage, which hides cancer cells from immune recognition, (2) coercion, which directly or indirectly interferes with immune effector cells, and (3) cytoprotection, which shields malignant cells from immune cytotoxicity. Blocking the ability of neoplastic cells to evade the host immune system is crucial for increasing the efficacy of modern immunotherapy and conventional therapeutic strategies that ultimately activate anticancer immunosurveillance. Here, we review key hallmarks of cancer immune evasion under the "three Cs" framework and discuss promising strategies targeting such immunoevasive mechanisms.

Keywords:  T cell exhaustion; T(REG) cells; antigen presentation; cytotoxic T lymphocytes; dendritic cells; exclusion; immune checkpoint inhibitors; immunogenic cell death; tumor-associated macrophages; type I interferon

DOI:  https://doi.org/10.1016/j.ccell.2024.09.010
Science. 2024 Oct 11. 386(6718): eadl4492

Epigenetic regulators of clonal hematopoiesis control CD8 T cell stemness during immunotherapy.

Tae Gun Kang, Xin Lan, Tian Mi, Hongfeng Chen, Shanta Alli, Song-Eun Lim, Sheetal Bhatara, Anoop Babu Vasandan, Grace Ward, Sofia Bentivegna, Josh Jang, Marianne L Spatz, Jin-Hwan Han, Balthasar Clemens Schlotmann, Jakob Schmidt Jespersen, Christopher Derenzo, Peter Vogel, Jiyang Yu, Stephen Baylin, Peter Jones, Casey O'Connell, Kirsten Grønbæk, Ben Youngblood, Caitlin C Zebley.

Epigenetic reinforcement of T cell exhaustion is known to be a major barrier limiting T cell responses during immunotherapy. However, the core epigenetic regulators restricting antitumor immunity during prolonged antigen exposure are not clear. We investigated three commonly mutated epigenetic regulators that promote clonal hematopoiesis to determine whether they affect T cell stemness and response to checkpoint blockade immunotherapy. CD8 T cells lacking Dnmt3a, Tet2, or Asxl1 preserved a progenitor-exhausted (Tpex) population for more than 1 year during chronic antigen exposure without undergoing malignant transformation. Asxl1 controlled the self-renewal capacity of T cells and reduced CD8 T cell differentiation through H2AK119 ubiquitination and epigenetic modification of the polycomb group-repressive deubiquitinase pathway. Asxl1-deficient T cells synergized with anti-PD-L1 immunotherapy to improve tumor control in experimental models and conferred a survival advantage to mutated T cells from treated patients.

DOI: https://doi.org/10.1126/science.adl4492
Ageing Res Rev. 2024 Oct 05. pii: S1568-1637(24)00340-4. [Epub ahead of print]101 102522

Mitochondrial Extracellular Vesicles (mitoEVs): Emerging mediators of cell-to-cell communication in health, aging and age-related diseases.

Roberto Iorio, Sabrina Petricca, Giovanna Di Emidio, Stefano Falone, Carla Tatone.

  Mitochondria are metabolic and signalling hubs that integrate a plethora of interconnected processes to maintain cell homeostasis. They are also dormant mediators of inflammation and cell death, and with aging damages affecting mitochondria gradually accumulate, resulting in the manifestation of age-associated disorders. In addition to coordinate multiple intracellular functions, mitochondria mediate intercellular and inter-organ cross talk in different physiological and stress conditions. To fulfil this task, mitochondrial signalling has evolved distinct and complex conventional and unconventional routes of horizontal/vertical mitochondrial transfer. In this regard, great interest has been focused on the ability of extracellular vesicles (EVs), such as exosomes and microvesicles, to carry selected mitochondrial cargoes to target cells, in response to internal and external cues. Over the past years, the field of mitochondrial EVs (mitoEVs) has grown exponentially, revealing unexpected heterogeneity of these structures associated with an ever-expanding mitochondrial function, though the full extent of the underlying mechanisms is far from being elucidated. Therefore, emerging subsets of EVs encompass exophers, migrasomes, mitophers, mitovesicles, and mitolysosomes that can act locally or over long-distances to restore mitochondrial homeostasis and cell functionality, or to amplify disease. This review provides a comprehensive overview of our current understanding of the biology and trafficking of MitoEVs in different physiological and pathological conditions. Additionally, a specific focus on the role of mitoEVs in aging and the onset and progression of different age-related diseases is discussed.

Keywords:  Age-related diseases; Bioenergetic remodelling; Cancer; Intercellular communication; Mitochondria-specific ectocytosis; Mitochondrial derived vesicles (MDVs); Mitochondrial extracellular vesicles (mitoEVs); Mitochondrial quality control (MQC)

DOI:  https://doi.org/10.1016/j.arr.2024.102522
Nat Genet. 2024 Oct 10.

Human DNA polymerase ε is a source of C>T mutations at CpG dinucleotides.

Marketa Tomkova, Michael John McClellan, Gilles Crevel, Akbar Muhammed Shahid, Nandini Mozumdar, Jakub Tomek, Emelie Shepherd, Sue Cotterill, Benjamin Schuster-Böckler, Skirmantas Kriaucionis.

C-to-T transitions in CpG dinucleotides are the most prevalent mutations in human cancers and genetic diseases. These mutations have been attributed to deamination of 5-methylcytosine (5mC), an epigenetic modification found on CpGs. We recently linked CpG>TpG mutations to replication and hypothesized that errors introduced by polymerase ε (Pol ε) may represent an alternative source of mutations. Here we present a new method called polymerase error rate sequencing (PER-seq) to measure the error spectrum of DNA polymerases in isolation. We find that the most common human cancer-associated Pol ε mutant (P286R) produces an excess of CpG>TpG errors, phenocopying the mutation spectrum of tumors carrying this mutation and deficiencies in mismatch repair. Notably, we also discover that wild-type Pol ε has a sevenfold higher error rate when replicating 5mCpG compared to C in other contexts. Together, our results from PER-seq and human cancers demonstrate that replication errors are a major contributor to CpG>TpG mutagenesis in replicating cells, fundamentally changing our understanding of this important disease-causing mutational mechanism.

DOI: https://doi.org/10.1038/s41588-024-01945-x
Aging Cell. 2024 Oct 11. e14377

Contextualizing aging clocks and properly describing biological age.

Adiv A Johnson, Maxim N Shokhirev.

  Usage of the phrase "biological age" has picked up considerably since the advent of aging clocks and it has become commonplace to describe an aging clock's output as biological age. In contrast to this labeling, biological age is also often depicted as a more abstract concept that helps explain how individuals are aging internally, externally, and functionally. Given that the bulk of molecular aging is tissue-specific and aging itself is a remarkably complex, multifarious process, it is unsurprising that most surveyed scientists agree that aging cannot be quantified via a single metric. We share this sentiment and argue that, just like it would not be reasonable to assume that an individual with an ideal grip strength, VO2 max, or any other aging biomarker is biologically young, we should be careful not to conflate an aging clock with whole-body biological aging. To address this, we recommend that researchers describe the output of an aging clock based on the type of input data used or the name of the clock itself. Epigenetic aging clocks produce epigenetic age, transcriptomic aging clocks produce transcriptomic age, and so forth. If a clock has a unique name, such as our recently developed epigenetic aging clock CheekAge, the name of the clock can double as the output. As a compromise solution, aging biomarkers can be described as indicators of biological age. We feel that these recommendations will help scientists and the public differentiate between aging biomarkers and the much more elusive concept of biological age.

Keywords:  aging biomarker; aging clock; biohorology; biological age; chronological age; mortality

DOI:  https://doi.org/10.1111/acel.14377
bioRxiv. 2024 Sep 28. pii: 2024.09.27.615276. [Epub ahead of print]

Selection promotes age-dependent degeneration of the mitochondrial genome.

Ekaterina Korotkevich, Daniel N Conrad, Zev J Gartner, Patrick H O'Farrell.

Somatic mutations in mitochondrial genomes (mtDNA) accumulate exponentially during aging. Using single cell sequencing, we characterize the spectrum of age-accumulated mtDNA mutations in mouse and human liver and identify directional forces that accelerate the accumulation of mutations beyond the rate predicted by a neutral model. "Driver" mutations that give genomes a replicative advantage rose to high cellular abundance and carried along "passenger" mutations, some of which are deleterious. In addition, alleles that alter mtDNA-encoded proteins selectively increased in abundance overtime, strongly supporting the idea of a "destructive" selection that favors genomes lacking function. Overall, this combination of selective forces acting in hepatocytes promotes somatic accumulation of mutations in coding regions of mtDNA that are otherwise conserved in evolution. We propose that these selective processes could contribute to the population prevalence of mtDNA mutations, accelerate the course of heteroplasmic mitochondrial diseases and promote age-associated erosion of the mitochondrial genome.

DOI: https://doi.org/10.1101/2024.09.27.615276
bioRxiv. 2024 Sep 24. pii: 2024.09.20.614121. [Epub ahead of print]

Germline loss diminishes somatic mitochondria but confers preservation of respiratory function during aging and hypothermia.

Hyejin Hwang, Brandon J Berry, Claudette St Croix, Andrew P Wojtovich, Sruti P Shiva, Arjumand Ghazi.

Reproductive status influences metabolism and health across lifespan in diverse ways and mitochondrial function playing a critical role in mediating this relationship. Using the Caenorhabditis elegans germline ablation model, we investigated the impact of germline stem cell (GSC) loss on mitochondrial dynamics and respiratory function. Our results show that GSC loss reduces mitochondrial volume and respiratory function in young adulthood but preserves mitochondrial activity during aging and upon exposure to hypothermic stress, correlating with enhanced survival. We found that the transcription factor NHR-49/PPARα, but not DAF-16/FOXO3A, was essential for preserving mitochondrial function and hypothermia resistance in these long-lived mutants. Together, these findings reveal the impact of germline signals on somatic mitochondrial health and underscore the intricate relationship between reproductive fitness and organismal health.

DOI: https://doi.org/10.1101/2024.09.20.614121
Nat Aging. 2024 Oct 08.

The brain-body energy conservation model of aging.

Evan D Shaulson, Alan A Cohen, Martin Picard.

Aging involves seemingly paradoxical changes in energy metabolism. Molecular damage accumulation increases cellular energy expenditure, yet whole-body energy expenditure remains stable or decreases with age. We resolve this apparent contradiction by positioning the brain as the mediator and broker in the organismal energy economy. As somatic tissues accumulate damage over time, costly intracellular stress responses are activated, causing aging or senescent cells to secrete cytokines that convey increased cellular energy demand (hypermetabolism) to the brain. To conserve energy in the face of a shrinking energy budget, the brain deploys energy conservation responses, which suppress low-priority processes, producing fatigue, physical inactivity, blunted sensory capacities, immune alterations and endocrine 'deficits'. We term this cascade the brain-body energy conservation (BEC) model of aging. The BEC outlines (1) the energetic cost of cellular aging, (2) how brain perception of senescence-associated hypermetabolism may drive the phenotypic manifestations of aging and (3) energetic principles underlying the modifiability of aging trajectories by stressors and geroscience interventions.

DOI: https://doi.org/10.1038/s43587-024-00716-x
EBioMedicine. 2024 Oct 10. pii: S2352-3964(24)00425-0. [Epub ahead of print]109 105389

Single cell atlas reveals multilayered metabolic heterogeneity across tumour types.

Zhe Zhou, Di Dong, Yuyao Yuan, Juan Luo, Xiao-Ding Liu, Long-Yun Chen, Guangxi Wang, Yuxin Yin.

  BACKGROUND: Metabolic reprogramming plays a pivotal role in cancer progression, contributing to substantial intratumour heterogeneity and influencing tumour behaviour. However, a systematic characterization of metabolic heterogeneity across multiple cancer types at the single-cell level remains limited.METHODS: We integrated 296 tumour and normal samples spanning six common cancer types to construct a single-cell compendium of metabolic gene expression profiles and identify cell type-specific metabolic properties and reprogramming patterns. A computational approach based on non-negative matrix factorization (NMF) was utilised to identify metabolic meta-programs (MMPs) showing intratumour heterogeneity. In-vitro cell experiments were conducted to confirm the associations between MMPs and chemotherapy resistance, as well as the function of key metabolic regulators. Survival analyses were performed to assess clinical relevance of cellular metabolic properties.
FINDINGS: Our analysis revealed shared glycolysis upregulation and divergent regulation of citric acid cycle across different cell types. In malignant cells, we identified a colorectal cancer-specific MMP associated with resistance to the cuproptosis inducer elesclomol, validated through in-vitro cell experiments. Furthermore, our findings enabled the stratification of patients into distinct prognostic subtypes based on metabolic properties of specific cell types, such as myeloid cells.
INTERPRETATION: This study presents a nuanced understanding of multilayered metabolic heterogeneity, offering valuable insights into potential personalized therapies targeting tumour metabolism.
FUNDING: National Key Research and Development Program of China (2021YFA1300601). National Natural Science Foundation of China (key grants 82030081 and 81874235). The Shenzhen High-level Hospital Construction Fund and Shenzhen Basic Research Key Project (JCYJ20220818102811024). The Lam Chung Nin Foundation for Systems Biomedicine.

Keywords:  Cancer metabolism; Chemotherapy resistance; Metabolic heterogeneity; Pan-cancer analysis; scRNA-seq

DOI:  https://doi.org/10.1016/j.ebiom.2024.105389
Proc Natl Acad Sci U S A. 2024 Oct 15. 121(42): e2411672121

Nuclear compensatory evolution driven by mito-nuclear incompatibilities.

Debora Princepe, Marcus A M de Aguiar.

  Mitochondrial function relies on the coordinated expression of mitochondrial and nuclear genes, exhibiting remarkable resilience despite high mitochondrial mutation rates. The nuclear compensation mechanism suggests deleterious mitochondrial alleles drive compensatory nuclear mutations to preserve mito-nuclear compatibility. However, prevalence and factors conditioning this phenomenon remain debated due to its conflicting evidence. Here, we investigate how mito-nuclear incompatibilities impact substitutions in a model for species radiation. Mating success depends on genetic compatibility (nuclear DNA) and spatial proximity. Populations evolve from partially compatible mito-nuclear states, simulating mitochondrial DNA (mtDNA) introgression. Mutations do not confer advantages nor disadvantages, but individual fecundity declines with increasing incompatibilities, selecting for mito-nuclear coordination. We find that selection for mito-nuclear compatibility affects each genome differently based on their initial state. In compatible gene pairs, selection reduces substitutions in both genomes, while in incompatible nuclear genes, it consistently promotes compensation, facilitated by more mismatches. Interestingly, high mitochondrial mutation rates can reduce nuclear compensation by increasing mtDNA rectification, while substitutions in initially compatible nuclear gene are boosted. Finally, the presence of incompatibilities accelerates species radiation, but equilibrium richness is not directly correlated to substitution rates, revealing the complex dynamics triggered by mitochondrial introgression and mito-nuclear coevolution. Our study provides a perspective on nuclear compensation and the role of mito-nuclear incompatibilities in speciation by exploring extreme scenarios and identifying trends that empirical data alone cannot reveal. We emphasize the challenges in detecting these dynamics and propose analyzing specific genomic signatures could shed light on this evolutionary process.

Keywords:  mito-nuclear coevolution; mitochondrial mutation rate; mtDNA introgression; nuclear compensation

DOI:  https://doi.org/10.1073/pnas.2411672121
bioRxiv. 2024 Sep 27. pii: 2024.09.26.615177. [Epub ahead of print]

Endocrine persistence in ER+ breast cancer is accompanied by metabolic vulnerability in oxidative phosphorylation.

Steven Tau, Mary D Chamberlin, Huijuan Yang, Jonathan D Marotti, Alyssa M Roberts, Melissa M Carmichael, Lauren Cressey, Christo Dragnev, Eugene Demidenko, Riley A Hampsch, Shannon M Soucy, Fred Kolling, Kimberley S Samkoe, James V Alvarez, Arminja N Kettenbach, Todd W Miller.

Despite adjuvant treatment with endocrine therapies, estrogen receptor-positive (ER+) breast cancers recur in a significant proportion of patients. Recurrences are attributable to clinically undetectable endocrine-tolerant persister cancer cells that retain tumor-forming potential. Therefore, strategies targeting such persister cells may prevent recurrent disease. Using CRISPR-Cas9 genome-wide knockout screening in ER+ breast cancer cells, we identified a survival mechanism involving metabolic reprogramming with reliance upon mitochondrial respiration in endocrine-tolerant persister cells. Quantitative proteomic profiling showed reduced levels of glycolytic proteins in persisters. Metabolic tracing of glucose revealed an energy-depleted state in persisters where oxidative phosphorylation was required to generate ATP. A phase II clinical trial was conducted to evaluate changes in mitochondrial markers in primary ER+/HER2-breast tumors induced by neoadjuvant endocrine therapy ( NCT04568616 ). In an analysis of tumor specimens from 32 patients, tumors exhibiting residual cell proliferation after aromatase inhibitor-induced estrogen deprivation with letrozole showed increased mitochondrial content. Genetic profiling and barcode lineage tracing showed that endocrine-tolerant persistence occurred stochastically without genetic predisposition. Mice bearing cell line- and patient-derived xenografts were used to measure the anti-tumor effects of mitochondrial complex I inhibition in the context of endocrine therapy. Pharmacological inhibition of complex I suppressed the tumor-forming potential of persisters and synergized with the anti-estrogen fulvestrant to induce regression of patient-derived xenografts. These findings indicate that mitochondrial metabolism is essential in endocrine-tolerant persister ER+ breast cancer cells and warrant the development of treatment strategies to leverage this vulnerability in the context of endocrine-sensitive disease.Statement of Significance: Endocrine-tolerant persister cancer cells that survive endocrine therapy can cause recurrent disease. Persister cells exhibit increased energetic dependence upon mitochondria for survival and tumor re-growth potential.

DOI: https://doi.org/10.1101/2024.09.26.615177
Nat Commun. 2024 Oct 11. 15(1): 8685

An automated network-based tool to search for metabolic vulnerabilities in cancer.

Luis V Valcárcel, Edurne San José-Enériz, Raquel Ordoñez, Iñigo Apaolaza, Danel Olaverri-Mendizabal, Naroa Barrena, Ana Valcárcel, Leire Garate, Jesús San Miguel, Antonio Pineda-Lucena, Xabier Agirre, Felipe Prósper, Francisco J Planes.

The development of computational tools for the systematic prediction of metabolic vulnerabilities of cancer cells constitutes a central question in systems biology. Here, we present gmctool, a freely accessible online tool that allows us to accomplish this task in a simple, efficient and intuitive environment. gmctool exploits the concept of genetic Minimal Cut Sets (gMCSs), a theoretical approach to synthetic lethality based on genome-scale metabolic networks, including a unique database of synthetic lethals computed from Human1, the most recent metabolic reconstruction of human cells. gmctool introduces qualitative and quantitative improvements over our previously developed algorithms to predict, visualize and analyze metabolic vulnerabilities in cancer, demonstrating a superior performance than competing algorithms. A detailed illustration of gmctool is presented for multiple myeloma (MM), an incurable hematological malignancy. We provide in vitro experimental evidence for the essentiality of CTPS1 (CTPS synthase) and UAP1 (UDP-N-Acetylglucosamine Pyrophosphorylase 1) in specific MM patient subgroups.

DOI: https://doi.org/10.1038/s41467-024-52725-4