bims-camemi 2023-07-02 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2023‒07‒02
forty-one papers selected by
Christian Frezza, Universität zu Köln

Mitochondrial uncoupling inhibits reductive carboxylation in cancer cells.
Single-cell multi-omics of mitochondrial DNA disorders reveals dynamics of purifying selection across human immune cells.
Exercise increases the metabolic benefits of weight loss.
Circadian mechanisms in adipose tissue bioenergetics and plasticity.
Reprogramming tumour-associated macrophages to outcompete cancer cells.
The mitochondrial Ca2+ channel MCU is critical for tumor growth by supporting cell cycle progression and proliferation.
Aurora kinase A/AURKA functionally interacts with the mitochondrial ATP synthase to regulate energy metabolism and cell death.
Beggars banquet: Metabolism in the tumor immune microenvironment and cancer therapy.
Metabolic orchestration of cell death by AMPK-mediated phosphorylation of RIPK1.
mTORC2-NDRG1-CDC42 axis couples fasting to mitochondrial fission.
The unfolded protein response of the endoplasmic reticulum supports mitochondrial biogenesis by buffering non-imported proteins.
Neural stem cell metabolism revisited: a critical role for mitochondria.
Nicotinamide Riboside Improves Cardiac Function and Prolongs Survival After Disruption of the Cardiomyocyte Clock.
Targeting Fatty Acid Reprogramming Suppresses CARM1-expressing Ovarian Cancer.
Mitochondrial fitness sustains healthy muscle aging.
Flux estimation analysis systematically characterizes the metabolic shifts of the central metabolism pathway in human cancer.
Human peroxisomal NAD+/NADH homeostasis is regulated by two independent NAD(H) shuttle systems.
The bidirectional relationship between metabolism and cell cycle control.
Loss of chromosome Y in primary tumors.
Fifty years of the mitochondrial pyruvate carrier: New insights into its structure, function, and inhibition.
Mitochondrial control of sleep.
Energetic Stress-Induced Metabolic Regulation by Extracellular Vesicles.
Mitochondrial transfer from cancer associated fibroblasts increases migration in aggressive breast cancer.
Oxygen availability and body mass modulate ectotherm responses to ocean warming.
Critical role of antioxidant programs in enzalutamide-resistant prostate cancer.
Interferon signaling promotes tolerance to chromosomal instability during metastatic evolution in renal cancer.
cGLRs are a diverse family of pattern recognition receptors in innate immunity.
Circadian clocks are modulated by compartmentalized oscillating translation.
Mechanical control of the mammalian circadian clock via YAP/TAZ and TEAD.
5-Aminolevulinic acid bypasses mitochondrial complex I deficiency and corrects physiological dysfunctions in Drosophila.
Lysine metabolism at the nexus of crotonylation and tumor immunity.
Phase separation of FSP1 promotes ferroptosis.
Lysosomal LAMP proteins regulate lysosomal pH by direct inhibition of the TMEM175 channel.
A cancer-associated METTL14 mutation induces aberrant m6A modification, affecting tumor growth.
Cancer aneuploidies are shaped primarily by effects on tumour fitness.
Dietary restriction mitigates the age-associated decline in mouse B cell receptor repertoire diversity.
Single-cell multiomic analyses sheds light on mitochondrial mutational selection.
A spatially resolved single-cell genomic atlas of the adult human breast.
Long noncoding RNA MALAT1 is dynamically regulated in leader cells during collective cancer invasion.
Raman-stable isotope technology for tracking single-cell plant metabolism.
Spatially resolved single-cell translatomics at molecular resolution.

Mol Cancer Res. 2023 Jun 26. pii: MCR-23-0049. [Epub ahead of print]

Mitochondrial uncoupling inhibits reductive carboxylation in cancer cells.

Haowen Jiang, Clifford Jiajun He, Albert M Li, Bo He, Yang Li, Meng-Ning Zhou, Jiangbin Ye.

When the electron transport chain (ETC) function is impaired, cancer cells rely on reductive carboxylation (RC) to convert α-ketoglutarate (αKG) to citrate for macromolecular synthesis, thereby promoting tumor growth. Currently, there is no viable therapy to inhibit RC for cancer treatment. In this study, we demonstrate that the mitochondrial uncoupler treatment effectively inhibits RC in cancer cells. Mitochondrial uncoupler treatment activates the ETC and increases the NAD+/NADH ratio. Using U-13C-glutamine and 1-13C-glutamine tracers, we show that mitochondrial uncoupling accelerates the oxidative TCA cycle and blocks RC under hypoxia, in von Hippel-Lindau (VHL) tumor suppressor-deficient kidney cancer cells, or under anchorage-independent growth condition. Together, these data demonstrate that mitochondrial uncoupling redirects α-KG from RC back to the oxidative TCA cycle, highlighting that the NAD+/NADH ratio is one key switch that determines the metabolic fate of α-KG. Inhibiting RC could be a key mechanism by which mitochondrial uncouplers inhibit tumor growth.

DOI: https://doi.org/10.1158/1541-7786.MCR-23-0049
Nat Genet. 2023 Jun 29.

Single-cell multi-omics of mitochondrial DNA disorders reveals dynamics of purifying selection across human immune cells.

Caleb A Lareau, Sonia M Dubois, Frank A Buquicchio, Yu-Hsin Hsieh, Kopal Garg, Pauline Kautz, Lena Nitsch, Samantha D Praktiknjo, Patrick Maschmeyer, Jeffrey M Verboon, Jacob C Gutierrez, Yajie Yin, Evgenij Fiskin, Wendy Luo, Eleni P Mimitou, Christoph Muus, Rhea Malhotra, Sumit Parikh, Mark D Fleming, Lena Oevermann, Johannes Schulte, Cornelia Eckert, Anshul Kundaje, Peter Smibert, Santosha A Vardhana, Ansuman T Satpathy, Aviv Regev, Vijay G Sankaran, Suneet Agarwal, Leif S Ludwig.

Pathogenic mutations in mitochondrial DNA (mtDNA) compromise cellular metabolism, contributing to cellular heterogeneity and disease. Diverse mutations are associated with diverse clinical phenotypes, suggesting distinct organ- and cell-type-specific metabolic vulnerabilities. Here we establish a multi-omics approach to quantify deletions in mtDNA alongside cell state features in single cells derived from six patients across the phenotypic spectrum of single large-scale mtDNA deletions (SLSMDs). By profiling 206,663 cells, we reveal the dynamics of pathogenic mtDNA deletion heteroplasmy consistent with purifying selection and distinct metabolic vulnerabilities across T-cell states in vivo and validate these observations in vitro. By extending analyses to hematopoietic and erythroid progenitors, we reveal mtDNA dynamics and cell-type-specific gene regulatory adaptations, demonstrating the context-dependence of perturbing mitochondrial genomic integrity. Collectively, we report pathogenic mtDNA heteroplasmy dynamics of individual blood and immune cells across lineages, demonstrating the power of single-cell multi-omics for revealing fundamental properties of mitochondrial genetics.

DOI: https://doi.org/10.1038/s41588-023-01433-8
Nat Metab. 2023 Jun 26.

Exercise increases the metabolic benefits of weight loss.

DOI: https://doi.org/10.1038/s42255-023-00842-7
Genes Dev. 2023 Jun 26.

Circadian mechanisms in adipose tissue bioenergetics and plasticity.

Chelsea Hepler, Joseph Bass.

  The circadian clock plays an essential role in coordinating feeding and metabolic rhythms with the light/dark cycle. Disruption of clocks is associated with increased adiposity and metabolic disorders, whereas aligning feeding time with cell-autonomous rhythms in metabolism improves health. Here, we provide a comprehensive overview of recent literature in adipose tissue biology as well as our understanding of molecular mechanisms underlying the circadian regulation of transcription, metabolism, and inflammation in adipose tissue. We highlight recent efforts to uncover the mechanistic links between clocks and adipocyte metabolism, as well as its application to dietary and behavioral interventions to improve health and mitigate obesity.

Keywords:  adipocyte; adipose tissue; circadian clock; circadian rhythms; inflammation; metabolism; plasticity; thermogenesis; transcription

DOI:  https://doi.org/10.1101/gad.350759.123
Nature. 2023 Jun 28.

Reprogramming tumour-associated macrophages to outcompete cancer cells.

Xian Zhang, Shun Li, Isha Malik, Mytrang H Do, Liangliang Ji, Chun Chou, Wei Shi, Kristelle J Capistrano, Jing Zhang, Ting-Wei Hsu, Briana G Nixon, Ke Xu, Xinxin Wang, Andrea Ballabio, Laura S Schmidt, W Marston Linehan, Ming O Li.

In metazoan organisms, cell competition acts as a quality control mechanism to eliminate unfit cells in favour of their more robust neighbours1,2. This mechanism has the potential to be maladapted, promoting the selection of aggressive cancer cells3-6. Tumours are metabolically active and are populated by stroma cells7,8, but how environmental factors affect cancer cell competition remains largely unknown. Here we show that tumour-associated macrophages (TAMs) can be dietarily or genetically reprogrammed to outcompete MYC-overexpressing cancer cells. In a mouse model of breast cancer, MYC overexpression resulted in an mTORC1-dependent 'winner' cancer cell state. A low-protein diet inhibited mTORC1 signalling in cancer cells and reduced tumour growth, owing unexpectedly to activation of the transcription factors TFEB and TFE3 and mTORC1 in TAMs. Diet-derived cytosolic amino acids are sensed by Rag GTPases through the GTPase-activating proteins GATOR1 and FLCN to control Rag GTPase effectors including TFEB and TFE39-14. Depletion of GATOR1 in TAMs suppressed the activation of TFEB, TFE3 and mTORC1 under the low-protein diet condition, causing accelerated tumour growth; conversely, depletion of FLCN or Rag GTPases in TAMs activated TFEB, TFE3 and mTORC1 under the normal protein diet condition, causing decelerated tumour growth. Furthermore, mTORC1 hyperactivation in TAMs and cancer cells and their competitive fitness were dependent on the endolysosomal engulfment regulator PIKfyve. Thus, noncanonical engulfment-mediated Rag GTPase-independent mTORC1 signalling in TAMs controls competition between TAMs and cancer cells, which defines a novel innate immune tumour suppression pathway that could be targeted for cancer therapy.

DOI: https://doi.org/10.1038/s41586-023-06256-5
Front Cell Dev Biol. 2023 ;11 1082213

The mitochondrial Ca2+ channel MCU is critical for tumor growth by supporting cell cycle progression and proliferation.

Emily Fernandez Garcia, Usha Paudel, Michael C Noji, Caitlyn E Bowman, Anil K Rustgi, Jason R Pitarresi, Kathryn E Wellen, Zolt Arany, Jillian S Weissenrieder, J Kevin Foskett.

  Introduction: The mitochondrial uniporter (MCU) Ca2+ ion channel represents the primary means for Ca2+ uptake by mitochondria. Mitochondrial matrix Ca2+ plays critical roles in mitochondrial bioenergetics by impinging upon respiration, energy production and flux of biochemical intermediates through the TCA cycle. Inhibition of MCU in oncogenic cell lines results in an energetic crisis and reduced cell proliferation unless media is supplemented with nucleosides, pyruvate or α-KG. Nevertheless, the roles of MCU-mediated Ca2+ influx in cancer cells remain unclear, in part because of a lack of genetic models. Methods: MCU was genetically deleted in transformed murine fibroblasts for study in vitro and in vivo. Tumor formation and growth were studied in murine xenograft models. Proliferation, cell invasion, spheroid formation and cell cycle progression were measured in vitro. The effects of MCU deletion on survival and cell-death were determined by probing for live/death markers. Mitochondrial bioenergetics were studied by measuring mitochondrial matrix Ca2+ concentration, membrane potential, global dehydrogenase activity, respiration, ROS production and inactivating-phosphorylation of pyruvate dehydrogenase. The effects of MCU rescue on metabolism were examined by tracing of glucose and glutamine utilization for fueling of mitochondrial respiration. Results: Transformation of primary fibroblasts in vitro was associated with increased MCU expression, enhanced MCU-mediated Ca2+ uptake, altered mitochondrial matrix Ca2+ concentration responses to agonist stimulation, suppression of inactivating-phosphorylation of pyruvate dehydrogenase and a modest increase of mitochondrial respiration. Genetic MCU deletion inhibited growth of HEK293T cells and transformed fibroblasts in mouse xenograft models, associated with reduced proliferation and delayed cell-cycle progression. MCU deletion inhibited cancer stem cell-like spheroid formation and cell invasion in vitro, both predictors of metastatic potential. Surprisingly, mitochondrial matrix [Ca2+], membrane potential, global dehydrogenase activity, respiration and ROS production were unaffected. In contrast, MCU deletion elevated glycolysis and glutaminolysis, strongly sensitized cell proliferation to glucose and glutamine limitation, and altered agonist-induced cytoplasmic Ca2+ signals. Conclusion: Our results reveal a dependence of tumorigenesis on MCU, mediated by a reliance on MCU for cell metabolism and Ca2+ dynamics necessary for cell-cycle progression and cell proliferation.

Keywords:  calcium; cancer; metabolism; mitochondria; stable isotope tracing; uniporter

DOI:  https://doi.org/10.3389/fcell.2023.1082213
Cell Death Discov. 2023 Jun 29. 9(1): 203

Aurora kinase A/AURKA functionally interacts with the mitochondrial ATP synthase to regulate energy metabolism and cell death.

Rakesh Kumar Sharma, Abderrahman Chafik, Giulia Bertolin.

Cancer cells often hijack metabolic pathways to obtain the energy required to sustain their proliferation. Understanding the molecular mechanisms underlying cancer cell metabolism is key to fine-tune the metabolic preference of specific tumors, and potentially offer new therapeutic strategies. Here, we show that the pharmacological inhibition of mitochondrial Complex V delays the cell cycle by arresting breast cancer cell models in the G0/G1 phase. Under these conditions, the abundance of the multifunctional protein Aurora kinase A/AURKA is specifically lowered. We then demonstrate that AURKA functionally interacts with the mitochondrial Complex V core subunits ATP5F1A and ATP5F1B. Altering the AURKA/ATP5F1A/ATP5F1B nexus is sufficient to trigger G0/G1 arrest, and this is accompanied by decreased glycolysis and mitochondrial respiration rates. Last, we discover that the roles of the AURKA/ATP5F1A/ATP5F1B nexus depend on the specific metabolic propensity of triple-negative breast cancer cell lines, where they correlate with cell fate. On one hand, the nexus induces G0/G1 arrest in cells relying on oxidative phosphorylation as the main source of energy. On the other hand, it allows to bypass cell cycle arrest and it triggers cell death in cells with a glycolytic metabolism. Altogether, we provide evidence that AURKA and mitochondrial Complex V subunits cooperate to maintain cell metabolism in breast cancer cells. Our work paves the way to novel anti-cancer therapies targeting the AURKA/ATP5F1A/ATP5F1B nexus to lower cancer cell metabolism and proliferation.

DOI: https://doi.org/10.1038/s41420-023-01501-2
Cell Metab. 2023 Jun 20. pii: S1550-4131(23)00213-9. [Epub ahead of print]

Beggars banquet: Metabolism in the tumor immune microenvironment and cancer therapy.

Weiping Zou, Douglas R Green.

  Metabolic programming in the tumor microenvironment (TME) alters tumor immunity and immunotherapeutic response in tumor-bearing mice and patients with cancer. Here, we review immune-related functions of core metabolic pathways, key metabolites, and crucial nutrient transporters in the TME, discuss their metabolic, signaling, and epigenetic impact on tumor immunity and immunotherapy, and explore how these insights can be applied to the development of more effective modalities to potentiate the function of T cells and sensitize tumor cell receptivity to immune attack, thereby overcoming therapeutic resistance.

Keywords:  T cell; checkpoint; immunotherapy; metabolism; metabolite; tumor microenvironment

DOI:  https://doi.org/10.1016/j.cmet.2023.06.003
Science. 2023 Jun 30. 380(6652): 1372-1380

Metabolic orchestration of cell death by AMPK-mediated phosphorylation of RIPK1.

Tao Zhang, Daichao Xu, Elijah Trefts, Mingming Lv, Hiroyuki Inuzuka, Guobin Song, Min Liu, Jianlin Lu, Jianping Liu, Chen Chu, Min Wang, Huibing Wang, Huyan Meng, Hui Liu, Yuan Zhuang, Xingxing Xie, Fabin Dang, Dongxian Guan, Yuqin Men, Shuwen Jiang, Cong Jiang, Xiaoming Dai, Jing Liu, Zhen Wang, Peiqiang Yan, Jingchao Wang, Zhenbo Tu, Mrigya Babuta, Emily Erickson, Alissandra L Hillis, Christian C Dibble, John M Asara, Gyongy Szabo, Piotr Sicinski, Ji Miao, Yu-Ru Lee, Lifeng Pan, Reuben J Shaw, Junying Yuan, Wenyi Wei.

Adenosine monophosphate-activated protein kinase (AMPK) activity is stimulated to promote metabolic adaptation upon energy stress. However, sustained metabolic stress may cause cell death. The mechanisms by which AMPK dictates cell death are not fully understood. We report that metabolic stress promoted receptor-interacting protein kinase 1 (RIPK1) activation mediated by TRAIL receptors, whereas AMPK inhibited RIPK1 by phosphorylation at Ser415 to suppress energy stress-induced cell death. Inhibiting pS415-RIPK1 by Ampk deficiency or RIPK1 S415A mutation promoted RIPK1 activation. Furthermore, genetic inactivation of RIPK1 protected against ischemic injury in myeloid Ampkα1-deficient mice. Our studies reveal that AMPK phosphorylation of RIPK1 represents a crucial metabolic checkpoint, which dictates cell fate response to metabolic stress, and highlight a previously unappreciated role for the AMPK-RIPK1 axis in integrating metabolism, cell death, and inflammation.

DOI: https://doi.org/10.1126/science.abn1725
Nat Cell Biol. 2023 Jun 29.

mTORC2-NDRG1-CDC42 axis couples fasting to mitochondrial fission.

Nuria Martinez-Lopez, Pamela Mattar, Miriam Toledo, Henrietta Bains, Manu Kalyani, Marie Louise Aoun, Mridul Sharma, Laura Beth J McIntire, Leslie Gunther-Cummins, Frank P Macaluso, Jennifer T Aguilan, Simone Sidoli, Mathieu Bourdenx, Rajat Singh.

Fasting triggers diverse physiological adaptations including increases in circulating fatty acids and mitochondrial respiration to facilitate organismal survival. The mechanisms driving mitochondrial adaptations and respiratory sufficiency during fasting remain incompletely understood. Here we show that fasting or lipid availability stimulates mTORC2 activity. Activation of mTORC2 and phosphorylation of its downstream target NDRG1 at serine 336 sustains mitochondrial fission and respiratory sufficiency. Time-lapse imaging shows that NDRG1, but not the phosphorylation-deficient NDRG1Ser336Ala mutant, engages with mitochondria to facilitate fission in control cells, as well as in those lacking DRP1. Using proteomics, a small interfering RNA screen, and epistasis experiments, we show that mTORC2-phosphorylated NDRG1 cooperates with small GTPase CDC42 and effectors and regulators of CDC42 to orchestrate fission. Accordingly, RictorKO, NDRG1Ser336Ala mutants and Cdc42-deficient cells each display mitochondrial phenotypes reminiscent of fission failure. During nutrient surplus, mTOR complexes perform anabolic functions; however, paradoxical reactivation of mTORC2 during fasting unexpectedly drives mitochondrial fission and respiration.

DOI: https://doi.org/10.1038/s41556-023-01163-3
Mol Biol Cell. 2023 Jun 28. mbcE23050205

The unfolded protein response of the endoplasmic reticulum supports mitochondrial biogenesis by buffering non-imported proteins.

Katharina Knöringer, Carina Groh, Lena Krämer, Kevin C Stein, Katja G Hansen, Jannik Zimmermann, Bruce Morgan, Johannes M Herrmann, Judith Frydman, Felix Boos.

Almost all mitochondrial proteins are synthesized in the cytosol and subsequently targeted to mitochondria. The accumulation of non-imported precursor proteins occurring upon mitochondrial dysfunction can challenge cellular protein homeostasis. Here we show that blocking protein translocation into mitochondria results in the accumulation of mitochondrial membrane proteins at the endoplasmic reticulum, thereby triggering the unfolded protein response (UPRER). Moreover, we find that mitochondrial membrane proteins are also routed to the ER under physiological conditions. The level of ER-resident mitochondrial precursors is enhanced by import defects as well as metabolic stimuli that increase the expression of mitochondrial proteins. Under such conditions, the UPRER is crucial to maintain protein homeostasis and cellular fitness. We propose the ER serves as a physiological buffer zone for those mitochondrial precursors that cannot be immediately imported into mitochondria while engaging the UPRER to adjust the ER proteostasis capacity to the extent of precursor accumulation.

DOI: https://doi.org/10.1091/mbc.E23-05-0205
Trends Endocrinol Metab. 2023 Jun 26. pii: S1043-2760(23)00110-8. [Epub ahead of print]

Neural stem cell metabolism revisited: a critical role for mitochondria.

Valentina Scandella, Francesco Petrelli, Darcie L Moore, Simon M G Braun, Marlen Knobloch.

  Metabolism has emerged as a key regulator of stem cell behavior. Mitochondria are crucial metabolic organelles that are important for differentiated cells, yet considered less so for stem cells. However, recent studies have shown that mitochondria influence stem cell maintenance and fate decisions, inviting a revised look at this topic. In this review, we cover the current literature addressing the role of mitochondrial metabolism in mouse and human neural stem cells (NSCs) in the embryonic and adult brain. We summarize how mitochondria are implicated in fate regulation and how substrate oxidation affects NSC quiescence. We further explore single-cell RNA sequencing (scRNA-seq) data for metabolic signatures of adult NSCs, highlight emerging technologies reporting on metabolic signatures, and discuss mitochondrial metabolism in other stem cells.

Keywords:  metabolism; mitochondria; neural stem cells; quiescence

DOI:  https://doi.org/10.1016/j.tem.2023.05.008
Front Mol Med. 2022 ;pii: 887733. [Epub ahead of print]2

Nicotinamide Riboside Improves Cardiac Function and Prolongs Survival After Disruption of the Cardiomyocyte Clock.

Pieterjan Dierickx, Bryce J Carpenter, Isaac Celwyn, Daniel P Kelly, Joseph A Baur, Mitchell A Lazar.

  The REV-ERB nuclear receptors are key components of the circadian clock. Loss of REV-ERBs in the mouse heart causes dilated cardiomyopathy and premature lethality. This is associated with a marked reduction in NAD+ production, but whether this plays a role in the pathophysiology of this heart failure model is not known. Here, we show that supplementation with the NAD+ precursor NR as a dietary supplement improves heart function and extends the lifespan of female mice lacking cardiac REV-ERBs. Thus, boosting NAD+ levels can improve cardiac function in a setting of heart failure caused by disruption of circadian clock factors, providing new insights into the links between the circadian clock, energy metabolism, and cardiac function.

Keywords:  NAD+; cardiac metabolism; circadian clock; heart failure; nuclear hormone receptors

DOI:  https://doi.org/10.3389/fmmed.2022.887733
Cancer Res Commun. 2023 Jun;3(6): 1067-1077

Targeting Fatty Acid Reprogramming Suppresses CARM1-expressing Ovarian Cancer.

Simona Lombardi, Aaron R Goldman, Hsin-Yao Tang, Andrew V Kossenkov, Heng Liu, Wei Zhou, Meenhard Herlyn, Jianhuang Lin, Rugang Zhang.

The arginine methyltransferase CARM1 exhibits high expression levels in several human cancers, with the trend also observed in ovarian cancer. However, therapeutic approaches targeting tumors that overexpress CARM1 have not been explored. Cancer cells exploit metabolic reprogramming such as fatty acids for their survival. Here we report that CARM1 promotes monounsaturated fatty acid synthesis and fatty acid reprogramming represents a metabolic vulnerability for CARM1-expressing ovarian cancer. CARM1 promotes the expression of genes encoding rate-limiting enzymes of de novo fatty acid metabolism such as acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FASN). In addition, CARM1 upregulates stearoyl-CoA desaturase 1 (SCD1) that produces monounsaturated fatty acid by desaturation. Thus, CARM1 enhances de novo fatty acids synthesis which was subsequently utilized for synthesis of monounsaturated fatty acids. Consequently, inhibition of SCD1 suppresses the growth of ovarian cancer cells in a CARM1 status-dependent manner, which was rescued by the addition of monounsaturated fatty acids. Consistently, CARM1-expressing cells were more tolerant to the addition of saturated fatty acids. Indeed, SCD1 inhibition demonstrated efficacy against ovarian cancer in both orthotopic xenograft and syngeneic mouse models in a CARM1-dependent manner. In summary, our data show that CARM1 reprograms fatty acid metabolism and targeting SCD1 through pharmacological inhibition can serve as a potent therapeutic approach for CARM1-expressing ovarian cancers.Significance: CARM1 reprograms fatty acid metabolism transcriptionally to support ovarian cancer growth by producing monounsaturated fatty acids, supporting SCD1 inhibition as a rational strategy for treating CARM1-expressing ovarian cancer.

DOI: https://doi.org/10.1158/2767-9764.CRC-23-0030
Aging (Albany NY). 2023 Jun 24. 15

Mitochondrial fitness sustains healthy muscle aging.

Andrea Irazoki, Antonio Zorzano, David Sebastián.



Keywords:  aging; mitochondria; mitochondrial dynamics; mitophagy; sarcopenia

DOI:  https://doi.org/10.18632/aging.204857
Front Oncol. 2023 ;13 1117810

Flux estimation analysis systematically characterizes the metabolic shifts of the central metabolism pathway in human cancer.

Grace Yang, Shaoyang Huang, Kevin Hu, Alex Lu, Jonathan Yang, Noah Meroueh, Pengtao Dang, Yijie Wang, Haiqi Zhu, Sha Cao, Chi Zhang.

  Introduction: Glucose and glutamine are major carbon and energy sources that promote the rapid proliferation of cancer cells. Metabolic shifts observed on cell lines or mouse models may not reflect the general metabolic shifts in real human cancer tissue.Method: In this study, we conducted a computational characterization of the flux distribution and variations of the central energy metabolism and key branches in a pan-cancer analysis, including the glycolytic pathway, production of lactate, tricarboxylic acid (TCA) cycle, nucleic acid synthesis, glutaminolysis, glutamate, glutamine, and glutathione metabolism, and amino acid synthesis, in 11 cancer subtypes and nine matched adjacent normal tissue types using TCGA transcriptomics data.
Result: Our analysis confirms the increased influx in glucose uptake and glycolysis and decreased upper part of the TCA cycle, i.e., the Warburg effect, in almost all the analyzed cancer. However, increased lactate production and the second half of the TCA cycle were only seen in certain cancer types. More interestingly, we failed to detect significantly altered glutaminolysis in cancer tissues compared to their adjacent normal tissues. A systems biology model of metabolic shifts through cancer and tissue types is further developed and analyzed. We observed that (1) normal tissues have distinct metabolic phenotypes; (2) cancer types have drastically different metabolic shifts compared to their adjacent normal controls; and (3) the different shifts in tissue-specific metabolic phenotypes result in a converged metabolic phenotype through cancer types and cancer progression.
Discussion: This study strongly suggests the possibility of having a unified framework for studies of cancer-inducing stressors, adaptive metabolic reprogramming, and cancerous behaviors.

Keywords:  TCA cycle; cancer metabolism; flux estimation; glutaminolysis; systems biology

DOI:  https://doi.org/10.3389/fonc.2023.1117810
Free Radic Biol Med. 2023 Jun 22. pii: S0891-5849(23)00507-5. [Epub ahead of print]

Human peroxisomal NAD+/NADH homeostasis is regulated by two independent NAD(H) shuttle systems.

Serhii Chornyi, Cláudio F Costa, Lodewijk IJlst, Marc Fransen, Ronald J A Wanders, Carlo W T van Roermund, Hans R Waterham.

  Reduced (NADH) and oxidized (NAD+) nicotinamide adenine dinucleotides are ubiquitous hydride-donating/accepting cofactors that are essential for cellular bioenergetics. Peroxisomes are single-membrane-bounded organelles that are involved in multiple lipid metabolism pathways, including beta-oxidation of fatty acids, and which contain several NAD(H)-dependent enzymes. Although maintenance of NAD(H) homeostasis in peroxisomes is considered essential for peroxisomal beta-oxidation, little is known about the regulation thereof. To resolve this issue, we have developed methods to specifically measure intraperoxisomal NADH levels in human cells using peroxisome-targeted NADH biosensors. By targeted CRISPR-Cas9-mediated genome editing of human cells, we showed with these sensors that the NAD+/NADH ratio in cytosol and peroxisomes are closely connected and that this crosstalk is mediated by intraperoxisomal lactate and malate dehydrogenases, generated via translational stop codon readthrough of the LDHB and MDH1 mRNAs. Our study provides evidence for the existence of two independent redox shuttle systems in human peroxisomes that regulate peroxisomal NAD+/NADH homeostasis. This is the first study that shows a specific metabolic function of protein isoforms generated by translational stop codon readthrough in humans.

Keywords:  Beta-oxidation; Bioenergetics; Cofactor; Dehydrogenase; Metabolism; Redox balance

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.06.020
Trends Cell Biol. 2023 Jun 27. pii: S0962-8924(23)00110-1. [Epub ahead of print]

The bidirectional relationship between metabolism and cell cycle control.

Frances F Diehl, Kiera M Sapp, Matthew G Vander Heiden.

  The relationship between metabolism and cell cycle progression is complex and bidirectional. Cells must rewire metabolism to meet changing biosynthetic demands across cell cycle phases. In turn, metabolism can influence cell cycle progression through direct regulation of cell cycle proteins, through nutrient-sensing signaling pathways, and through its impact on cell growth, which is linked to cell division. Furthermore, metabolism is a key player in mediating quiescence-proliferation transitions in physiologically important cell types, such as stem cells. How metabolism impacts cell cycle progression, exit, and re-entry, as well as how these processes impact metabolism, is not fully understood. Recent advances uncovering mechanistic links between cell cycle regulators and metabolic processes demonstrate a complex relationship between metabolism and cell cycle control, with many questions remaining.

Keywords:  cell growth; mitochondria; mitosis; proliferation; quiescence; translation

DOI:  https://doi.org/10.1016/j.tcb.2023.05.012
Cell. 2023 Jun 22. pii: S0092-8674(23)00646-3. [Epub ahead of print]

Loss of chromosome Y in primary tumors.

Meifang Qi, Jiali Pang, Irene Mitsiades, Andrew A Lane, Esther Rheinbay.

  Certain cancer types afflict female and male patients disproportionately. The reasons include differences in male/female physiology, effect of sex hormones, risk behavior, environmental exposures, and genetics of the sex chromosomes X and Y. Loss of Y (LOY) is common in peripheral blood cells in aging men, and this phenomenon is associated with several diseases. However, the frequency and role of LOY in tumors is little understood. Here, we present a comprehensive catalog of LOY in >5,000 primary tumors from male patients in the TCGA. We show that LOY rates vary by tumor type and provide evidence for LOY being either a passenger or driver event depending on context. LOY in uveal melanoma specifically is associated with age and survival and is an independent predictor of poor outcome. LOY creates common dependencies on DDX3X and EIF1AX in male cell lines, suggesting that LOY generates unique vulnerabilities that could be therapeutically exploited.

Keywords:  Y chromosome; cancer genomics; sex chromosome; somatic copy number variation; uveal melanoma

DOI:  https://doi.org/10.1016/j.cell.2023.06.006
Acta Physiol (Oxf). 2023 Jun 27. e14016

Fifty years of the mitochondrial pyruvate carrier: New insights into its structure, function, and inhibition.

Sotiria Tavoulari, Maximilian Sichrovsky, Edmund R S Kunji.

  The mitochondrial pyruvate carrier (MPC) resides in the mitochondrial inner membrane, where it links cytosolic and mitochondrial metabolism by transporting pyruvate produced in glycolysis into the mitochondrial matrix. Due to its central metabolic role, it has been proposed as a potential drug target for diabetes, non-alcoholic fatty liver disease, neurodegeneration, and cancers relying on mitochondrial metabolism. Little is known about the structure and mechanism of MPC, as the proteins involved were only identified a decade ago and technical difficulties concerning their purification and stability have hindered progress in functional and structural analyses. The functional unit of MPC is a hetero-dimer comprising two small homologous membrane proteins, MPC1/MPC2 in humans, with the alternative complex MPC1L/MPC2 forming in the testis, but MPC proteins are found throughout the tree of life. The predicted topology of each protomer consists of an amphipathic helix followed by three transmembrane helices. An increasing number of inhibitors are being identified, expanding MPC pharmacology and providing insights into the inhibitory mechanism. Here, we provide critical insights on the composition, structure, and function of the complex and we summarize the different classes of small molecule inhibitors and their potential in therapeutics.

Keywords:  metabolism; mitochondria; pyruvate transport; small molecule inhibitors; transport mechanism

DOI:  https://doi.org/10.1111/apha.14016
Curr Opin Neurobiol. 2023 Jun 28. pii: S0959-4388(23)00058-2. [Epub ahead of print]81 102733

Mitochondrial control of sleep.

Celina Hartmann, Anissa Kempf.

  The function of sleep remains one of biology's biggest mysteries. A solution to this problem is likely to come from a better understanding of sleep homeostasis, and in particular of the cellular and molecular processes that sense sleep need and settle sleep debt. Here, we highlight recent work in the fruit fly showing that changes in the mitochondrial redox state of sleep-promoting neurons lie at the heart of a homeostatic sleep-regulatory mechanism. Since the function of homeostatically controlled behaviours is often linked to the regulated variable itself, these findings corroborate with the hypothesis that sleep serves a metabolic function.

Keywords:  Drosophila; Excitability; Metabolism; Mitochondria; OXPHOS; Oxidative phosphorylation; ROS; Reactive oxygen species; Redox state; Sleep; Sleep homeostasis; Sleep need

DOI:  https://doi.org/10.1016/j.conb.2023.102733
Compr Physiol. 2023 06 26. 13(3): 5051-5068

Energetic Stress-Induced Metabolic Regulation by Extracellular Vesicles.

Clair Crewe.

Recent studies have demonstrated that extracellular vesicles (EVs) serve powerful and complex functions in metabolic regulation and metabolic-associated disease, although this field of research is still in its infancy. EVs are released into the extracellular space from all cells and carry a wide range of cargo including miRNAs, mRNA, DNA, proteins, and metabolites that have robust signaling effects in receiving cells. EV production is stimulated by all major stress pathways and, as such, has a role in both restoring homeostasis during stress and perpetuating disease. In metabolic regulation, the dominant stress signal is a lack of energy due to either nutrient deficits or damaged mitochondria from nutrient excess. This stress signal is termed "energetic stress," which triggers a robust and evolutionarily conserved response that engages major cellular stress pathways, the ER unfolded protein response, the hypoxia response, the antioxidant response, and autophagy. This article proposes the model that energetic stress is the dominant stimulator of EV release with a focus on metabolically important cells such as hepatocytes, adipocytes, myocytes, and pancreatic β-cells. Furthermore, this article will discuss how the cargo in stress-stimulated EVs regulates metabolism in receiving cells in both beneficial and detrimental ways. © 2023 American Physiological Society. Compr Physiol 13:5051-5068, 2023.

DOI: https://doi.org/10.1002/cphy.c230001
J Cell Sci. 2023 Jun 26. pii: jcs.260419. [Epub ahead of print]

Mitochondrial transfer from cancer associated fibroblasts increases migration in aggressive breast cancer.

Kayla F Goliwas, Sarah Libring, Emily Berestesky, Shayan Gholizadeh, Samantha C Schwager, Andra R Frost, Thomas R Gaborski, Jian Zhang, Cynthia A Reinhart-King.

  Cancer associated fibroblasts (CAFs) have distinct roles within the tumor microenvironment, which may impact the mode and efficacy of tumor cell migration. CAFs are known to increase invasion of less-aggressive breast cancer cells through matrix remodeling and leader-follower dynamics. Here, we demonstrate that CAFs communicate with breast cancer cells through the formation of contact-dependent tunneling nanotubes (TNTs) that allow for the exchange of cargo between cell types. The transferring of CAF mitochondria is an integral cargo component, and CAF mitochondria are sufficient to increase the 3D migration of cancer cells. This cargo transfer results in an increase in mitochondrial ATP production in cancer cells while having negligible impact on glycolytic ATP production. Manually increasing mitochondrial oxidative phosphorylation (OXPHOS) by providing extra substrates for OXPHOS fails to enhance cancer cell migration unless glycolysis is maintained at a constant level. Together, these data indicate that tumor-stromal crosstalk via TNTs and the associated metabolic symbiosis is a finely controlled mechanism by which tumor cells co-opt their microenvironment to promote cancer progression and may become a potential therapeutic target.

Keywords:  ATP production.; Bioenergetics; CAF; Reverse Warburg effect; Tumor microenvironment; Tumor spheroid; Tunneling nanotube

DOI:  https://doi.org/10.1242/jcs.260419
Nat Commun. 2023 06 27. 14(1): 3811

Oxygen availability and body mass modulate ectotherm responses to ocean warming.

Murray I Duncan, Fiorenza Micheli, Thomas H Boag, J Andres Marquez, Hailey Deres, Curtis A Deutsch, Erik A Sperling.

In an ocean that is rapidly warming and losing oxygen, accurate forecasting of species' responses must consider how this environmental change affects fundamental aspects of their physiology. Here, we develop an absolute metabolic index (ΦA) that quantifies how ocean temperature, dissolved oxygen and organismal mass interact to constrain the total oxygen budget an organism can use to fuel sustainable levels of aerobic metabolism. We calibrate species-specific parameters of ΦA with physiological measurements for red abalone (Haliotis rufescens) and purple urchin (Strongylocentrotus purpuratus). ΦA models highlight that the temperature where oxygen supply is greatest shifts cooler when water loses oxygen or organisms grow larger, providing a mechanistic explanation for observed thermal preference patterns. Viable habitat forecasts are disproportionally deleterious for red abalone, revealing how species-specific physiologies modulate the intensity of a common climate signal, captured in the newly developed ΦA framework.

DOI: https://doi.org/10.1038/s41467-023-39438-w
Oncogene. 2023 Jun 24.

Critical role of antioxidant programs in enzalutamide-resistant prostate cancer.

Eliot B Blatt, Karla Parra, Antje Neeb, Lorenzo Buroni, Denisa Bogdan, Wei Yuan, Yunpeng Gao, Collin Gilbreath, Alec Paschalis, Suzanne Carreira, Ralph J DeBerardinis, Ram S Mani, Johann S de Bono, Ganesh V Raj.

Therapy resistance to second-generation androgen receptor (AR) antagonists, such as enzalutamide, is common in patients with advanced prostate cancer (PCa). To understand the metabolic alterations involved in enzalutamide resistance, we performed metabolomic, transcriptomic, and cistromic analyses of enzalutamide-sensitive and -resistant PCa cells, xenografts, patient-derived organoids, patient-derived explants, and tumors. We noted dramatically higher basal and inducible levels of reactive oxygen species (ROS) in enzalutamide-resistant PCa and castration-resistant PCa (CRPC), in comparison to enzalutamide-sensitive PCa cells or primary therapy-naive tumors respectively. Unbiased metabolomic evaluation identified that glutamine metabolism was consistently upregulated in enzalutamide-resistant PCa cells and CRPC tumors. Stable isotope tracing studies suggest that this enhanced glutamine metabolism drives an antioxidant program that allows these cells to tolerate higher basal levels of ROS. Inhibition of glutamine metabolism with either a small-molecule glutaminase inhibitor or genetic knockout of glutaminase enhanced ROS levels, and blocked the growth of enzalutamide-resistant PCa. The critical role of compensatory antioxidant pathways in maintaining enzalutamide-resistant PCa cells was validated by targeting another antioxidant program driver, ferredoxin 1. Taken together, our data identify a metabolic need to maintain antioxidant programs and a potentially targetable metabolic vulnerability in enzalutamide-resistant PCa.

DOI: https://doi.org/10.1038/s41388-023-02756-w
Nat Cancer. 2023 Jun 26.

Interferon signaling promotes tolerance to chromosomal instability during metastatic evolution in renal cancer.

Luigi Perelli, Federica Carbone, Li Zhang, Justin K Huang, Courtney Le, Hania Khan, Francesca Citron, Edoardo Del Poggetto, Tony Gutschner, Hideo Tomihara, Melinda Soeung, Rosalba Minelli, Sanjana Srinivasan, Michael Peoples, Truong Nguyen Anh Lam, Sebastian Lundgren, Ruohan Xia, Cihui Zhu, Alaa M T Mohamed, Jianhua Zhang, Kanishka Sircar, Alessandro Sgambato, JianJun Gao, Eric Jonasch, Giulio F Draetta, Andrew Futreal, Ziad Bakouny, Eliezer M Van Allen, Toni Choueiri, Sabina Signoretti, Pavlos Msaouel, Kevin Litchfield, Samra Turajlic, Linghua Wang, Ying Bei Chen, Renzo G Di Natale, A Ari Hakimi, Virginia Giuliani, Timothy P Heffernan, Andrea Viale, Christopher A Bristow, Nizar M Tannir, Alessandro Carugo, Giannicola Genovese.

Molecular routes to metastatic dissemination are critical determinants of aggressive cancers. Through in vivo CRISPR-Cas9 genome editing, we generated somatic mosaic genetically engineered models that faithfully recapitulate metastatic renal tumors. Disruption of 9p21 locus is an evolutionary driver to systemic disease through the rapid acquisition of complex karyotypes in cancer cells. Cross-species analysis revealed that recurrent patterns of copy number variations, including 21q loss and dysregulation of the interferon pathway, are major drivers of metastatic potential. In vitro and in vivo genomic engineering, leveraging loss-of-function studies, along with a model of partial trisomy of chromosome 21q, demonstrated a dosage-dependent effect of the interferon receptor genes cluster as an adaptive mechanism to deleterious chromosomal instability in metastatic progression. This work provides critical knowledge on drivers of renal cell carcinoma progression and defines the primary role of interferon signaling in constraining the propagation of aneuploid clones in cancer evolution.

DOI: https://doi.org/10.1038/s43018-023-00584-1
Cell. 2023 Jun 20. pii: S0092-8674(23)00590-1. [Epub ahead of print]

cGLRs are a diverse family of pattern recognition receptors in innate immunity.

Yao Li, Kailey M Slavik, Hunter C Toyoda, Benjamin R Morehouse, Carina C de Oliveira Mann, Anamaria Elek, Shani Levy, Zhenwei Wang, Kepler S Mears, Jingjing Liu, Dmitry Kashin, Ximing Guo, Tali Mass, Arnau Sebé-Pedrós, Frank Schwede, Philip J Kranzusch.

  Cyclic GMP-AMP synthase (cGAS) is an enzyme in human cells that controls an immune response to cytosolic DNA. Upon binding DNA, cGAS synthesizes a nucleotide signal 2'3'-cGAMP that activates STING-dependent downstream immunity. Here, we discover that cGAS-like receptors (cGLRs) constitute a major family of pattern recognition receptors in innate immunity. Building on recent analysis in Drosophila, we identify >3,000 cGLRs present in nearly all metazoan phyla. A forward biochemical screening of 150 animal cGLRs reveals a conserved mechanism of signaling including response to dsDNA and dsRNA ligands and synthesis of isomers of the nucleotide signals cGAMP, c-UMP-AMP, and c-di-AMP. Combining structural biology and in vivo analysis in coral and oyster animals, we explain how synthesis of distinct nucleotide signals enables cells to control discrete cGLR-STING signaling pathways. Our results reveal cGLRs as a widespread family of pattern recognition receptors and establish molecular rules that govern nucleotide signaling in animal immunity.

Keywords:  STING; cGAS; cGLR; cyclic dinucleotides; innate immunity; pattern recognition receptor

DOI:  https://doi.org/10.1016/j.cell.2023.05.038
Cell. 2023 Jun 20. pii: S0092-8674(23)00599-8. [Epub ahead of print]

Circadian clocks are modulated by compartmentalized oscillating translation.

Yanrong Zhuang, Zhiyuan Li, Shiyue Xiong, Chujie Sun, Boya Li, Shuangcheng Alivia Wu, Jiali Lyu, Xiang Shi, Liang Yang, Yutong Chen, Zhangbin Bao, Xi Li, Chuhanwen Sun, Yuling Chen, Haiteng Deng, Tingting Li, Qingfeng Wu, Ling Qi, Yue Huang, Xuerui Yang, Yi Lin.

  Terrestrial organisms developed circadian rhythms for adaptation to Earth's quasi-24-h rotation. Achieving precise rhythms requires diurnal oscillation of fundamental biological processes, such as rhythmic shifts in the cellular translational landscape; however, regulatory mechanisms underlying rhythmic translation remain elusive. Here, we identified mammalian ATXN2 and ATXN2L as cooperating master regulators of rhythmic translation, through oscillating phase separation in the suprachiasmatic nucleus along circadian cycles. The spatiotemporal oscillating condensates facilitate sequential initiation of multiple cycling processes, from mRNA processing to protein translation, for selective genes including core clock genes. Depleting ATXN2 or 2L induces opposite alterations to the circadian period, whereas the absence of both disrupts translational activation cycles and weakens circadian rhythmicity in mice. Such cellular defect can be rescued by wild type, but not phase-separation-defective ATXN2. Together, we revealed that oscillating translation is regulated by spatiotemporal condensation of two master regulators to achieve precise circadian rhythm in mammals.

Keywords:  ATXN2; ATXN2L; circadian rhythm; clock genes; membrane-less organelle; neurodegeneration; phase separation; rhythmic translation; suprachiasmatic nucleus; translational regulation

DOI:  https://doi.org/10.1016/j.cell.2023.05.045
J Cell Biol. 2023 Sep 04. pii: e202209120. [Epub ahead of print]222(9):

Mechanical control of the mammalian circadian clock via YAP/TAZ and TEAD.

Juan F Abenza, Leone Rossetti, Malèke Mouelhi, Javier Burgués, Ion Andreu, Keith Kennedy, Pere Roca-Cusachs, Santiago Marco, Jordi García-Ojalvo, Xavier Trepat.

Autonomous circadian clocks exist in nearly every mammalian cell type. These cellular clocks are subjected to a multilayered regulation sensitive to the mechanochemical cell microenvironment. Whereas the biochemical signaling that controls the cellular circadian clock is increasingly well understood, mechanisms underlying regulation by mechanical cues are largely unknown. Here we show that the fibroblast circadian clock is mechanically regulated through YAP/TAZ nuclear levels. We use high-throughput analysis of single-cell circadian rhythms and apply controlled mechanical, biochemical, and genetic perturbations to study the expression of the clock gene Rev-erbα. We observe that Rev-erbα circadian oscillations are disrupted with YAP/TAZ nuclear translocation. By targeted mutations and overexpression of YAP/TAZ, we show that this mechanobiological regulation, which also impacts core components of the clock such as Bmal1 and Cry1, depends on the binding of YAP/TAZ to the transcriptional effector TEAD. This mechanism could explain the impairment of circadian rhythms observed when YAP/TAZ activity is upregulated, as in cancer and aging.

DOI: https://doi.org/10.1083/jcb.202209120
Hum Mol Genet. 2023 Jun 26. pii: ddad092. [Epub ahead of print]

5-Aminolevulinic acid bypasses mitochondrial complex I deficiency and corrects physiological dysfunctions in Drosophila.

Naoko Nozawa, Marie Noguchi, Kanako Shinno, Taro Saito, Akiko Asada, Takuya Ishii, Kiwamu Takahashi, Masahiro Ishizuka, Kanae Ando.

Complex I (CI) deficiency in mitochondrial oxidative phosphorylation (OXPHOS) is the most common cause of mitochondrial diseases, and limited evidence-based treatment options exist. While CI provides the most electrons to OXPHOS, complex II (CII) is another entry point of electrons. Enhancement of this pathway may compensate for a loss of CI; however, the effects of boosting CII activity on CI deficiency are unclear at the animal level. 5-Aminolevulinic acid (5-ALA) is a crucial precursor of heme, which is essential for CII, complex III, complex IV (CIV), and cytochrome c activities. Here, we show that feeding a combination of 5-ALA hydrochloride and sodium ferrous citrate (5-ALA-HCl + SFC) increases ATP production and suppresses defective phenotypes in Drosophila with CI deficiency. Knockdown of sicily, a Drosophila homolog of the critical CI assembly protein NDUFAF6, caused CI deficiency, accumulation of lactate and pyruvate, and detrimental phenotypes such as abnormal neuromuscular junction development, locomotor dysfunctions, and premature death. 5-ALA-HCl + SFC feeding increased ATP levels without recovery of CI activity. The activities of CII and CIV were upregulated, and accumulation of lactate and pyruvate was suppressed. 5-ALA-HCl + SFC feeding improved neuromuscular junction development and locomotor functions in sicily-knockdown flies. These results suggest that 5-ALA-HCl + SFC shifts metabolic programs to cope with CI deficiency.

DOI: https://doi.org/10.1093/hmg/ddad092
Cell Res. 2023 Jun 28.

Lysine metabolism at the nexus of crotonylation and tumor immunity.

Fangchao Wei, Jason W Locasale.

DOI: https://doi.org/10.1038/s41422-023-00841-z
Nature. 2023 Jun 28.

Phase separation of FSP1 promotes ferroptosis.

Toshitaka Nakamura, Clara Hipp, André Santos Dias Mourão, Jan Borggräfe, Maceler Aldrovandi, Bernhard Henkelmann, Jonas Wanninger, Eikan Mishima, Elena Lytton, David Emler, Bettina Proneth, Michael Sattler, Marcus Conrad.

Ferroptosis is evolving as a highly promising approach to combat difficult-to-treat tumour entities including therapy-refractory and dedifferentiating cancers1-3. Recently, ferroptosis suppressor protein-1 (FSP1), along with extramitochondrial ubiquinone or exogenous vitamin K and NAD(P)H/H+ as an electron donor, has been identified as the second ferroptosis-suppressing system, which efficiently prevents lipid peroxidation independently of the cyst(e)ine-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis4-6. To develop FSP1 inhibitors as next-generation therapeutic ferroptosis inducers, here we performed a small molecule library screen and identified the compound class of 3-phenylquinazolinones (represented by icFSP1) as potent FSP1 inhibitors. We show that icFSP1, unlike iFSP1, the first described on-target FSP1 inhibitor5, does not competitively inhibit FSP1 enzyme activity, but instead triggers subcellular relocalization of FSP1 from the membrane and FSP1 condensation before ferroptosis induction, in synergism with GPX4 inhibition. icFSP1-induced FSP1 condensates show droplet-like properties consistent with phase separation, an emerging and widespread mechanism to modulate biological activity7. N-terminal myristoylation, distinct amino acid residues and intrinsically disordered, low-complexity regions in FSP1 were identified to be essential for FSP1-dependent phase separation in cells and in vitro. We further demonstrate that icFSP1 impairs tumour growth and induces FSP1 condensates in tumours in vivo. Hence, our results suggest that icFSP1 exhibits a unique mechanism of action and synergizes with ferroptosis-inducing agents to potentiate the ferroptotic cell death response, thus providing a rationale for targeting FSP1-dependent phase separation as an efficient anti-cancer therapy.

DOI: https://doi.org/10.1038/s41586-023-06255-6
Mol Cell. 2023 Jun 27. pii: S1097-2765(23)00426-4. [Epub ahead of print]

Lysosomal LAMP proteins regulate lysosomal pH by direct inhibition of the TMEM175 channel.

Jiyuan Zhang, Weizhong Zeng, Yan Han, Wan-Ru Lee, Jen Liou, Youxing Jiang.

  Maintaining a highly acidic lysosomal pH is central to cellular physiology. Here, we use functional proteomics, single-particle cryo-EM, electrophysiology, and in vivo imaging to unravel a key biological function of human lysosome-associated membrane proteins (LAMP-1 and LAMP-2) in regulating lysosomal pH homeostasis. Despite being widely used as a lysosomal marker, the physiological functions of the LAMP proteins have long been overlooked. We show that LAMP-1 and LAMP-2 directly interact with and inhibit the activity of the lysosomal cation channel TMEM175, a key player in lysosomal pH homeostasis implicated in Parkinson's disease. This LAMP inhibition mitigates the proton conduction of TMEM175 and facilitates lysosomal acidification to a lower pH environment crucial for optimal hydrolase activity. Disrupting the LAMP-TMEM175 interaction alkalinizes the lysosomal pH and compromises the lysosomal hydrolytic function. In light of the ever-increasing importance of lysosomes to cellular physiology and diseases, our data have widespread implications for lysosomal biology.

Keywords:  LAMP-1 and LAMP-2; TMEM175; lysosomal LAMP proteins; lysosomal hydrolytic function; lysosomal pH homeostasis; lysosome acidification; risk factor for Parkinson’s disease

DOI:  https://doi.org/10.1016/j.molcel.2023.06.004
Cell Rep. 2023 Jun 23. pii: S2211-1247(23)00699-X. [Epub ahead of print]42(7): 112688

A cancer-associated METTL14 mutation induces aberrant m6A modification, affecting tumor growth.

Kotaro Miyake, Pedro Henrique Costa Cruz, Izumi Nagatomo, Yuki Kato, Daisuke Motooka, Shingo Satoh, Yuichi Adachi, Yoshito Takeda, Yukio Kawahara, Atsushi Kumanogoh.

  The methyltransferase-like 3 (METTL3)-/METTL14-containing complex predominantly catalyzes N6-methyladenosine (m6A) modification, which affects mRNA stability. Although the METTL14 R298P mutation is found in multiple cancer types, its biological effects are not completely understood. Here, we show that the heterozygous R298P mutation promotes cancer cell proliferation, whereas the homozygous mutation reduces proliferation. Methylated RNA immunoprecipitation sequencing analysis indicates that the R298P mutation reduces m6A modification at canonical motifs. Furthermore, this mutation induces m6A modification at aberrant motifs, which is evident only in cell lines harboring the homozygous mutation. The aberrant recognition of m6A modification sites alters the methylation efficiency at surrounding canonical motifs. One example is c-MET mRNA, which is highly methylated at canonical motifs close to the aberrantly methylated sites. Consequently, c-MET mRNA is severely destabilized, reducing c-Myc expression and suppressing cell proliferation. These data suggest that the METTL14 R298P mutation affects target recognition for m6A modification, perturbing gene expression patterns and cell growth.

Keywords:  CP: Cancer; CP: Molecular biology; METTL14; MeRIP-seq; RNA methylation; c-MET; c-Myc; endometrial cancer; m6A; mutational hotspot

DOI:  https://doi.org/10.1016/j.celrep.2023.112688
Nature. 2023 Jun 28.

Cancer aneuploidies are shaped primarily by effects on tumour fitness.

Juliann Shih, Shahab Sarmashghi, Nadja Zhakula-Kostadinova, Shu Zhang, Yohanna Georgis, Stephanie H Hoyt, Michael S Cuoco, Galen F Gao, Liam F Spurr, Ashton C Berger, Gavin Ha, Veronica Rendo, Hui Shen, Matthew Meyerson, Andrew D Cherniack, Alison M Taylor, Rameen Beroukhim.

Aneuploidies-whole-chromosome or whole-arm imbalances-are the most prevalent alteration in cancer genomes1,2. However, it is still debated whether their prevalence is due to selection or ease of generation as passenger events1,2. Here we developed a method, BISCUT, that identifies loci subject to fitness advantages or disadvantages by interrogating length distributions of telomere- or centromere-bounded copy-number events. These loci were significantly enriched for known cancer driver genes, including genes not detected through analysis of focal copy-number events, and were often lineage specific. BISCUT identified the helicase-encoding gene WRN as a haploinsufficient tumour-suppressor gene on chromosome 8p, which is supported by several lines of evidence. We also formally quantified the role of selection and mechanical biases in driving aneuploidy, finding that rates of arm-level copy-number alterations are most highly correlated with their effects on cellular fitness1,2. These results provide insight into the driving forces behind aneuploidy and its contribution to tumorigenesis.

DOI: https://doi.org/10.1038/s41586-023-06266-3
Cell Rep. 2023 Jun 28. pii: S2211-1247(23)00733-7. [Epub ahead of print]42(7): 112722

Dietary restriction mitigates the age-associated decline in mouse B cell receptor repertoire diversity.

Carolina Monzó, Lisonia Gkioni, Andreas Beyer, Dario Riccardo Valenzano, Sebastian Grönke, Linda Partridge.

  Aging impairs the capacity to respond to novel antigens, reducing immune protection against pathogens and vaccine efficacy. Dietary restriction (DR) extends life- and health span in diverse animals. However, little is known about the capacity of DR to combat the decline in immune function. Here, we study the changes in B cell receptor (BCR) repertoire during aging in DR and control mice. By sequencing the variable region of the BCR heavy chain in the spleen, we show that DR preserves diversity and attenuates the increase in clonal expansions throughout aging. Remarkably, mice starting DR in mid-life have repertoire diversity and clonal expansion rates indistinguishable from chronic DR mice. In contrast, in the intestine, these traits are unaffected by either age or DR. Reduced within-individual B cell repertoire diversity and increased clonal expansions are correlated with higher morbidity, suggesting a potential contribution of B cell repertoire dynamics to health during aging.

Keywords:  B cell receptor repertoire; CP: Immunology; adaptive immunity; aging; dietary restriction; late onset; mice

DOI:  https://doi.org/10.1016/j.celrep.2023.112722
Nat Genet. 2023 Jun 29.

Single-cell multiomic analyses sheds light on mitochondrial mutational selection.

Sarah J Pickett, Gavin Hudson, Laura C Greaves.

DOI: https://doi.org/10.1038/s41588-023-01436-5
Nature. 2023 Jun 28.

A spatially resolved single-cell genomic atlas of the adult human breast.

Tapsi Kumar, Kevin Nee, Runmin Wei, Siyuan He, Quy H Nguyen, Shanshan Bai, Kerrigan Blake, Maren Pein, Yanwen Gong, Emi Sei, Min Hu, Anna K Casasent, Aatish Thennavan, Jianzhuo Li, Tuan Tran, Ken Chen, Benedikt Nilges, Nachiket Kashikar, Oliver Braubach, Bassem Ben Cheikh, Nadya Nikulina, Hui Chen, Mediget Teshome, Brian Menegaz, Huma Javaid, Chandandeep Nagi, Jessica Montalvan, Tatyana Lev, Sharmila Mallya, Delia F Tifrea, Robert Edwards, Erin Lin, Ritesh Parajuli, Summer Hanson, Sebastian Winocour, Alastair Thompson, Bora Lim, Devon A Lawson, Kai Kessenbrock, Nicholas Navin.

The adult human breast is comprised of an intricate network of epithelial ducts and lobules that are embedded in connective and adipose tissue1-3. Although most previous studies have focused on the breast epithelial system4-6, many of the non-epithelial cell types remain understudied. Here we constructed the comprehensive Human Breast Cell Atlas (HBCA) at single-cell and spatial resolution. Our single-cell transcriptomics study profiled 714,331 cells from 126 women, and 117,346 nuclei from 20 women, identifying 12 major cell types and 58 biological cell states. These data reveal abundant perivascular, endothelial and immune cell populations, and highly diverse luminal epithelial cell states. Spatial mapping using four different technologies revealed an unexpectedly rich ecosystem of tissue-resident immune cells, as well as distinct molecular differences between ductal and lobular regions. Collectively, these data provide a reference of the adult normal breast tissue for studying mammary biology and diseases such as breast cancer.

DOI: https://doi.org/10.1038/s41586-023-06252-9
Proc Natl Acad Sci U S A. 2023 07 04. 120(27): e2305410120

Long noncoding RNA MALAT1 is dynamically regulated in leader cells during collective cancer invasion.

Ninghao Zhu, Mona Ahmed, Yanlin Li, Joseph C Liao, Pak Kin Wong.

  Cancer cells collectively invade using a leader-follower organization, but the regulation of leader cells during this dynamic process is poorly understood. Using a dual double-stranded locked nucleic acid (LNA) nanobiosensor that tracks long noncoding RNA (lncRNA) dynamics in live single cells, we monitored the spatiotemporal distribution of lncRNA during collective cancer invasion. We show that the lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) is dynamically regulated in the invading fronts of cancer cells and patient-derived spheroids. MALAT1 transcripts exhibit distinct abundance, diffusivity, and distribution between leader and follower cells. MALAT1 expression increases when a cancer cell becomes a leader and decreases when the collective migration process stops. Transient knockdown of MALAT1 prevents the formation of leader cells and abolishes the invasion of cancer cells. Taken together, our single-cell analysis suggests that MALAT1 is dynamically regulated in leader cells during collective cancer invasion.

Keywords:  biosensor; bladder cancer; lncRNA; metastasis; single cell analysis

DOI:  https://doi.org/10.1073/pnas.2305410120
Trends Plant Sci. 2023 Jun 26. pii: S1360-1385(23)00171-1. [Epub ahead of print]

Raman-stable isotope technology for tracking single-cell plant metabolism.

Zhihao Zhan, Mostafa Gouda, Xiaoli Li.

DOI: https://doi.org/10.1016/j.tplants.2023.05.014
Science. 2023 Jun 30. 380(6652): eadd3067

Spatially resolved single-cell translatomics at molecular resolution.

Hu Zeng, Jiahao Huang, Jingyi Ren, Connie Kangni Wang, Zefang Tang, Haowen Zhou, Yiming Zhou, Hailing Shi, Abhishek Aditham, Xin Sui, Hongyu Chen, Jennifer A Lo, Xiao Wang.

The precise control of messenger RNA (mRNA) translation is a crucial step in posttranscriptional gene regulation of cellular physiology. However, it remains a challenge to systematically study mRNA translation at the transcriptomic scale with spatial and single-cell resolution. Here, we report the development of ribosome-bound mRNA mapping (RIBOmap), a highly multiplexed three-dimensional in situ profiling method to detect cellular translatome. RIBOmap profiling of 981 genes in HeLa cells revealed cell cycle-dependent translational control and colocalized translation of functional gene modules. We mapped 5413 genes in mouse brain tissues, yielding spatially resolved single-cell translatomic profiles for 119,173 cells and revealing cell type-specific and brain region-specific translational regulation, including translation remodeling during oligodendrocyte maturation. Our method detected widespread patterns of localized translation in neuronal and glial cells in intact brain tissue networks.

DOI: https://doi.org/10.1126/science.add3067