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Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, arises in skeletal muscle and remains in an undifferentiated state due to transcriptional and post-transcriptional regulators. Among its subtypes, fusion-negative RMS (FN-RMS) accounts for the majority of diagnoses in the pediatric population. MicroRNAs (miRNAs) are non-coding RNAs that modulate cell identity via post-transcriptional regulation of messenger RNAs (mRNAs). In this study, we identify miRNAs impacting FN-RMS cell identity, revealing miR-449a and miR-340 as major regulators of the cell cycle and p53 signaling. Through miR-eCLIP technology, we demonstrate that miR-449a and miR-340 directly target transcripts involved in glycolysis and mitochondrial pyruvate transport, inhibiting the mitochondrial pyruvate carrier (MPC) complex. Pharmacological MPC inhibition induces a similar metabolic shift, reducing metastatic potential and leading to cell cycle exit. Overall, miR-449 and miR-340 orchestrate FN-RMS cell identity, positioning MPC inhibition as a strategy to shift FN-RMS cells toward a non-tumorigenic, quiescent state. [Display omitted] • miR-449a/miR-340 downregulation in FN-RMS targets cell cycle, histone, and glycolysis pathways • miRNA reintroduction alters cell identity, impacting transcriptome, epigenome, and metabolism • MPC inhibition or miR-449a/miR-340 drive cell cycle exit, reducing FN-RMS metastatic potential Pozzo et al. identify miR-449a and miR-340 as regulators of the FN-RMS cell cycle and p53 pathways. Multiomics analyses show that these miRNAs rewire cell identity and metabolism, reducing proliferation and metastatic potential; pharmacological MPC inhibition mirrors their impact in FN-RMS models. [ABSTRACT FROM AUTHOR]

Hypoxia-inducible factor-1α (HIF1α) attenuates mitochondrial activity while promoting glycolysis. However, lower glycolysis is compromised in human clear cell renal cell carcinomas, in which HIF1α acts as a tumor suppressor by inhibiting cell-autonomous proliferation. Here, we find that, unexpectedly, HIF1α suppresses lower glycolysis after the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) step, leading to reduced lactate secretion in different tumor cell types when cells encounter a limited pyruvate supply such as that typically found in the tumor microenvironment in vivo. This is because HIF1α-dependent attenuation of mitochondrial oxygen consumption increases the NADH/NAD+ ratio that suppresses the activity of the NADH-sensitive GAPDH glycolytic enzyme. This is manifested when pyruvate supply is limited, since pyruvate acts as an electron acceptor that prevents the increment of the NADH/NAD+ ratio. Furthermore, this anti-glycolytic function provides a molecular basis to explain how HIF1α can suppress tumor cell proliferation by increasing the NADH/NAD+ ratio. [Display omitted] • HIF1α suppresses lower glycolysis when pyruvate supply is limited • Insufficient pyruvate facilitates HIF1α-dependent elevation of NADH/NAD+ ratio • Inhibition of NADH/NAD+ elevation restores lower glycolysis upon HIF1α activation • HIF1α-dependent increase in NADH/NAD+ ratio reduces cell proliferation In this article, Urrutia et al. explain the metabolic pattern of ccRCC tumors characterized by the suppression of lower glycolysis and constitutive HIF1α activation. Urrutia et al. show that HIF1α elevates the NADH/NAD+ ratio, which attenuates lower glycolysis when pyruvate supply is limited, as occurs in the solid tumor microenvironment. [ABSTRACT FROM AUTHOR]

A functional electron transport chain (ETC) is crucial for supporting bioenergetics and biosynthesis. Accordingly, ETC inhibition decreases proliferation in cancer cells but does not seem to impair stem cell proliferation. However, it remains unclear how stem cells metabolically adapt. In this study, we show that pharmacological inhibition of complex III of the ETC in skeletal stem and progenitor cells induces glycolysis side pathways and reroutes the tricarboxylic acid (TCA) cycle to regenerate NAD+ and preserve cell proliferation. These metabolic changes also culminate in increased succinate and 2-hydroxyglutarate levels that inhibit Ten-eleven translocation (TET) DNA demethylase activity, thereby preserving self-renewal and multilineage potential. Mechanistically, mitochondrial malate dehydrogenase and reverse succinate dehydrogenase activity proved to be essential for the metabolic rewiring in response to ETC inhibition. Together, these data show that the metabolic plasticity of skeletal stem and progenitor cells allows them to bypass ETC blockade and preserve their self-renewal. [Display omitted] • Skeletal stem/progenitor cells can proliferate upon electron transport chain blockade • Succinate dehydrogenase is reversed with fumarate functioning as electron acceptor • Pyruvate and aspartate are critical for NAD+ regeneration and proliferation • Metabolic changes prevent DNA demethylation and preserve self-renewal Blocking mitochondrial respiration decreases proliferation in tumor cells but not in stem cells, although mechanistic insight is lacking. Tournaire et al. report that skeletal progenitors bypass this inhibition by reversing succinate dehydrogenase activity and using alternative NAD+ regenerating pathways. This metabolic plasticity maintains proliferation and self-renewal, improving bone regeneration. [ABSTRACT FROM AUTHOR]

Macrophages are often prominently present in the tumor microenvironment, where distinct macrophage populations can differentially affect tumor progression. Although metabolism influences macrophage function, studies on the metabolic characteristics of ex vivo tumor-associated macrophage (TAM) subsets are rather limited. Using transcriptomic and metabolic analyses, we now reveal that pro-inflammatory major histocompatibility complex (MHC)-IIhi TAMs display a hampered tricarboxylic acid (TCA) cycle, while reparative MHC-IIlo TAMs show higher oxidative and glycolytic metabolism. Although both TAM subsets rapidly exchange lactate in high-lactate conditions, only MHC-IIlo TAMs use lactate as an additional carbon source. Accordingly, lactate supports the oxidative metabolism in MHC-IIlo TAMs, while it decreases the metabolic activity of MHC-IIhi TAMs. Lactate subtly affects the transcriptome of MHC-IIlo TAMs, increases L-arginine metabolism, and enhances the T cell suppressive capacity of these TAMs. Overall, our data uncover the metabolic intricacies of distinct TAM subsets and identify lactate as a carbon source and metabolic and functional regulator of TAMs. [Display omitted] • TAM subsets are transcriptionally and metabolically distinct • TAM subsets differentially use lactate as a carbon source to fuel the TCA cycle • Lactate differentially affects TAM subset metabolism, derogating MHC-IIhi TAMs • Lactate affects the MHC-IIlo TAM transcriptome, stimulating T cell suppression Metabolic characteristics of ex vivo tumor-associated macrophages (TAMs) are an understudied topic in immunometabolism. Geeraerts et al. unravel the metabolism of TAM subsets co-existing within mouse lung carcinoma. Lactate differentially impacts these TAM subsets by harming the metabolism of anti-tumoral TAMs and promoting pro-tumoral TAMs' suppressive capacity and metabolic activity. [ABSTRACT FROM AUTHOR]

Cancer cells display an increased plasticity in their lipid metabolism, which includes the conversion of palmitate to sapienate via the enzyme fatty acid desaturase 2 (FADS2). We find that FADS2 expression correlates with mammalian target of rapamycin (mTOR) signaling and sterol regulatory element-binding protein 1 (SREBP-1) activity across multiple cancer types and is prognostic in some cancer types. Accordingly, activating mTOR signaling by deleting tuberous sclerosis complex 2 (Tsc2) or overexpression of SREBP-1/2 is sufficient to increase FADS2 mRNA expression and sapienate metabolism in mouse embryonic fibroblasts (MEFs) and U87 glioblastoma cells, respectively. Conversely, inhibiting mTOR signaling decreases FADS2 expression and sapienate biosynthesis in MEFs with Tsc2 deletion, HUH7 hepatocellular carcinoma cells, and orthotopic HUH7 liver xenografts. In conclusion, we show that mTOR signaling and SREBP activity are sufficient to activate sapienate metabolism by increasing FADS2 expression. Consequently, targeting mTOR signaling can reduce sapienate metabolism in vivo. • FADS2 expression is prognostic in some cancers • FADS2 is a target of SREBP-1 and SREBP-2 • SREBP activity and mTOR signaling regulate FADS2-mediated sapienate metabolism • Torin1 treatment reduces FADS2 expression and sapienate metabolism in xenografts Triki et al. report that FADS2 expression is prognostic in some cancers and that FADS2-mediated sapienate metabolism is regulated by mTOR signaling. Mechanistically, FADS2 is a target of SREBP-1/2. Inhibition of mTOR or SREBP reduces FADS2 expression and sapienate metabolism in cancer cells and liver xenografts. [ABSTRACT FROM AUTHOR]

Correct functioning of chondrocytes is crucial for long bone growth and fracture repair. These cells are highly anabolic but survive and function in an avascular environment, implying specific metabolic requirements that are, however, poorly characterized. Here, we show that chondrocyte identity and function are closely linked with glutamine metabolism in a feedforward process. The master chondrogenic transcription factor SOX9 stimulates glutamine metabolism by increasing glutamine consumption and levels of glutaminase 1 (GLS1), a rate-controlling enzyme in this pathway. Consecutively, GLS1 action is critical for chondrocyte properties and function via a tripartite mechanism. First, glutamine controls chondrogenic gene expression epigenetically through glutamate dehydrogenase-dependent acetyl-CoA synthesis, necessary for histone acetylation. Second, transaminase-mediated aspartate synthesis supports chondrocyte proliferation and matrix synthesis. Third, glutamine-derived glutathione synthesis avoids harmful reactive oxygen species accumulation and allows chondrocyte survival in the avascular growth plate. Collectively, our study identifies glutamine as a metabolic regulator of cartilage fitness during bone development. • The chondrogenic transcription factor SOX9 induces glutamine metabolism • Glutamine-derived acetyl-CoA epigenetically regulates chondrogenic gene expression • Transaminase-driven glutamine-derived aspartate controls chondrocyte biosynthesis • Glutamine-dependent glutathione synthesis maintains chondrocyte redox homeostasis Growth plate chondrocytes survive and function in an avascular environment, but their nutritional requirements are poorly characterized. Stegen et al. now demonstrate that the key chondrogenic transcription factor SOX9 induces glutamine metabolism, and this metabolic adaptation is in turn necessary to support chondrocyte gene expression, biosynthesis, and redox homeostasis. [ABSTRACT FROM AUTHOR]

Summary Cellular aspartate drives cancer cell proliferation, but signaling pathways that rewire aspartate biosynthesis to control cell growth remain largely unknown. Hypoxia-inducible factor-1α (HIF1α) can suppress tumor cell proliferation. Here, we discovered that HIF1α acts as a direct repressor of aspartate biosynthesis involving the suppression of several key aspartate-producing proteins, including cytosolic glutamic-oxaloacetic transaminase-1 (GOT1) and mitochondrial GOT2. Accordingly, HIF1α suppresses aspartate production from both glutamine oxidation as well as the glutamine reductive pathway. Strikingly, the addition of aspartate to the culture medium is sufficient to relieve HIF1α-dependent repression of tumor cell proliferation. Furthermore, these key aspartate-producing players are specifically repressed in VHL-deficient human renal carcinomas, a paradigmatic tumor type in which HIF1α acts as a tumor suppressor, highlighting the in vivo relevance of these findings. In conclusion, we show that HIF1α inhibits cytosolic and mitochondrial aspartate biosynthesis and that this mechanism is the molecular basis for HIF1α tumor suppressor activity. Graphical Abstract Highlights • HIF1α reduces intracellular aspartate levels • HIF1α impairs oxidative and reductive aspartate biosynthesis • The aspartate-generating GOT1 and GOT2 enzymes are repressed by HIF1α • Aspartate supplementation counteracts the antiproliferative influence of HIF1α Meléndez-Rodríguez et al. show that HIF1α impairs oxidative and reductive aspartate biogenesis, which consequently drives HIF1α-dependent suppression of tumor cell proliferation. Mechanistically, HIF1α represses the aspartate-producing enzymes GOT1 and GOT2 in several biological settings, including human VHL-deficient renal cell carcinoma, in which HIF1α can act as a tumor suppressor. [ABSTRACT FROM AUTHOR]