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Oncogene-targeted and immune checkpoint the rapies have revolutionized the clinical management of malignant melanoma and now offer hope to patients with advanced disease. Intimately connected to patients' overall clinical risk is whether the initial primary melanoma lesion will metastasize and cause advanced disease, but underlying mechanisms are not entirely understood. A subset of melanomas display heightened peroxisome proliferator-activated receptor y coactivator 1-a (PGC1[alpha]) expression that maintains cell survival cues by promoting mitochondrial function, but also suppresses metastatic spread. Here, we show that PGC1[alpha] expression in melanoma cells was silenced by chromatin modifications that involve promoter H3K27 trimethylation. Pharmacological EZH2 inhibition diminished H3K27me3 histone markers, increased PGC1[alpha] expression, and functionally suppressed invasion within PGC1[alpha]-silenced melanoma cells. Mechanistically, PGC1[alpha] silencing activated transcription factor 12 (TCF12), to increase expression of WNT5A, which in turn stabilized YAP protein levels to promote melanoma migration and metastasis. Accordingly, inhibition of components of this transcription-signaling axis, including TCF12, WNT5A, or YAP, blocked melanoma migration in vitro and metastasis in vivo. These results indicate that epigenetic control of melanoma metastasis involved altered expression of PGC1[alpha] and an association with the inherent metabolic state of the tumor., Introduction Recent breakthroughs in the clinical management of malignant melanoma, which include treatment using BRAF(V600E)-targeted drugs and immune checkpoint-blocking antibodies, now improve survival for patients with advanced stage disease (1). [...]

Cannabinoid receptor 1 (CB-1) antagonists are potential candidates for treating obesity and metabolic complications. Despite clear metabolic benefits, unwanted side effects in the brain pose issues for patients. With the hope of overcoming this obstacle, CB-1 in peripheral tissues has become a potential drug target. Previous studies had suggested that liver CB-1 would be an excellent target to prevent development of nonalcoholic steatohepatitis (NAFLD). However, in this issue of the JCI, Wang et al. showed that CB-1 was barely detectable in the liver and deletion of CB-1 in hepatocytes provided no metabolic benefits against NAFLD. These contradictory results raise substantial concerns about the potential benefits of peripheral CB-1 blockers against NAFLD., Sources of liver fat in metabolic diseases NAFLD is a continuum of liver pathologies, usually seen in overweight or obese people, that can be described in three progressive stages: (a) [...]

The present research is framed within the study of Catholic schools and more specifically, in the commemorative books that these centres promoted and published. In order to carry out the study, a total of 34 books have been analysed. They all deal with the history of different Catholic schools in the Balearic Islands (Spain). The involvement of educational community members (students, alumni, teachers, families, ecc.) in the production of the books, together with the institutional and reputational use made of them, link these historiographical products to both the genre of public history and the field of corporate history. In order to understand the nature of these links, as well as the idiosyncrasy of these monographs, this study aims to shed light on the "who", "what" and "how", that is, on the authorship, content and format of the commemorative books in question. The results obtained show that the commemorative books, apart from offering a wealth of useful data regarding the past of Catholic schools, help to better understand the evolution of a historiographical practice that has formed the basis of "new" historiographical genres related to the public and corporate use of history. [ABSTRACT FROM AUTHOR]

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Mitochondrial diseases are a group of disorders defined by defects in oxidative phosphorylation caused by nuclear‐ or mitochondrial‐encoded gene mutations. A main cellular phenotype of mitochondrial disease mutations is redox imbalances and inflammatory signaling underlying pathogenic signatures of these patients. One method to rescue this cell death vulnerability is the inhibition of mitochondrial translation using tetracyclines. However, the mechanisms whereby tetracyclines promote cell survival are unknown. Here, we show that tetracyclines inhibit the mitochondrial ribosome and promote survival through suppression of endoplasmic reticulum (ER) stress. Tetracyclines increase mitochondrial levels of the mitoribosome quality control factor MALSU1 (Mitochondrial Assembly of Ribosomal Large Subunit 1) and promote its recruitment to the mitoribosome large subunit, where MALSU1 is necessary for tetracycline‐induced survival and suppression of ER stress. Glucose starvation induces ER stress to activate the unfolded protein response and IRE1α‐mediated cell death that is inhibited by tetracyclines. These studies establish a new interorganelle communication whereby inhibition of the mitoribosome signals to the ER to promote survival, implicating basic mechanisms of cell survival and treatment of mitochondrial diseases. Synopsis: This study identifies a link between mitochondrial protein translation and endoplasmic reticulum stress, where activation of mitoribosome quality control suppresses unfolded protein responses. These results illustrate a novel interorganelle communication that adds insight into mechanisms of cell survival in normal physiology and disease.Mitoribosome targeting with tetracyclines rescues mitochondrial mutant cells from cell death depending on mitoribosome quality control protein MALSU1.MALSU1 is recruited to the mitoribosome large subunit upon tetracycline treatment.Consistent with cell survival responses, tetracyclines attenuate activation of the UPR in the endoplasmic reticulum, which is dependent on MALSU1. [ABSTRACT FROM AUTHOR]

While targeted treatment against BRAF(V600E) improve survival for melanoma patients, many will see their cancer recur. Here we provide data indicating that epigenetic suppression of PGC1α defines an aggressive subset of chronic BRAF-inhibitor treated melanomas. A metabolism-centered pharmacological screen further identifies statins (HMGCR inhibitors) as a collateral vulnerability within PGC1α-suppressed BRAF-inhibitor resistant melanomas. Lower PGC1α levels mechanistically causes reduced RAB6B and RAB27A expression, whereby their combined re-expression reverses statin vulnerability. BRAF-inhibitor resistant cells with reduced PGC1α have increased integrin-FAK signaling and improved extracellular matrix detached survival cues that helps explain their increased metastatic ability. Statin treatment blocks cell growth by lowering RAB6B and RAB27A prenylation that reduces their membrane association and affects integrin localization and downstream signaling required for growth. These results suggest that chronic adaptation to BRAF-targeted treatments drive novel collateral metabolic vulnerabilities, and that HMGCR inhibitors may offer a strategy to treat melanomas recurring with suppressed PGC1α expression. Melanoma phenotypic switching contributes to targeted BRAF treatment resistance. Here the authors identify a subset of BRAF treatment-resistant melanomas with suppressed PGC1a expression that are sensitive to HMGCR inhibitors. [ABSTRACT FROM AUTHOR]

In obesity and type 2 diabetes, Glut4 glucose transporter expression is decreased selectively in adipocytes (1). Adipose-specific knockout or overexpression of Glut4 alters systemic insulin sensitivity (2). Here we show, using DNA array analyses, that nicotinamide N-methyltransferase (Nnmt) is the most strongly reciprocally regulated gene when comparing gene expression in white adipose tissue (WAT) from adipose-specific Glut4-knockout or adipose-specific Glut4-overexpressing mice with their respective controls. NNMT methylates nicotinamide (vitamin B3) using S-adenosylmethionine (SAM) as a methyl donor (3,4). Nicotinamide is a precursor of [NAD.sup.+], an important cofactor linking cellular redox states with energy metabolism (5). SAM provides propylamine for polyamine biosynthesis and donates a methyl group for histone methylation (6). Polyamine flux including synthesis, catabolism and excretion, is controlled by the rate-limiting enzymes ornithine decarboxylase (ODC) and spermidine-spermine N1-acetyltransferase (SSAT; encoded by Satl) and by polyamine oxidase (PAO), and has a major role in energy metabolism (7,8). We report that NNMT expression is increased in WAT and liver of obese and diabetic mice. Nnmt knockdown in WAT and liver protects against diet-induced obesity by augmenting cellular energy expenditure. NNMT inhibition increases adipose SAM and [NAD.sup.+] levels and upregulates ODC and SSAT activity as well as expression, owing to the effects of NNMT on histone H3 lysine 4 methylation in adipose tissue. Direct evidence for increased polyamine flux resulting from NNMT inhibition includes elevated urinary excretion and adipocyte secretion of diacetylspermine, a product of polyamine metabolism. NNMT inhibition in adipocytes increases oxygen consumption in an ODC-, SSAT- and PAO-dependent manner. Thus, NNMT is a novel regulator of histone methylation, polyamine flux and [NAD.sup.+]-dependent SIRT1 signalling, and is a unique and attractive target for treating obesity and type 2 diabetes., Nnmt is expressed at high levels in adipose tissue and liver and at lower levels in other organs (3,4). Nnmt is increased in multiple cancers (9,10), neuro-degenerative diseases (11), and [...]

Mitochondria provide essential metabolites and adenosine triphosphate (ATP) for the regulation of energy homeostasis. For instance, liver mitochondria are a vital source of gluconeogenic precursors under a fasted state. However, the regulatory mechanisms at the level of mitochondrial membrane transport are not fully understood. Here, we report that a liver-specific mitochondrial inner-membrane carrier SLC25A47 is required for hepatic gluconeogenesis and energy homeostasis. Genome-wide association studies found significant associations between SLC25A47 and fasting glucose, HbA1c, and cholesterol levels in humans. In mice, we demonstrated that liver-specific depletion of SLC25A47 impaired hepatic gluconeogenesis selectively from lactate, while significantly enhancing whole-body energy expenditure and the hepatic expression of FGF21. These metabolic changes were not a consequence of general liver dysfunction because acute SLC25A47 depletion in adult mice was sufficient to enhance hepatic FGF21 production, pyruvate tolerance, and insulin tolerance independent of liver damage and mitochondrial dysfunction. Mechanistically, SLC25A47 depletion leads to impaired hepatic pyruvate flux and malate accumulation in the mitochondria, thereby restricting hepatic gluconeogenesis. Together, the present study identified a crucial node in the liver mitochondria that regulates fasting-induced gluconeogenesis and energy homeostasis. [ABSTRACT FROM AUTHOR]