Uncoupling protein 2 (UCP2) is involved in various physiological and pathological processes such as insulin secretion, stem cell differentiation, cancer, and aging. However, its biochemical and physiological function is still under debate. Here we show that UCP2 is a metabolite transporter that regulates substrate oxidation in mitochondria. To shed light on its biochemical role, we first studied the effects of its silencing on the mitochondrial oxidation of glucose and glutamine. Compared with wild-type, UCP2-silenced human hepatocellular carcinoma (HepG2) cells, grown in the presence of glucose, showed a higher inner mitochondrial membrane potential and ATP:ADP ratio associated with a lower lactate release. Opposite results were obtained in the presence of glutamine instead of glucose. UCP2 reconstituted in lipid vesicles catalyzed the exchange of malate, oxaloacetate, and aspartate for phosphate plus a proton from opposite sides of the membrane. The higher levels of citric acid cycle intermediates found in the mitochondria of siUCP2-HepG2 cells compared with those found in wild-type cells in addition to the transport data indicate that, by exporting C4 compounds out of mitochondria, UCP2 limits the oxidation of acetyl-CoA-producing substrates such as glucose and enhances glutaminolysis, preventing the mitochondrial accumulation of C4 metabolites derived from glutamine. Our work reveals a unique regulatory mechanism in cell bioenergetics and provokes a substantial reconsideration of the physiological and pathological functions ascribed to UCP2 based on its purported uncoupling properties. mitochondrial carrier | glucose and glutamine metabolism | Warburg effect | metabolic reprogramming | diabetes M itochondria couple respiratory oxidation of nutrients to ATP synthesis through an electrochemical proton gradient. Proton leak allows partial uncoupling of oxidative phosphorylation, producing heat. Through this mechanism, Uncoupling protein (UCP)1, a member of the mitochondrial carrier family (MCF), regulates adaptive thermogenesis in mammals. In 1997 a protein similar to UCP1 was cloned and named UCP2 (1) based on the assumption that the sequence homology implied a similar function. Whereas UCP1 has a clear-cut uncoupling activity relevant to nonshivering thermogenesis, this is not the case for UCP2. UCP2 has been involved in numerous physiopathological conditions including metabolic disorders, inflammation, ischemic shock, cancer, and aging. Furthermore, changes in UCP2 expression affect metabolic functions (2, 3). It has been suggested that these metabolic actions of UCP2 are due to a mild UCP1-like uncoupling activity (4, 5) that, combined with the generally low levels of UCP2 expression, would regulate the release of reactive oxygen species (ROS) (6) without significantly affecting energy conservation. Although fatty acid-dependent proton transport mediated by UCP2 was reported in reconstituted liposomes (7), a mounting body of evidence argues against UCP2 having an uncoupling activity in vivo (8, 9) and sugge...

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Clear cell renal cell carcinoma (ccRCC) is the most frequent histological kidney cancer subtype. Over the last decade, significant progress has been made in identifying the genetic and metabolic alterations driving ccRCC development. In particular, an integrated approach using transcriptomics, metabolomics, and lipidomics has led to a better understanding of ccRCC as a metabolic disease. The metabolic profiling of this cancer could help define and predict its behavior in terms of aggressiveness, prognosis, and therapeutic responsiveness, and would be an innovative strategy for choosing the optimal therapy for a specific patient. This review article describes the current state-of-the-art in research on ccRCC metabolic pathways and potential therapeutic applications. In addition, the clinical implication of pharmacometabolomic intervention is analyzed, which represents a new field for novel stage-related and patient-tailored strategies according to the specific susceptibility to new classes of drugs.

Renal cell carcinoma (RCC) is the seventh most common cancer in men and the ninth most common cancer in women worldwide. There is plenty of evidence about the role of the immune system in surveillance against tumors. Thanks to a better understanding of immunosurveillance mechanisms, immunotherapy has been introduced as a promising cancer treatment in recent years. Renal cell carcinoma (RCC) has long been thought chemoresistant but highly immunogenic. Considering that up to 30% of the patients present metastatic disease at diagnosis, and around 20–30% of patients undergoing surgery will suffer recurrence, we need to identify novel therapeutic targets. The introduction of immune checkpoint inhibitors (ICIs) in the clinical management of RCC has revolutionized the therapeutic approach against this tumor. Several clinical trials have shown that therapy with ICIs in combination or ICIs and the tyrosine kinase inhibitor has a very good response rate. In this review article we summarize the mechanisms of immunity modulation and immune checkpoints in RCC and discuss the potential therapeutic strategies in renal cancer treatment.

MicroRNAs (miRNAs) are emerging as biomarkers for the detection and prognosis of cancers due to their inherent stability and resilience. To summarize the evidence regarding the role of urinary miRNAs (umiRNAs) in the detection, prognosis, and therapy of genitourinary cancers, we performed a systematic review of the most important scientific databases using the following keywords: (urinary miRNA) AND (prostate cancer); (urinary miRNA) AND (bladder cancer); (urinary miRNA) AND (renal cancer); (urinary miRNA) AND (testicular cancer); (urinary miRNA) AND (urothelial cancer). Of all, 1364 articles were screened. Only original studies in the English language on human specimens were considered for inclusion in our systematic review. Thus, a convenient sample of 60 original articles was identified. UmiRNAs are up- or downregulated in prostate cancer and may serve as potential non-invasive molecular biomarkers. Several umiRNAs have been identified as diagnostic biomarkers of urothelial carcinoma and bladder cancer (BC), allowing us to discriminate malignant from nonmalignant forms of hematuria. UmiRNAs could serve as therapeutic targets or recurrence markers of non-muscle-invasive BC and could predict the aggressivity and prognosis of muscle-invasive BC. In renal cell carcinoma, miRNAs have been identified as predictors of tumor detection, aggressiveness, and progression to metastasis. UmiRNAs could play an important role in the diagnosis, prognosis, and therapy of urological cancers.