DDIT4 (DNA-damage-inducible transcript 4)

Review on DDIT4 (DNA-damage-inducible transcript 4), with data on DNA, on the protein encoded, and where the gene is implicated

Regulation of TFEB and V-ATPases by mTORC1

TORC1 is a key regulator of cell growth in response to nutrients and acts at the surface of the late endosome. This study identifies V-ATPase genes as transcriptional targets of TORC1 and implicates the transcription factor TFEB as an important mediator of TORC1-dependent gene expression and TORC1-regulated endocytosis

Abrogating GPT2 in triple negative breast cancer inhibits tumor growth and promotes autophagy

Uncontrolled proliferation and altered metabolic reprogramming are hallmarks of cancer. Active glycolysis and glutaminolysis are characteristic features of these hallmarks and required for tumorigenesis. A fine balance between cancer metabolism and autophagy is a prerequisite of homeostasis within cancer cells. Here we show that glutamate pyruvate transaminase 2 (GPT2), which serves as a pivot between glycolysis and glutaminolysis, is highly upregulated in aggressive breast cancers, particularly the triple negative breast cancer (TNBC) subtype. Abrogation of this enzyme results in decreased TCA cycle intermediates, which promotes the rewiring of glucose carbon atoms and alterations in nutrient levels. Concordantly, loss of GPT2 results in an impairment of mechanistic target of rapamycin complex 1 (mTORC1) activity as well as the induction of autophagy. Furthermore, in vivo xenografts studies have shown that autophagy induction correlates with decreased tumor growth and that markers of induced autophagy correlate with low GPT2 levels in patient samples. Taken together, these findings indicate that cancer cells have a close network between metabolic and nutrient sensing pathways necessary to sustain tumorigenesis, and that aminotransferase reactions play an important role in maintaining this balance

Iron depletion suppresses mTORC1-directed signalling in intestinal Caco-2 cells via induction of REDD

Acknowledgements This work was supported by grants from the Biotechnology and Biological Science Research Council (BB/I007261/1 and BB/N002342/1) and The Scottish Government's Rural and Environment Science and Analytical Services Division (RESAS 854/11).Peer reviewedPublisher PD

Physiological trade-offs associated with fasting weight loss, resistance to exercise and behavioral traits in farmed gilthead sea bream (Sparus aurata) selected by growth

Three gilthead sea bream families representative of slow, intermediate and fast heritable growth in the Spanish PROGENSA (R) selection program were used to uncover the effects of such selection on energy partitioning through measurements of fasting weight loss, swimming performance and behavioral traits in one- and two-year-old fish. Firstly, selection for fast growth significantly increased fasting weight loss and decreased the hormonal ratio of circulating Igf-i/Gh in short-term fasting fish (17 days). This is indicative of a stronger negative energy balance that explains the reduced compensatory growth of fast-growing fish during the subsequent short-term refeeding period (7 days). Selection for fast growth also decreased the critical speed (Ucrit, 6-7 BL sxfffd; 1) at which fish become exhausted in a swim tunnel respirometer. The maximum metabolic rate (MMR), defined as the maximum rate of oxygen consumption during forced exercise, was almost equal in all fish families though the peak was achieved at a lowest speed in the fast-growing family. Since circulating levels of lactate were also slightly decreased in freeswimming fish of this family group, it appears likely that the relative energy contribution of anaerobic metabolism to physical activity was lowered in genetically fast-growing fish. Selection for heritable growth also altered activity behavior because slow-growing families displayed an anticipatory food response associated with more pronounced daily rhythms of physical activity. Also, respiratory frequency and body weight showed and opposite correlation in slow- and fast-growing free-swimming fish as part of the complex trade-offs of growth, behavior and energy metabolism. Altogether, these results indicate that selective breeding for fast growth might limit the anaerobic fitness that would help to cope with limited oxygen availability in a scenario of climate change.We acknowledge the support of Veronica de las Heras and the Animalarium Service of IATS (Felix Alvarez and Jose Ramon Mateo) for their support in fish rearing

Is REDD1 a Metabolic Éminence Grise?

Regulated in development and DNA damage response 1 (REDD1) has been functionally linked to the control of diverse cellular processes due, at least in part, to its ability to repress mammalian or mechanistic Target of Rapamycin (mTOR) Complex-1 (mTORC1), a key protein complex controlled by hormonal and nutrient cues. Notably, emerging evidence suggests that REDD1 also regulates several pathways involved in modulating energy balance and metabolism. Herein, we discuss evidence implicating REDD1 as a key modulator of insulin action and metabolic function, including its potential contribution to mitochondrial biology and pancreatic islet function. Collectively, the available evidence suggests that REDD1 has a more prominent role in energy homeostasis than was previously thought, and implicates REDD1 as a potential therapeutic target for treatment of metabolic disorders

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field