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Background LncRNAs have been found to be involved in various aspects of biological processes. In this study, we aimed to uncover the molecular mechanisms of lncRNA EPB41L4A-AS1 in regulating glycolysis and glutaminolysis in cancer cells. Methods The expression of EPB41L4A-AS1 in cancer patients was analyzed in TCGA and GEO datasets. The level of cellular metabolism was determined by extracellular flux analyzer. The relationship between p53 and EPB41L4A-AS1 was explored by qRT-PCR, luciferase assay and ChIP assay. The interactions between EPB41L4A-AS1 and HDAC2 or NPM1 were determined by RNA immunoprecipitation, RNA pull-down assay and RNA-FISH- immunofluorescence. Findings EPB41L4A-AS1 was a p53-regulated gene. Low expression and deletion of lncRNA EPB41L4A-AS1 were found in a variety of human cancers and associated with poor prognosis of cancer patients. Knock down EPB41L4A-AS1 expression triggered Warburg effect, demonstrated as increased aerobic glycolysis and glutaminolysis. EPB41L4A-AS1 interacted and colocalized with HDAC2 and NPM1 in nucleolus. Silencing EPB41L4A-AS1 reduced the interaction between HDAC2 and NPM1, released HDAC2 from nucleolus and increased its distribution in nucleoplasm, enhanced HDAC2 occupation on VHL and VDAC1 promoter regions, and finally accelerated glycolysis and glutaminolysis. Depletion of EPB41L4A-AS1 increased the sensitivity of tumor to glutaminase inhibitor in tumor therapy. Interpretation EPB41L4A-AS1 functions as a repressor of the Warburg effect and plays important roles in metabolic reprogramming of cancer.

For example, when an LCE fiber is lifting a heavy load, a high contraction ratio produces a larger displacement and thus a higher external work output. A fast contraction rate, on the other hand, shortens the time required to lift the load and increases the work efficiency of the LCE fiber. In nature, human skeletal muscle can produce larger than 40% contraction at a contraction rate of higher than 50% s −1 , [1,18] allowing it to perform intense movements. For example, when humans are doing sports, e.g., basketball shooting, their muscles can contract both substantially and rapidly. However, none of the LCE fibers reported so far can simultaneously deform with a large contraction ratio and fast contraction rate comparable to human muscles, restricting its applications to conduct intense movements. To date, thermal-responsive LCE fibers are capable of generating large deformation. [19][20][21][22] But the heating rate is limited by the low thermal conductivity of air, leading to a slow contraction of LCE. Second, although light is a precise and fast stimulus, it can only propagate along a straight line. Thus, photo-responsive LCE fibers are usually exposed to light only on one side and typically demonstrate bending deformation, bringing about difficulties to achieve substantial contractile deformation. [23][24][25][26] Overall, with the development of LCE fibers, the gap that LCE fibers can output large contraction at an ultrafast rate needs to be filled.Herein, we report electrothermal-responsive liquid metal (LM) containing LCE (LM-LCE) fibers that can export large contraction with an ultrafast speed. Comparing to rigid conductive fillers, the fluidic property of LM alleviates the restriction to the deformation of LCE, [27,28] ensuring a large contraction generated by LCE. As a high temporal resolution stimulus, the electrical trigger (e.g., voltage value and pulse time) can be adjusted to achieve high instantaneous input of electrical energy and rapidly heat the entire LM-LCE fibers, resulting in a high contraction rate. The electrothermal-responsive LM-LCE fibers can be used as artificial muscles to drive soft robots to perform various functions with intense actuation. Result and DiscussionLM-LCE fibers were fabricated as shown in Figure 1a. First, LCE fibers oriented along the long axis were prepared according to Liquid crystal elastomer (LCE) fibers are capable of large and reversible deformations, making them an ideal artificial muscle. However, limited to stimulating source and structural design, current LCE fibers have not yet achieved both large contraction ratio and fast contraction rate to perform the intense motion. In this work, electrothermal-responsive liquid metal (LM) containing LCE (LM-LCE) fibers is reported. By introducing flexible liquid metal, LM-LCE fibers retain deformability with a large contraction ratio similar to that of pure LCE fibers and are endowed with electrical responsiveness. Applying precisely controlled electrical stimulation, the contraction ratio and rate of LM-LCE fibers ...

Damage to mitochondria often results in the activation of both mitophagy and mitochondrial apoptosis. The elimination of dysfunctional mitochondria is necessary for mitochondrial quality maintenance and efficient energy supply. Here we report that miR-181a is a novel inhibitor of mitophagy. miR-181a is downregulated by mitochondrial uncouplers in human neuroblastoma SH-SY5Y cells. Overexpression of miR-181a inhibits mitochondrial uncoupling agents-induced mitophagy by inhibiting the degradation of mitochondrial proteins without affecting global autophagy. Knock down of endogenous miR-181a accelerates the autophagic degradation of damaged mitochondria. miR-181a directly targets Parkin E3 ubiquitin ligase and partially blocks the colocalization of mitochondria and autophagosomes/lysosomes. Re-expression of exogenous Parkin restores the inhibitory effect of miR-181a on mitophagy. Furthermore, miR-181a increases the sensitivity of neuroblastoma cells to mitochondrial uncoupler-induced apoptosis, whereas miR-181a antagomir prevents cell death. Because mitophagy defects are associated with a variety of human disorders, these findings indicate an important link between microRNA and Parkin-mediated mitophagy and highlights a potential therapeutic strategy for human diseases.