Nanosilver incurs an adaptive shunt of energy metabolism mode to glycolysis in tumor and nontumor cells.
Chen Yue,Wang Zhe,Xu Ming,Wang Xiang,Liu Rui,Liu Qian,Zhang Zhihong,Xia Tian,Zhao Jincai,Jiang Guibin,Xu Yong,Liu Sijin
Due to its significant antimicrobial properties, nanosilver (nAg) has been substantially used in a wide spectrum of areas. This has raised the concerns on the detrimental effects on environment and human health. Although numerous studies have documented nAg-mediated toxicity to cells or organisms, little attempt has been made to study the biological impacts of nAg on cells at nontoxic concentrations, namely, the distinct biological effects that can be separated from direct cytotoxicity. Here, we studied nAg-mediated effects on energy metabolism in cells under sublethal exposure. Treatment of nAg at nontoxic concentrations resulted in a decline of ATP synthesis and attenuation of respiratory chain function in nontumor HEK293T cells and tumor cells with differential respiration rate, including HepG2, HeLa, A498, and PC3 cells. Cellular energy homeostasis was switched from oxidative phosphorylation-based aerobic metabolism to anaerobic glycolysis, which is an adaption process to satisfy the energy demand for cell survival. Nanospheres with smaller size showed greater capability to alter cellular energy metabolism than those with larger size or nanoplates. Mechanistic investigation manifested that inhibition of PGC-1α by nAg was, at least partially, accountable for the transition from oxidative phosphorylation to glycolysis. Additionally, altered expression of a few energy metabolism-related genes (such as PFKFB3 and PDHA1) was also involved in the transition process. We further showed nAg-induced depolarization of mitochondrial membrane potential and reduction of respiratory chain complex activity. Together, our combined results uncovered the mechanisms by which nAg induced energy metabolism reprogramming in both tumor and nontumor cells under sublethal dosage.
Spatial mapping of juxtacrine axo-glial interactions identifies novel molecules in peripheral myelination.
Poitelon Y,Bogni S,Matafora V,Della-Flora Nunes G,Hurley E,Ghidinelli M,Katzenellenbogen B S,Taveggia C,Silvestri N,Bachi A,Sannino A,Wrabetz L,Feltri M L
Cell-cell interactions promote juxtacrine signals in specific subcellular domains, which are difficult to capture in the complexity of the nervous system. For example, contact between axons and Schwann cells triggers signals required for radial sorting and myelination. Failure in this interaction causes dysmyelination and axonal degeneration. Despite its importance, few molecules at the axo-glial surface are known. To identify novel molecules in axo-glial interactions, we modified the 'pseudopodia' sub-fractionation system and isolated the projections that glia extend when they receive juxtacrine signals from axons. By proteomics we identified the signalling networks present at the glial-leading edge, and novel proteins, including members of the Prohibitin family. Glial-specific deletion of Prohibitin-2 in mice impairs axo-glial interactions and myelination. We thus validate a novel method to model morphogenesis and juxtacrine signalling, provide insights into the molecular organization of the axo-glial contact, and identify a novel class of molecules in myelination.
The Phr1 ubiquitin ligase promotes injury-induced axon self-destruction.
Babetto Elisabetta,Beirowski Bogdan,Russler Emilie V,Milbrandt Jeffrey,DiAntonio Aaron
Axon degeneration is an evolutionarily conserved process that drives the loss of damaged axons and is an early event in many neurological disorders, so it is important to identify the molecular constituents of this poorly understood mechanism. Here, we demonstrate that the Phr1 E3 ubiquitin ligase is a central component of this axon degeneration program. Loss of Phr1 results in prolonged survival of severed axons in both the peripheral and central nervous systems, as well as preservation of motor and sensory nerve terminals. Phr1 depletion increases the axonal level of the axon survival molecule nicotinamide mononucleotide adenyltransferase 2 (NMNAT2), and NMNAT2 is necessary for Phr1-dependent axon stability. The profound long-term protection of peripheral and central mammalian axons following Phr1 deletion suggests that pharmacological inhibition of Phr1 function may be an attractive therapeutic candidate for amelioration of axon loss in neurological disease.