Metallothionein Attenuated Arsenic-Induced Cytotoxicity: The Underlying Mechanism Reflected by Metabolomics and Lipidomics

Abstract

Arsenic ions (As3+) have been recognized as a hazard that threatens the health of humans. Metallothionein (MT) rich in cysteine may provide favorable binding sites for chelation of As3+. However, the influence of MT on As3+-induced toxicity and the underlying mechanism are poorly understood, especially at the metabolic level. Herein, the effects of MT on As3+-induced toxicity were evaluated. Cell viability analysis suggested that MT alleviated As3+-induced cytotoxicity. The metabolic response of PC12 cells to As3+ investigated by lipidomics and metabolomics indicated that the presence of As3+ disrupted phospholipids metabolism and induced cell membrane damage. Moreover, energy and amino acid metabolism were perturbed by As3+. The perturbation of As3+ on metabolism was further illustrated by the decrease of the mitochondrial membrane potential and the rise of cellular reactive oxygen species (ROS). On the contrary, MT rescued As3+-induced metabolic disorder and suppressed ROS accumulation. In addition, the binding process between As3+ and MT was characterized. The results proved that the As3+–MT complex was formed and chelated As3+-scavenged ROS, thus alleviating the toxic effects of As3+. These results revealed that MT would be a potential agent to reduce As3+-induced cytotoxicity.

Photoprotective Mechanism of Fucoxanthin in Ultraviolet B Irradiation-Induced Retinal Müller Cells Based on Lipidomics Analysis

“…48 Moreover, it plays an essential role in the glucose−alanine cycle in tissues and the liver in mammals. 39 The increased alanine levels were downregulated in the UVB-FX-treated group compared to that in positive control cells, demonstrating the antioxidative potential of FX. 49 Asparagine, an important amino acid regulator, is involved in multiple metabolic processes, including amino acid homeostasis, nucleotide synthesis, and cell proliferation.…”

“…The phospholipid bilayer and its associated lipids are the major part of the cellular membrane, existing as primary targets of ROS attack, which can easily leads to lipid peroxidation. 39 Levels of most PC lipids, including PC(13:0), PC(14:0), PC(15:0), PC(16:0), PC(16:1), and PC(22:1), were significantly reduced in cells in the positive control group but upregulated after incubation with FX. Moreover, the levels of PE, PI, PG, and PS were similarly restored in the UVB-FX-treated group, while LPC and LPE were downregulated compared with their abundance in the positive control group (Figure S4).…”

“…As reported in a previous study, oxidative damage can cause the collapse of ΔΨm and calcium overload (Figure 3D), which further trigger the release of apoptotic factors from mitochondria. 39 The accumulation of lipids such as FAs and TG is related to JNK phosphorylation (Figure 5A), which could induce cell inflammation and apoptosis. 40 The levels of FAs, for example FAHFA 20:4/18:0, in the positive control group were 70.06 ± 2.61% higher than that of the negative control (Figure 7).…”

“…Clearly, levels of lipids in the following subclasses were modulated in RMCs after UVB exposure and FX treatment: fatty acids (FAs), glycerophospholipids (PC, PE, LPC, LPE, PG, PI, PS), glycerol (diacylglycerol (DG), triacylglycerol (TG)), sphingolipids (Cer, SM), and alkyl- and alkenyl-substituted PEs (EtherPE) and PCs (EtherPC). The phospholipid bilayer and its associated lipids are the major part of the cellular membrane, existing as primary targets of ROS attack, which can easily leads to lipid peroxidation . Levels of most PC lipids, including PC(13:0), PC(14:0), PC(15:0), PC(16:0), PC(16:1), and PC(22:1), were significantly reduced in cells in the positive control group but upregulated after incubation with FX.…”

Interactions with Arsenic: Mechanisms of Toxicity and Cellular Resistance in Eukaryotic Microorganisms

“…Moreover, they might play a relevant function as ROS scavengers. Recently, it was proven that MTs can chelate As(III) in human cells [146], although many previous reports suggested this property [147][148][149][150]. In silico genomic analysis showed that MT genes are well represented in diverse groups of microalgae, but they are scarce in diatoms and dinoflagellates, two important groups of primary production in marine environments.…”