Role of calcium and mitochondria in MeHg-mediated cytotoxicity

Abstract

Methylmercury (MeHg) mediated cytotoxicity is associated with loss of intracellular calcium (Ca²⁺) homeostasis. The imbalance in Ca²⁺ physiology is believed to be associated with dysregulation of Ca²⁺ intracellular stores and/or increased permeability of the biomembranes to this ion. In this paper we summarize the contribution of glutamate dyshomeostasis in intracellular Ca²⁺ overload and highlight the mitochondrial dysfunctions induced by MeHg via Ca²⁺ overload. Mitochondrial disturbances elicited by Ca²⁺ may involve several molecular events (i.e., alterations in the activity of the mitochondrial electron transport chain complexes, mitochondrial proton gradient dissipation, mitochondrial permeability transition pore (MPTP) opening, thiol depletion, failure of energy metabolism, reactive oxygen species overproduction) that could culminate in cell death. Here we will focus on the role of oxidative stress in these phenomena. Additionally, possible antioxidant therapies that could be effective in the treatment of MeHg intoxication are briefly discussed.

Figure 1

Cycle of mercury and its bioaccumulation in aquatic food chain. The values of mercury levels in the plankton and fish are represented as ppm. All data presented in this figure were obtained from (FDA and EPA).

Figure 2

Schematic representation of the structures and space-filled models of methionine (a) and MeHg-Cys complex (b). Note the similarities in chemical structure between the MeHg-Cys conjugate and the amino acid methionine. The geometry-optimized using Universal Force Field (UFF). The representations (ball and stick, Vander Waals spheres) were obtained using the program PyMOL (Molecular Graphics System, Version 1.5.0.1, Schrödinger LLC).

Figure 3

Schematic representation of possible mechanisms and cellular targets involved in the neurotoxicity MeHg-induced: (1) glutamate dyshomeostasis and Ca²⁺ intracellular dysregulation; (2) mitochondrial dysfunction; (3) cytoskeletal disruption; (4) DNA damage; (5) SER dysfunction; (6) thiol depletion (especially glutathione). This scheme is merely representative and the scale of structures does not represent the real size.

Figure 4

MeHg as mediator of neuronal toxicity via Ca²⁺-mediated excitotoxicity: (1) glutamate (Glu) release from presynaptic neuron induced by MeHg; (2) increase of Glu into synaptic cleft; (3) Ca²⁺ influx via NMDA and Kainate receptors; (4) MeHg binds at Glu transporters in astrocytes; (5) mitochondria buffering the excess of Ca²⁺ intracellular; (6) MeHg causing mitochondrial and SER damage; (7) MTPT opening with release of pro-apoptotic factors induced by MeHg alone and/or excess of  [Ca²⁺]_m.

Figure 5

Schematic representation on the role of mitochondria and SER as intracellular Ca²⁺stores and on the cellular death induced by MeHg via Ca²⁺ dyshomeostasis. (a) Under low cytosolic  [Ca²⁺]_i  the SER preferentially moves Ca²⁺ from cytosol due its high affinity and low capacity to stores Ca²⁺; whereas (b) the mitochondria by presenting low affinity and high capacity to stores Ca²⁺ moves it under high cytosolic  [Ca²⁺]_i; (c) the disruption of Ca²⁺ regulation produced by MeHg in either of these stores can lead to release of neuronal proapoptotic factors that may trigger cell death pathways. The scheme presented here is merely representative, and the scale of the different cellular structures does not represent the real size.

Figure 6

Representation of different channels responsible for Ca²⁺ influx/efflux in mitochondria and the possible interaction of MeHg with these channels. VDAC: outer membrane voltage-dependent anion channel; RAM: rapid uptake model; MCU: inner membrane calcium uniporter channel; mRyR: mitochondrial ryanodine receptor; Ca²⁺/H⁺ antiporter; Na⁺/Ca²⁺ exchanger; MPTP: mitochondrial permeability transition pore. The scale of structures represented in this scheme does not represent the real size.

Figure 7

Pyramidal network involved in MeHg neurotoxicity: Arrows denote the interlinked possible pathways by which MeHg may cause cellular damage and the protective effect of natural and synthetic antioxidants against MeHg neurotoxicity by blocking oxidative events triggered via –SH depletion, ROS formation, and Ca²⁺ dyshomeostasis. For full details, see the text.

Figure 8

Possible role of Selenium (Se) on MeHg toxicity: (A) MeHg toxicity reduced by formation of complex MeHg-Se; (B) MeHg toxicity increased due Se depletion by formation of complex MeHg-Se: ↓  Selenoprotein activities and synthesis and  ↑  ROS.