Potential Role of Epigenetic Mechanism in Manganese Induced Neurotoxicity

Figure 2

Schematic summarizing the oxidative stress mediated apoptotic pathway through which manganese causes the dopaminergic cell death and is involved in neurotoxic effects. Mn enters neuronal cells via transferrin/DMT1 receptor. Inside cell, Mn primarily gets accumulated in mitochondria causing inhibition of complex I/II and F1ATPase and interferes with Ca²⁺ activated ATP production. This resulted in loss of mitochondrial potential with release of Cyt C. Mitochondrial dysfunction also causes the generation of oxidative stress (ROS/RNS). The oxidative stress resulting from dopamine autooxidation causes damage to DNA/RNA/protein/lipid and releases inflammatory mediators that activate ERK/MAPK pathway. Activated kinase phosphorylates FoxO, preventing its translocation to nucleus and activation of antioxidant enzyme genes. Mn may also cause the endoplasmic reticulum (ER) stress that resulted in activation of caspase-12 through unfolded protein response. Caspase-12 may further activate the other downstream multiple caspases which culminates in apoptotic cell death. Cyt C released upon mitochondrial damage activates caspase-3, a critical regulator of apoptosis. Caspase-3 proteolytically activates the protein kinase C δ (PKCδ) that again can activate ERK/MAPK pathway or on translocation to nucleus causes the expression of proapoptotic genes, resulting in mitochondrial mediated apoptotic cell death. Protein phosphatase 2A is a downstream substrate for PKCδ; activation of PP2A reduces the activity of tyrosine hydroxylase, inhibiting the dopamine production.