Noxious Iron-Calcium Connections in Neurodegeneration

Abstract

Iron and calcium share the common feature of being essential for normal neuronal function. Iron is required for mitochondrial function, synaptic plasticity, and the development of cognitive functions whereas cellular calcium signals mediate neurotransmitter exocytosis, axonal growth and synaptic plasticity, and control the expression of genes involved in learning and memory processes. Recent studies have revealed that cellular iron stimulates calcium signaling, leading to downstream activation of kinase cascades engaged in synaptic plasticity. The relationship between calcium and iron is Janus-faced, however. While under physiological conditions iron-mediated reactive oxygen species generation boosts normal calcium-dependent signaling pathways, excessive iron levels promote oxidative stress leading to the upsurge of unrestrained calcium signals that damage mitochondrial function, among other downstream targets. Similarly, increases in mitochondrial calcium to non-physiological levels result in mitochondrial dysfunction and a predicted loss of iron homeostasis. Hence, if uncontrolled, the iron/calcium self-feeding cycle becomes deleterious to neuronal function, leading eventually to neuronal death. Here, we review the multiple cell-damaging responses generated by the unregulated iron/calcium self-feeding cycle, such as excitotoxicity, free radical-mediated lipid peroxidation, and the oxidative modification of crucial components of iron and calcium homeostasis/signaling: the iron transporter DMT1, plasma membrane, and intracellular calcium channels and pumps. We discuss also how iron-induced dysregulation of mitochondrial calcium contributes to the generation of neurodegenerative conditions, including Alzheimer's disease (AD) and Parkinson's disease (PD).

Keywords: HIF-1; Nrf-2; ferroptosis; inflammation; mitochondria; neurodegenerative diseases; reactive oxygen species.

FIGURE 1

Regulation of HIF-1 activity by iron and calcium. HIF-1 activity is induced by hypoxia, which decreases the activity of HIF-1 hydrolases (PHD), by low iron (e.g., iron chelation), which also decreases the activity of HIF-1 hydrolases, and by low intracellular calcium, which decreases the interaction of HIF-1α with the von-Hippel-Lindau protein (see text). High intracellular calcium levels increase the rate of HIF-1 proteasomal degradation while high levels of iron both maintain the activity of HIF-1 hydrolases and, through enhanced ROS production increase the cellular levels of calcium by activation of RyR, IP₃R, and L-type calcium channels.

FIGURE 2

Neuronal pathways that increase calcium and iron levels. Increases in ROS due to mitochondrial dysfunction, inflammation, and NOX activation promote excessive ROS generation that promotes calcium release via RyR channels and increases redox-active iron by IRP1 activation. Through the Fenton reaction, iron induces lipid peroxidation that inhibits the PMCA calcium pump. In addition, excitotoxic conditions over-activate NMDA receptors (NMDAR), which results in increased cytoplasmic calcium levels and increases iron levels via DMT1 activation.

FIGURE 3

Iron and calcium-mediated cell death by ferroptosis. Increases in ROS due to mitochondrial dysfunction, non-physiological activation of NOX, excitotoxicity, inflammation, or other factors result in the increase of redox-active iron mediated by activation of IRP1. Through the Fenton reaction, iron induces lipid peroxidation that activates NMDAR and the SOCE system, which results in increased cytoplasmic calcium. Increased iron levels and lipid peroxidation mediate ferroptotic cell death, which may also be induced by unregulated calcium levels. Increased ROS levels decrease the intracellular GSH content, leading to ferroptosis, and activate the intracellular calcium channels RyR and IP3R, which adds to the increase in cytoplasmic calcium caused by iron-induced lipid peroxidation.

FIGURE 4

The self-feeding cycle ROS–Fe–Ca. Mitochondrial dysfunction promotes in increased ROS and activation IRP1, which results in increased iron accumulation. Excess iron promotes lipid peroxidation by hydroxyl radicals derived from the Fenton reaction. Lipid peroxidation modifies the activity of a variety of proteins involved in calcium homeostasis that results in massive calcium influx. Increased cytoplasmic calcium levels result in increased mitochondrial calcium and accentuated mitochondrial dysfunction, oxidative stress, and damage. If uncontrolled, this ROS–iron–calcium self-feeding cycle becomes deleterious to mitochondrial and neuronal function, leading eventually to apoptotic or ferroptotic cell death. In yet another aspect of this cycle, high intracellular calcium levels increase the rate of HIF-1 proteasome degradation, which results in increased ROS levels, product of decreased expression of antioxidant proteins.