Brain Iron Homeostasis: A Focus on Microglial Iron

Abstract

Iron is an essential trace element required for important brain functions including oxidative metabolism, synaptic plasticity, myelination, and the synthesis of neurotransmitters. Disruptions in brain iron homeostasis underlie many neurodegenerative diseases. Increasing evidence suggests that accumulation of brain iron and chronic neuroinflammation, characterized by microglia activation and secretion of proinflammatory cytokines, are hallmarks of neurodegenerative disorders including Alzheimer' s disease. While substantial efforts have led to an increased understanding of iron metabolism and the role of microglial cells in neuroinflammation, important questions still remain unanswered. Whether or not increased brain iron augments the inflammatory responses of microglial cells, including the molecular cues that guide such responses, is still unclear. How these brain macrophages accumulate, store, and utilize intracellular iron to carry out their various functions under normal and disease conditions is incompletely understood. Here, we describe the known and emerging mechanisms involved in microglial cell iron transport and metabolism as well as inflammatory responses in the brain, with a focus on AD.

Keywords: Alzheimer’s disease; cytokines; neurodegeneration; neuroimmune responses; neuroinflammation.

Figure 1

Iron and mitochondrial function. The mitochondrial electron transport chain contains multiple iron–sulfur clusters and heme-containing proteins necessary for ATP synthesis. NADH dehydrogenase (complex I) contains eight Fe–S clusters, succinate dehydrogenase (complex II) contains three Fe–S clusters and one heme moiety, while complex III (cytochrome bc1) contains one Fe–S cluster and several heme groups vital for its functions. Complex IV (cytochrome c oxidase) also contains two heme moieties. Aconitase, a key enzyme that catalyzes the stereo-specific isomerization of citrate to isocitrate through cis-aconitate in the tricarboxylic acid (TCA) cycle contain Fe–S clusters.

Figure 2

Iron trafficking and microglial cell polarization. (Left) Pro-inflammatory stimuli upregulate the expression of divalent metal transporter-1 (DMT-1) and the uptake of non-Tf-bound iron (NTBI). These effects are associated with increased labile iron and an expanded pool of ferritin. These changes reflect M1 polarization. (Right) Anti-inflammatory stimuli increase transferrin receptor (TfR) levels to upregulate Tf-bound iron (TBI) uptake by receptor-mediated endocytosis. In recycling endosomes, the low pH promotes the release of Fe³⁺ for ferrireduction, most likely by STEAP3. Fe²⁺ may be released into the cytosol through DMTI or another channel for use in mitochondria to promote heme production. We speculate that, under anti-inflammatory conditions, microglia may release ferritin (Ftn)-bound iron through lysosomal exocytosis to help oligodendrocyte function and neuronal repair.