Mitochondrial Iron Metabolism and Its Role in Neurodegeneration

Medical Scientist Training Program, University of Pittsburgh, Pittsburgh, PA, USA.
Journal of Alzheimer's disease: JAD (Impact Factor: 3.61). 01/2010; 20 Suppl 2:S551-68. DOI: 10.3233/JAD-2010-100354
Source: PubMed

ABSTRACT In addition to their well-established role in providing the cell with ATP, mitochondria are the source of iron-sulfur clusters (ISCs) and heme - prosthetic groups that are utilized by proteins throughout the cell in various critical processes. The post-transcriptional system that mammalian cells use to regulate intracellular iron homeostasis depends, in part, upon the synthesis of ISCs in mitochondria. Thus, proper mitochondrial function is crucial to cellular iron homeostasis. Many neurodegenerative diseases are marked by mitochondrial impairment, brain iron accumulation, and oxidative stress - pathologies that are inter-related. This review discusses the physiological role that mitochondria play in cellular iron homeostasis and, in so doing, attempts to clarify how mitochondrial dysfunction may initiate and/or contribute to iron dysregulation in the context of neurodegenerative disease. We review what is currently known about the entry of iron into mitochondria, the ways in which iron is utilized therein, and how mitochondria are integrated into the system of iron homeostasis in mammalian cells. Lastly, we turn to recent advances in our understanding of iron dysregulation in two neurodegenerative diseases (Alzheimer's disease and Parkinson's disease), and discuss the use of iron chelation as a potential therapeutic approach to neurodegenerative disease.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Synthesis of the iron-containing prosthetic groups-heme and iron-sulfur clusters-occurs in mitochondria. The mitochondrion is also an important producer of reactive oxygen species (ROS), which are derived from electrons leaking from the electron transport chain. The coexistence of both ROS and iron in the secluded space of the mitochondrion makes this organelle particularly prone to oxidative damage. Here, we review the elements that configure mitochondrial iron homeostasis and discuss the principles of iron-mediated ROS generation in mitochondria. We also review the evidence for mitochondrial dysfunction and iron accumulation in Alzheimer's disease, Huntington Disease, Friedreich's ataxia, and in particular Parkinson's disease. We postulate that a positive feedback loop of mitochondrial dysfunction, iron accumulation, and ROS production accounts for the process of cell death in various neurodegenerative diseases in which these features are present. Copyright © 2015. Published by Elsevier B.V.
    Mitochondrion 02/2015; DOI:10.1016/j.mito.2015.02.001 · 3.52 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Superparamagnetic iron oxide nanoparticles (SPIONs) are used in many biological applications, which necessitate intracellular targeting. Here, we investigate intracellular localization and gene expression in HeLa cells after treatment with functionalized SPIONs. Functional groups investigated included positive amino propyl silane (APS), polyethylene glycol and targeting peptides: nuclear targeting peptide (NTP) and/or cancer cell uptake promoting peptide (cRGD). Results revealed that the intracellular localization of SPIONs was strongly dependent on the surface chemistry. Nuclear targeted SPIONs functionalized with only NTP or both NTP and cRGD were mostly localized in perinuclear endosomes with a small fraction entering the nucleus. The biocompatibility of cells after treatment was also dependent on surface chemistry, where SPIONs functionalized with both NTP and cRGD exhibited a more significant reduction of cell proliferation compared to NTP or cRGD individually. Interestingly, gene expression after treatment with SPIONs was similar, regardless of the surface functionalization or intracellular localization. The results of this study showed that cellular uptake and intracellular localization predominantly depended on the surface chemistry, while gene expression exhibited a more generic response to SPION treatment.
    Nano brief reports and reviews 02/2014; 09(01). DOI:10.1142/S179329201450009X · 1.26 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ferritin is the main intracellular protein of iron storage with a central role in the regulation of iron metabolism and detoxification. Nucleotide insertions in the last exon of the ferritin light chain cause a neurodegenerative disease known as Neuroferritinopathy, characterized by iron deposition in the brain, particularly in the cerebellum, basal ganglia and motor cortex. The disease progresses relentlessly, leading to dystonia, chorea, motor disability and neuropsychiatry features. The characterization of a good animal model is required to compare and contrast specific features with the human disease, in order to gain new insights on the consequences of chronic iron overload on brain function and behavior. To this aim we studied an animal model expressing the pathogenic human FTL mutant 498InsTC under the phosphoglycerate kinase (PGK) promoter. Transgenic (Tg) mice showed strong accumulation of the mutated protein in the brain, which increased with age, and this was accompanied by brain accumulation of ferritin/iron bodies, the main pathologic hallmark of human neuroferritinopathy. Tg-mice were tested throughout development and aging at 2-, 8- and 18-months for motor coordination and balance (Beam Walking and Footprint tests). The Tg-mice showed a significant decrease in motor coordination at 8 and 18 months of age, with a shorter latency to fall and abnormal gait. Furthermore, one group of aged naïve subjects was challenged with two herbicides (Paraquat and Maneb) known to cause oxidative damage. The treatment led to a paradoxical increase in behavioral activation in the transgenic mice, suggestive of altered functioning of the dopaminergic system. Overall, data indicate that mice carrying the pathogenic FTL498InsTC mutation show motor deficits with a developmental profile suggestive of a progressive pathology, as in the human disease. These mice could be a powerful tool to study the neurodegenerative mechanisms leading to the disease and help developing specific therapeutic targets.
    PLoS ONE 02/2015; 10(2):e0118990. DOI:10.1371/journal.pone.0118990 · 3.53 Impact Factor


Available from