Article

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: 4.15). 01/2010; 20 Suppl 2(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.

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    • "Increasing evidence points to disrupted iron homeostasis as an important factor in neurodegeneration (Enns, 2003; Gogvadze et al., 2009; Jellinger, 2009; Mandemakers et al., 2007; Sas et al., 2007). Knowledge about the mechanisms that link iron accumulation with the loss of mitochondrial function is emerging (Horowitz and Greenamyre, 2010). "
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    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; 21. DOI:10.1016/j.mito.2015.02.001
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    • "Iron is a very potent oxidation–reduction agent that can create oxidative stress in cells and prior work suggests that neurons may be more sensitive to alterations in iron (LaVaute et al., 2001; Moos et al., 1998) than other cell types in the brain. Iron is also hypothesized to aggravate some key pathogenic processes related to PD including alpha-synuclein fibril formation (Olivares et al., 2009; Uversky et al., 2001) and mitochondrial dysfunction (Horowitz and Greenamyre, 2010; Lin et al., 2001). Finally, iron may simply be a remnant of neuronal cell death (He et al., 2003). "
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    ABSTRACT: Pathologic features of Parkinson's disease (PD) include death of dopaminergic neurons in the substantia nigra, presence of α-synuclein containing Lewy bodies, and iron accumulation in PD-related brain regions. The observed iron accumulation may be contributing to PD etiology but it also may be a byproduct of cell death or cellular dysfunction. To elucidate the possible role of iron accumulation in PD, we investigated genetic variation in 16 genes related to iron homeostasis in three case-control studies from the United States, Australia, and France. After screening 90 haplotype tagging single nucleotide polymorphisms (SNPs) within the genes of interest in the US study population, we investigated the five most promising gene regions in two additional independent case-control studies. For the pooled data set (1289 cases, 1391 controls) we observed a protective association (OR=0.83, 95% CI: 0.71-0.96) between PD and a haplotype composed of the A allele at rs1880669 and the T allele at rs1049296 in transferrin (TF; GeneID: 7018). Additionally, we observed a suggestive protective association (OR=0.87, 95% CI: 0.74-1.02) between PD and a haplotype composed of the G allele at rs10247962 and the A allele at rs4434553 in transferrin receptor 2 (TFR2; GeneID: 7036). We observed no associations in our pooled sample for haplotypes in SLC40A1, CYB561, or HFE. Taken together with previous findings in model systems, our results suggest that TF or a TF-TFR2 complex may have a role in the etiology of PD, possibly through iron misregulation or mitochondrial dysfunction within dopaminergic neurons.
    Neurobiology of Disease 10/2013; 62. DOI:10.1016/j.nbd.2013.09.019
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    • "Iron is also important to mitochondrial functions, where it is incorporated into Fe–S clusters and heme proteins (Hentze et al., 2004). The mechanism for mitochondrial uptake has not been categorically confirmed, though the two proposed pathways involve either (i) diffusion of NTBI or (ii) direct translocation of extracellular Fe 2 Tf via an endosomal pathway (Horowitz and Greenamyre, 2010). Within the mitochondria, the frataxin protein (implicated in Friedreich's ataxia) is suggested to act as a intramitochondrial iron chaperone (Richardson et al., 2010). "
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    ABSTRACT: Iron is the most abundant transition metal within the brain, and is vital for a number of cellular processes including neurotransmitter synthesis, myelination of neurons, and mitochondrial function. Redox cycling between ferrous and ferric iron is utilized in biology for various electron transfer reactions essential to life, yet this same chemistry mediates deleterious reactions with oxygen that induce oxidative stress. Consequently, there is a precise and tightly controlled mechanism to regulate iron in the brain. When iron is dysregulated, both conditions of iron overload and iron deficiencies are harmful to the brain. This review focuses on how iron metabolism is maintained in the brain, and how an alteration to iron and iron metabolism adversely affects neurological function.
    Frontiers in Aging Neuroscience 07/2013; 5(34):34. DOI:10.3389/fnagi.2013.00034
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