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


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.

15 Reads
    • "There are many reports that have demonstrated that mitochondria are targets of bA42, and mitochondrial dysfunction in AD is well documented (Misonou et al., 2000; Manczack et al., 2006; Horowitz and Greenamyre, 2010; Moreira et al., 2010; Rivas-Arancibia et al., 2011). Previous studies have shown that bA42 can bind to a great number of proteins and extracellular and intracellular macromolecules that affect normal neuronal function due to increases in the production of hydrogen 0306-4522/Ó 2015 IBRO. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Oxidative stress is a major risk factor for Alzheimeŕs Disease (AD) that has been suggested to be the trigger of AD pathology. However, whether oxidative damage precedes and contributes directly to the intracellular accumulation of beta amyloid 1-42 (βA42) peptide remains a matter of debate. Chronic exposure to low doses of ozone similar to the levels during a day of high pollution in México City causes a state of oxidative stress that elicits progressive neurodegeneration in the hippocampi of rats. Several reports have demonstrated that the mitochondria are among the first organelles to be affected by oxidative stress and βA42 toxicity and act as sites of the accumulation of βA42, which affects energy metabolism. However, the mechanisms related to the neurodegeneration process and organelle damage that occur in conditions of chronic exposure to low doses of ozone have not been demonstrated. To analyze the effect of chronic ozone chronic exposure on changes in the production and accumulation of the βA42 and βA40 peptides in the mitochondria of hippocampal neurons of rats exposed to ozone, we examined the mitochondrial expression levels of Presenilins 1 and 2and ADAM10 to detect changes related to the oxidative stress caused by low doses of ozone (0.25 ppm). The results revealed significant accumulations of βA42 peptide in the mitochondrial fractions on days 60 and 90 of ozone exposure along with reductions in beta amyloid 1-40 accumulation, significant overexpressions of Pres2 and significant reductions in ADAM 10 expression. Beta amyloid immunodetection revealed that there were some intracellular deposits of beta amyloid 1-42 and that βA42 and the mitochondrial markers OPA1 and COX1 colocalized. These results indicate that the time of exposure to ozone and the accumulation of βA42 in the mitochondria of the hippocampal cells of rats were correlated. Our results suggest that the accumulation of the βA42 peptide may promote mitochondrial dysfunction due to its accumulation and overproduction. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 07/2015; 304. DOI:10.1016/j.neuroscience.2015.07.011 · 3.36 Impact Factor
  • Source
    • "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). "
    [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; 21. DOI:10.1016/j.mito.2015.02.001 · 3.25 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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 · 5.08 Impact Factor
Show more


15 Reads
Available from