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.

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Available from: J. Timothy Greenamyre, Oct 06, 2015
    • "A relative increase illustrates a brain that is either increasing its iron absorption and/or decreasing its iron release. Increasing brain iron may be due to several factors including, but not limited to, the imbalance in iron transport and storage proteins, mitochondrial dysfunction, neurovascular mechanisms, and myelin breakdown and disrepair (Horowitz and Greenamyre, 2010;Zlokovic, 2005;Bartzokis, 2011). Late onset AD presents after age 65 which chronologically coincides with an increase in brain iron in subjects prone to iron overloading (Koedam et al., 2010) (Fig. 2). "
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    ABSTRACT: The dysregulation of iron metabolism in Alzheimer's disease is not accounted for in the current framework of the amyloid cascade hypothesis. Accumulating evidence suggests that impaired iron homeostasis is an early event in Alzheimer's disease progression. Iron dyshomeostasis leads to a loss of function in several enzymes requiring iron as a cofactor, the formation of toxic oxidative species, and the elevated production of beta-amyloid proteins. Several common genetic polymorphisms that cause increased iron levels and dyshomeostasis have been associated with Alzheimer's disease but the pathoetiology is not well understood. A full picture is necessary to explain how heterogeneous circumstances lead to iron loading and amyloid deposition. There is evidence to support a causative interplay between the concerted loss of iron homeostasis and amyloid plaque formation. We hypothesize that iron misregulation and beta-amyloid plaque pathology are synergistic in the process of neurodegeneration and ultimately cause a downward cascade of events that spiral into the manifestation of Alzheimer's disease. In this review, we amalgamate recent findings of brain iron metabolism in healthy versus Alzheimer's disease brains and consider unique mechanisms of iron transport in different brain cells as well as how disturbances in iron regulation lead to disease etiology and propagate Alzheimer's pathology. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Aug 2015 · Neurobiology of Disease
    • "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. "
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    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.
    No preview · Article · Jul 2015 · Neuroscience
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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.
    Full-text · Article · Feb 2015 · Mitochondrion
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