Mitochondrial iron homeostasis and its dysfunctions in neurodegenerative disorders

Mena, Natalia; Urrutia, Pamela J.; Lourido, Fernanda; Carrasco, Carlos; Núñez, Marco T.

doi:10.1016/j.mito.2015.02.001

Cited by 136 publications

(100 citation statements)

References 265 publications

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“…While the intensity in the mitochondrial membrane potential in the hippocampus following iron exposure decreased, the change was significant and could possibly contribute in oxidative stress. Increased generation of ROS in the hippocampus following iron exposure as observed in the present study could be associated with decreased mitochondrial membrane potential and is consistent with earlier reports [68,76]. ROS production may decrease the effectiveness of the antioxidant system and affects numerous cellular components [13].…”

Section: Discussionsupporting

confidence: 93%

“…Moreover, these data can further exhibit the possible mechanism by which NGEN exerts its neuroprotective effects. The underlying mechanism in iron neurotoxicity is primarily its effect on the mitochondria which play an important role in the energy metabolism by oxidative phosphorylation involving enzyme complexes [68,69]. The role of NADH dehydrogenase (complex I), succinic dehydrogenase (complex II), ubiquinone-cytochrome c oxidoreductase (complex III) and cytochrome oxidase (complex IV) is critical to orchestrate the flow of high energy electrons to molecular oxygen along the electron transport chain.…”

Section: Discussionmentioning

confidence: 99%

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Naringenin Mitigates Iron-Induced Anxiety-Like Behavioral Impairment, Mitochondrial Dysfunctions, Ectonucleotidases and Acetylcholinesterase Alteration Activities in Rat Hippocampus

et al. 2015

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Studies demonstrated that the iron chelating antioxidant restores brain dysfunction induced by iron toxicity in animals. Earlier, we found that iron overload-induced cerebral cortex apoptosis correlated with oxidative stress could be protected by naringenin (NGEN). In this respect, the present study is focused on the mechanisms associated with the protective efficacy of NGEN, natural flavonoid compound abundant in the peels of citrus fruit, on iron induced impairment of the anxiogenic-like behaviour, purinergic and cholinergic dysfunctions with oxidative stress related disorders on mitochondrial function in the rat hippocampus. Results showed that administration of NGEN (50 mg/kg/day) by gavage significantly ameliorated anxiogenic-like behaviour impairment induced by the exposure to 50 mg of Fe-dextran/kg/day intraperitoneally for 28 days in rats, decreased iron-induced reactive oxygen species formation and restored the iron-induced decrease of the acetylcholinesterase expression level, mitochondrial membrane potential and mitochondrial complexes activities in the hippocampus of rats. Moreover, NGEN was able to restore the alteration on the activity and expression of ectonucleotidases such as adenosine triphosphate diphosphohydrolase and 5'-nucleotidase, enzymes which hydrolyze and therefore control extracellular ATP and adenosine concentrations in the synaptic cleft. These results may contribute to a better understanding of the neuroprotective role of NGEN, emphasizing the influence of including this flavonoid in the diet for human health, possibly preventing brain injury associated with iron overload.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Naringenin Mitigates Iron-Induced Anxiety-Like Behavioral Impairment, Mitochondrial Dysfunctions, Ectonucleotidases and Acetylcholinesterase Alteration Activities in Rat Hippocampus

et al. 2015

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“…A growing set of observations indicates that iron plays a detrimental role in mitochondrial dysfunction, which may consequently lead to neuronal damage [14,47,48] . The mitochondrion maintains the synthesis of iron-sulfur clusters and heme, which is the most abundant iron-containing prosthetic group in a large variety of proteins.…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that ICH causes significant iron overload in the brain [31] , and the levels of brain iron in APP/PS1 transgenic mice are markedly greater than those in aged-matched control mice [9] . Together, the evidence indicates that excessive iron accumulation in neuronal cells is closely associated with massive oxidative damage and mitochondrial dysfunction, which subsequently lead to neurotoxicity [14,32] . Therefore, it is of great interest to determine whether HupA can ameliorate iron overload-induced neuronal damage and whether these effects could be attributable to its anti-oxidative capacity or its regulation of iron metabolism.…”

Section: Acta Pharmacologica Sinicamentioning

confidence: 99%

“…Abnormally high iron concentrations in the brain have been widely reported in AD patients [7,8] , and the well-known APP/PS1 transgenic mouse AD animal model [9] . Additionally, excess iron has been proven to cause neuronal damage in multiple in vitro and in vivo studies [10][11][12] because excess iron can generate reactive oxygen species (ROS) [13] and is closely associated with mitochondrial dysfunction [14] . Correspondingly, therapeutic strategies targeting iron dyshomeostasis have recently attracted considerable attention and have been both preclinically and clinically demonstrated to effectively decrease the progression of the neurological symptoms of AD [15][16][17][18] .…”

Section: Introductionmentioning

confidence: 99%

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Acetylcholinesterase-independent protective effects of huperzine A against iron overload-induced oxidative damage and aberrant iron metabolism signaling in rat cortical neurons

et al. 2016

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Aim: Iron dyshomeostasis is one of the primary causes of neuronal death in Alzheimer's disease (AD). Huperzine A (HupA), a natural inhibitor of acetylcholinesterase (AChE), is a licensed anti-AD drug in China and a nutraceutical in the United Sates. Here, we investigated the protective effects of HupA against iron overload-induced injury in neurons. Methods: Rat cortical neurons were treated with ferric ammonium citrate (FAC), and cell viability was assessed with MTT assays. Reactive oxygen species (ROS) assays and adenosine triphosphate (ATP) assays were performed to assess mitochondrial function. The labile iron pool (LIP) level, cytosolic-aconitase (c-aconitase) activity and iron uptake protein expression were measured to determine iron metabolism changes. The modified Ellman's method was used to evaluate AChE activity. Results: HupA significantly attenuated the iron overload-induced decrease in neuronal cell viability. This neuroprotective effect of HupA occurred concurrently with a decrease in ROS and an increase in ATP. Moreover, HupA treatment significantly blocked the upregulation of the LIP level and other aberrant iron metabolism changes induced by iron overload. Additionally, another specific AChE inhibitor, donepezil (Don), at a concentration that caused AChE inhibition equivalent to that of HupA negatively, influenced the aberrant changes in ROS, ATP or LIP that were induced by excessive iron. Conclusion: We provide the first demonstration of the protective effects of HupA against iron overload-induced neuronal damage. This beneficial role of HupA may be attributed to its attenuation of oxidative stress and mitochondrial dysfunction and elevation of LIP, and these effects are not associated with its AChE-inhibiting effect.

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Iron Homeostasis and Neurodegeneration

2016

Iron Metabolism

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Mitochondrial iron homeostasis and its dysfunctions in neurodegenerative disorders

Cited by 136 publications

References 265 publications

Naringenin Mitigates Iron-Induced Anxiety-Like Behavioral Impairment, Mitochondrial Dysfunctions, Ectonucleotidases and Acetylcholinesterase Alteration Activities in Rat Hippocampus

Naringenin Mitigates Iron-Induced Anxiety-Like Behavioral Impairment, Mitochondrial Dysfunctions, Ectonucleotidases and Acetylcholinesterase Alteration Activities in Rat Hippocampus

Acetylcholinesterase-independent protective effects of huperzine A against iron overload-induced oxidative damage and aberrant iron metabolism signaling in rat cortical neurons

Iron Homeostasis and Neurodegeneration

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