Parkinson’s Disease: The Mitochondria-Iron Link

Muñoz, Yorka; Carrasco, Carlos; Campos, Joaquín D.; Aguirre, Pabla; Núñez, Marco T.

doi:10.1155/2016/7049108

Cited by 46 publications

(50 citation statements)

References 322 publications

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“…CT51 also distributed in the cytoplasm, an indication that in cells CT51 exhibits both mitochondrial and cytoplasmic distribution. Arguably, distribution of CT51 to the mitochondrion should decrease the risk of oxidative damage in this organelle, considering that mitochondria contain redox-active iron and continuously generate ROS, a propitious environment for hydroxyl radical generation and the ensuing hydroxyl radical-mediated damage [ 53 ].…”

Section: Resultsmentioning

confidence: 99%

Development of an iron-selective antioxidant probe with protective effects on neuronal function

García‐Beltrán¹,

Mena²,

Aguirre³

et al. 2017

PLoS ONE

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Iron accumulation, oxidative stress and calcium signaling dysregulation are common pathognomonic signs of several neurodegenerative diseases, including Parkinson´s and Alzheimer’s diseases, Friedreich ataxia and Huntington’s disease. Given their therapeutic potential, the identification of multifunctional compounds that suppress these damaging features is highly desirable. Here, we report the synthesis and characterization of N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-2-(7-hydroxy-2-oxo-2H-chromen-4-yl)acetamide, named CT51, which exhibited potent free radical neutralizing activity both in vitro and in cells. CT51 bound Fe2+ with high selectivity and Fe3+ with somewhat lower affinity. Cyclic voltammetric analysis revealed irreversible binding of Fe3+ to CT51, an important finding since stopping Fe2+/Fe3+ cycling in cells should prevent hydroxyl radical production resulting from the Fenton-Haber-Weiss cycle. When added to human neuroblastoma cells, CT51 freely permeated the cell membrane and distributed to both mitochondria and cytoplasm. Intracellularly, CT51 bound iron reversibly and protected against lipid peroxidation. Treatment of primary hippocampal neurons with CT51 reduced the sustained calcium release induced by an agonist of ryanodine receptor-calcium channels. These protective properties of CT51 on cellular function highlight its possible therapeutic use in diseases with significant oxidative, iron and calcium dysregulation.

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Section: Resultsmentioning

confidence: 99%

Development of an iron-selective antioxidant probe with protective effects on neuronal function

García‐Beltrán¹,

Mena²,

Aguirre³

et al. 2017

PLoS ONE

Self Cite

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“…Mitochondria have active iron exchange with the cytoplasm, required for the synthesis of iron sulphur clusters, which are integral components of complex I and II and sensitive to oxidative stress. Consequently, inhibition of complex I by rotenone, MPTP and paraquat poisoning have been shown to result in iron accumulation in association with PD [ 71 ]. Inhibition of the ubiquitin proteasome system also causes cellular iron dyshomeostasis, further adding to the positive feedback on ROS generation and α-Syn aggregation [ 72 ].…”

Section: Mitochondrial Dysfunction In Sporadic Parkinson’s Diseasementioning

confidence: 99%

Mitochondrial Dysfunction in Parkinson’s Disease: New Mechanistic Insights and Therapeutic Perspectives

Park

Davis

Sue

2018

Curr Neurol Neurosci Rep

425

328

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Purpose of ReviewParkinson’s disease (PD) is a complex neurodegenerative disorder, the aetiology of which is still largely unknown. Overwhelming evidence indicates that mitochondrial dysfunction is a central factor in PD pathophysiology. Here we review recent developments around mitochondrial dysfunction in familial and sporadic PD, with a brief overview of emerging therapies targeting mitochondrial dysfunction.Recent FindingsIncreasing evidence supports the critical role for mitochondrial dysfunction in the development of sporadic PD, while the involvement of familial PD-related genes in the regulation of mitochondrial biology has been expanded by the discovery of new mitochondria-associated disease loci and the identification of their novel functions.SummaryRecent research has expanded knowledge on the mechanistic details underlying mitochondrial dysfunction in PD, with the discovery of new therapeutic targets providing invaluable insights into the essential role of mitochondria in PD pathogenesis and unique opportunities for drug development.

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“…The precise molecular basis remains unclear. Although the initial causes of PD are not clearly determined, factors such as aging, oligomerization of α-synuclein (α-syn), mitochondrial dysfunction, oxidative stress, and neuroinflammation appear to play a pathogenic role in this disease [ 59 ]. The prominent neuropathological manifestation of PD is the degeneration of neurons containing neuromelanin in substantia nigra pars compacta, resulting in a loss of dopamine and the presence of cytoplasmic inclusions of proteins, called Lewy Bodies (LB), composed mainly of filaments of α-syn [ 60 ].…”

Section: Molecular Interactions and The Links Between Tauopathies mentioning

confidence: 99%

Neuroimmune Tau Mechanisms: Their Role in the Progression of Neuronal Degeneration

Cortés¹,

Andrade²,

Guzmán‐Martínez³

et al. 2018

IJMS

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Progressive neurodegenerative pathologies in aged populations are an issue of major concern worldwide. The microtubule-associated protein tau is able to self-aggregate to form abnormal supramolecular structures that include small oligomers up to complex polymers. Tauopathies correspond to a group of diseases that share tau pathology as a common etiological agent. Since microglial cells play a preponderant role in innate immunity and are the main source of proinflammatory factors in the central nervous system (CNS), the alterations in the cross-talks between microglia and neuronal cells are the main focus of studies concerning the origins of tauopathies. According to evidence from a series of studies, these changes generate a feedback mechanism reactivating microglia and provoking constant cellular damage. Thus, the previously summarized mechanisms could explain the onset and progression of different tauopathies and their functional/behavioral effects, opening the window towards an understanding of the molecular basis of anomalous tau interactions. Despite clinical and pathological differences, increasing experimental evidence indicates an overlap between tauopathies and synucleinopathies, considering that neuroinflammatory events are involved and the existence of protein misfolding. Neurofibrillary tangles of pathological tau (NFT) and Lewy bodies appear to coexist in certain brain areas. Thus, the co-occurrence of synucleinopathies with tauopathies is evidenced by several investigations, in which NFT were found in the substantia nigra of patients with Parkinson’s disease, suggesting that the pathologies share some common features at the level of neuroinflammatory events.

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Parkinson’s Disease: The Mitochondria-Iron Link

Cited by 46 publications

References 322 publications

Development of an iron-selective antioxidant probe with protective effects on neuronal function

Development of an iron-selective antioxidant probe with protective effects on neuronal function

Mitochondrial Dysfunction in Parkinson’s Disease: New Mechanistic Insights and Therapeutic Perspectives

Neuroimmune Tau Mechanisms: Their Role in the Progression of Neuronal Degeneration

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