Stem Cell Modeling of Neuroferritinopathy Reveals Iron as a Determinant of Senescence and Ferroptosis during Neuronal Aging

Cozzi, Anna; Orellana, Daniel; Santambrogio, Paolo; Rubio, Alicia; Cancellieri, Cinzia; Giannelli, Serena; Ripamonti, Maddalena; Taverna, Stefano; Lullo, Giulia Di; Rovida, Ermanna; Ferrari, Maurizio; Forni, Gian Luca; Fiorillo, Chiara; Broccoli, Vania; Levi, Sonia

doi:10.1016/j.stemcr.2019.09.002

Cited by 54 publications

(45 citation statements)

References 42 publications

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“…The toxic potential of excess iron lies in its ability to generate reactive oxygen species,10 which damage DNA,11 irreversibly modify proteins via highly reactive aldehydes12 and stimulate release of iron from storage proteins leading to generation of further reactive oxygen species 5. This can ultimately end in iron-mediated cell death 13. Excess brain iron is also important in key pathophysiological pathways specific to PD 9.…”

Section: Introductionmentioning

confidence: 99%

Brain iron deposition is linked with cognitive severity in Parkinson’s disease

Thomas

Leyland

Schrag

et al. 2020

J Neurol Neurosurg Psychiatry

146

127

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BackgroundDementia is common in Parkinson’s disease (PD) but measures that track cognitive change in PD are lacking. Brain tissue iron accumulates with age and co-localises with pathological proteins linked to PD dementia such as amyloid. We used quantitative susceptibility mapping (QSM) to detect changes related to cognitive change in PD.MethodsWe assessed 100 patients with early-stage to mid-stage PD, and 37 age-matched controls using the Montreal Cognitive Assessment (MoCA), a validated clinical algorithm for risk of cognitive decline in PD, measures of visuoperceptual function and the Movement Disorders Society Unified Parkinson’s Disease Rating Scale part 3 (UPDRS-III). We investigated the association between these measures and QSM, an MRI technique sensitive to brain tissue iron content.ResultsWe found QSM increases (consistent with higher brain tissue iron content) in PD compared with controls in prefrontal cortex and putamen (p<0.05 corrected for multiple comparisons). Whole brain regression analyses within the PD group identified QSM increases covarying: (1) with lower MoCA scores in the hippocampus and thalamus, (2) with poorer visual function and with higher dementia risk scores in parietal, frontal and medial occipital cortices, (3) with higher UPDRS-III scores in the putamen (all p<0.05 corrected for multiple comparisons). In contrast, atrophy, measured using voxel-based morphometry, showed no differences between groups, or in association with clinical measures.ConclusionsBrain tissue iron, measured using QSM, can track cognitive involvement in PD. This may be useful to detect signs of early cognitive change to stratify groups for clinical trials and monitor disease progression.

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Section: Introductionmentioning

confidence: 99%

Brain iron deposition is linked with cognitive severity in Parkinson’s disease

Thomas

Leyland

Schrag

et al. 2020

J Neurol Neurosurg Psychiatry

146

127

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“…The latter results in cells either activating the molecular network (which could be seen as a self-defense response) or, as an alternative, increasing their death by ferroptosis. A recent study demonstrated that human fibroblasts and neurons exposed to non-ferritin-dependent iron undergo both cell senescence and cell death by ferroptosis, suggesting that iron is a key player in the mechanisms leading to aging and neurodegeneration [ 118 ]. CRISPR/Cas9 technology was employed to obtain induced pluripotent stem cells (iPSC) from neuroferritinophaty (NF) patients.…”

Section: Molecular Mechanisms Of Adult Stem Cell Senescence and Agmentioning

confidence: 99%

Targeting Cardiac Stem Cell Senescence to Treat Cardiac Aging and Disease

Cianflone

Torella

Biamonte

et al. 2020

Cells

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Adult stem/progenitor are a small population of cells that reside in tissue-specific niches and possess the potential to differentiate in all cell types of the organ in which they operate. Adult stem cells are implicated with the homeostasis, regeneration, and aging of all tissues. Tissue-specific adult stem cell senescence has emerged as an attractive theory for the decline in mammalian tissue and organ function during aging. Cardiac aging, in particular, manifests as functional tissue degeneration that leads to heart failure. Adult cardiac stem/progenitor cell (CSC) senescence has been accordingly associated with physiological and pathological processes encompassing both non-age and age-related decline in cardiac tissue repair and organ dysfunction and disease. Senescence is a highly active and dynamic cell process with a first classical hallmark represented by its replicative limit, which is the establishment of a stable growth arrest over time that is mainly secondary to DNA damage and reactive oxygen species (ROS) accumulation elicited by different intrinsic stimuli (like metabolism), as well as external stimuli and age. Replicative senescence is mainly executed by telomere shortening, the activation of the p53/p16INK4/Rb molecular pathways, and chromatin remodeling. In addition, senescent cells produce and secrete a complex mixture of molecules, commonly known as the senescence-associated secretory phenotype (SASP), that regulate most of their non-cell-autonomous effects. In this review, we discuss the molecular and cellular mechanisms regulating different characteristics of the senescence phenotype and their consequences for adult CSCs in particular. Because senescent cells contribute to the outcome of a variety of cardiac diseases, including age-related and unrelated cardiac diseases like diabetic cardiomyopathy and anthracycline cardiotoxicity, therapies that target senescent cell clearance are actively being explored. Moreover, the further understanding of the reversibility of the senescence phenotype will help to develop novel rational therapeutic strategies.

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“…It can inhibit glutathione peroxidase 4 (GPx4) and delete the corresponding GPx4 gene to cause glutathione depletion. As such, cellular LPO accumulates in phospholipids containing polyunsaturated fatty acids [22][23][24]. Cellular Fe 2+ catalyzes the conversion of LPO to LOO • , which directly triggers cell death [5,[25][26][27][28][29][30][31][32][33].…”

Section: Resultsmentioning

confidence: 99%

Simultaneous Study of Anti-Ferroptosis and Antioxidant Mechanisms of Butein and (S)-Butin

Liu

Cai

et al. 2020

Molecules

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To elucidate the mechanism of anti-ferroptosis and examine structural optimization in natural phenolics, cellular and chemical assays were performed with 2′-hydroxy chalcone butein and dihydroflavone (S)-butin. C11-BODIPY staining and flow cytometric assays suggest that butein more effectively inhibits ferroptosis in erastin-treated bone marrow-derived mesenchymal stem cells than (S)-butin. Butein also exhibited higher antioxidant percentages than (S)-butin in five antioxidant assays: linoleic acid emulsion assay, Fe3+-reducing antioxidant power assay, Cu2+-reducing antioxidant power assay, 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide radical (PTIO•)-trapping assay, and α,α-diphenyl-β-picrylhydrazyl radical (DPPH•)-trapping assay. Their reaction products with DPPH• were further analyzed using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UPLC-ESI-Q-TOF-MS). Butein and (S)-butin produced a butein 5,5-dimer (m/z 542, 271, 253, 225, 135, and 91) and a (S)-butin 5′,5′-dimer (m/z 542, 389, 269, 253, and 151), respectively. Interestingly, butein forms a cross dimer with (S)-butin (m/z 542, 523, 433, 419, 415, 406, and 375). Therefore, we conclude that butein and (S)-butin exert anti-ferroptotic action via an antioxidant pathway (especially the hydrogen atom transfer pathway). Following this pathway, butein and (S)-butin yield both self-dimers and cross dimers. Butein displays superior antioxidant or anti-ferroptosis action to (S)-butin. This can be attributed the decrease in π-π conjugation in butein due to saturation of its α,β-double bond and loss of its 2′-hydroxy group upon biocatalytical isomerization.

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Stem Cell Modeling of Neuroferritinopathy Reveals Iron as a Determinant of Senescence and Ferroptosis during Neuronal Aging

Cited by 54 publications

References 42 publications

Brain iron deposition is linked with cognitive severity in Parkinson’s disease

Brain iron deposition is linked with cognitive severity in Parkinson’s disease

Targeting Cardiac Stem Cell Senescence to Treat Cardiac Aging and Disease

Simultaneous Study of Anti-Ferroptosis and Antioxidant Mechanisms of Butein and (S)-Butin

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