Link of impaired metal ion homeostasis to mitochondrial dysfunction in neurons

Nam, Eunju; Han, J.; Suh, Jong‐Min; Yi, Yelim; Lim, Mi Hee

doi:10.1016/j.cbpa.2017.09.009

Cited by 58 publications

(38 citation statements)

References 42 publications

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“…T ransition metal ions are critical components in the nervous systems, playing various structural and catalytic roles (1)(2)(3). In particular, copper is an indispensable element for energy metabolism, antioxidant defense, and the synthesis of neurotransmitters (4)(5)(6)(7). Thus, the uptake and efflux of intracellular copper are tightly regulated in the brain (4,6).…”

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confidence: 99%

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Mechanistic approaches for chemically modifying the coordination sphere of copper–amyloid-β complexes

Han

Lee

Kim

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Neurotoxic implications of the interactions between Cu(I/II) and amyloid-β (Aβ) indicate a connection between amyloid cascade hypothesis and metal ion hypothesis with respect to the neurodegeneration associated with Alzheimer’s disease (AD). Herein, we report a mechanistic strategy for modifying the first coordination sphere of Cu(II) bound to Aβ utilizing a rationally designed peptide modifier, L1. Upon reacting with L1, a metal-binding histidine (His) residue, His14, in Cu(II)–Aβ was modified through either covalent adduct formation, oxidation, or both. Consequently, the reactivity of L1 with Cu(II)–Aβ was able to disrupt binding of Cu(II) to Aβ and result in chemically modified Aβ with altered aggregation and toxicity profiles. Our molecular-level mechanistic studies revealed that such L1-mediated modifications toward Cu(II)–Aβ could stem from the molecule’s ability to 1) interact with Cu(II)–Aβ and 2) foster copper–O2 chemistry. Collectively, our work demonstrates the development of an effective approach to modify Cu(II)–Aβ at a metal-binding amino acid residue and consequently alter Aβ’s coordination to copper, aggregation, and toxicity, supplemented with an in-depth mechanistic perspective regarding such reactivity.

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confidence: 99%

“…Thus, the uptake and efflux of intracellular copper are tightly regulated in the brain (4,6). Upon copper ion dyshomeostasis, vital copper-mediated functions become compromised with neurotoxicity observed in neurodegenerative disorders such as Alzheimer's disease (AD) (4)(5)(6)(7)(8)(9).…”

mentioning

confidence: 99%

Mechanistic approaches for chemically modifying the coordination sphere of copper–amyloid-β complexes

Han

Lee

Kim

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…20 It has been confirmed that Mn can induce apoptosis via the involvement of ER stress and mitochondrial dysfunction. 7,21 The GRP78 protein is a key regulator in ER stress signalling pathways that are However, to cope with excessive ER stress, this protective signalling pathway was changed to a pro-apoptotic response. The CHOP, also known as growth arrest and DNA damage 153 (GADD153), is a major element of ER stress-mediated apoptosis that strongly depends on ATF4.…”

Section: Discussionmentioning

confidence: 99%

Manganese activates autophagy to alleviate endoplasmic reticulum stress–induced apoptosis via PERK pathway

Liu

Yan

Wang

et al. 2019

J Cellular Molecular Medi

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Overexposure to manganese (Mn) is neurotoxic. Our previous research has demonstrated that the interaction of endoplasmic reticulum (ER) stress and autophagy participates in the early stage of Mn‐mediated neurotoxicity in mouse. However, the mechanisms of ER stress signalling pathways in the initiation of autophagy remain confused. In the current study, we first validated that ER stress–mediated cell apoptosis is accompanied by autophagy in SH‐SY5Y cells. Then, we found that inhibiting ER stress with 4‐phenylbutyrate (4‐PBA) decreased ER stress–related protein expression and reduced cell apoptosis, whereas blocking autophagy with 3‐methyladenine (3‐MA) increased cell apoptosis. These data indicate that protective autophagy was activated to alleviate ER stress–mediated apoptosis. Knockdown of the protein kinase RNA‐like ER kinase (PERK) gene inhibited Mn‐induced autophagy and weakened the interaction between ATF4 and the LC3 promoter. Our results reveal a novel molecular mechanism in which ER stress may regulate autophagy via the PERK/eIF2α/ATF4 signalling pathway. Additionally, Mn may activate protective autophagy to alleviate ER stress–mediated apoptosis via the PERK/eIF2α/ATF4 signalling pathway in SH‐SY5Y cells.

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“…It is unknown how zinc alters mitochondrial function in VSMCs. A recent review by Nam et al [ 91 ] summarized the role of metals, including zinc, in mitochondrial function in neurons. In these cells, accumulation of zinc in mitochondria alters mitochondrial membrane potential, reduces oxygen consumption, and increases ROS production [ 92 , 93 , 94 , 95 ].…”

Section: Mitochondrial Dysfunction and Zinc Homeostasis In Agingmentioning

confidence: 99%

NADPH Oxidases and Mitochondria in Vascular Senescence

Salazar

2018

IJMS

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Aging is the major risk factor in the development of cardiovascular diseases (CVDs), including hypertension, atherosclerosis, and myocardial infarction. Oxidative stress caused by overproduction of reactive oxygen species (ROS) and/or by reduced expression of antioxidant enzymes is a major contributor to the progression of vascular senescence, pathologic remodeling of the vascular wall, and disease. Both oxidative stress and inflammation promote the development of senescence, a process by which cells stop proliferating and become dysfunctional. This review focuses on the role of the mitochondria and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases Nox1 and Nox4 in vascular senescence, and their contribution to the development of atherosclerosis. Recent findings are reviewed, supporting a critical role of the mitochondrial regulator peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1α (PGC-1α), the inflammatory gene nuclear factor κB (NF-κB), zinc, the zinc transporters (ZnTs) ZnT3 and ZnT10, and angiotensin II (Ang II) in mitochondrial function, and their role in telomere stability, which provides new mechanistic insights into a previously proposed unified theory of aging.

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Link of impaired metal ion homeostasis to mitochondrial dysfunction in neurons

Cited by 58 publications

References 42 publications

Mechanistic approaches for chemically modifying the coordination sphere of copper–amyloid-β complexes

Mechanistic approaches for chemically modifying the coordination sphere of copper–amyloid-β complexes

Manganese activates autophagy to alleviate endoplasmic reticulum stress–induced apoptosis via PERK pathway

NADPH Oxidases and Mitochondria in Vascular Senescence

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