The emerging role of lysosomes in copper homeostasis

Polishchuk, Elena; Polishchuk, Roman

doi:10.1039/c6mt00058d

Cited by 76 publications

(71 citation statements)

References 90 publications

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“…In vitro experiments have shown that excessive addition of copper to the cell culture medium can induce autophagy, and the autophagy here is recognized as a cellular defense mechanism that can reduce cell death [100]. The elevation of copper has been observed in lysosomes, the organelles involved in autophagy [101]. In the redox cycle of metal ions, elevation of copper promotes autophagy and apoptosis of glioma cells by reactive oxygen species and JNK activation [102,103].…”

Section: Coppermentioning

confidence: 99%

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Wang

Yin

Liu

et al. 2020

Transl Neurodegener

296

188

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Background: The homeostasis of metal ions, such as iron, copper, zinc and calcium, in the brain is crucial for maintaining normal physiological functions. Studies have shown that imbalance of these metal ions in the brain is closely related to the onset and progression of Alzheimer's disease (AD), the most common neurodegenerative disorder in the elderly. Main body: Erroneous deposition/distribution of the metal ions in different brain regions induces oxidative stress. The metal ions imbalance and oxidative stress together or independently promote amyloid-β (Aβ) overproduction by activating βor γ-secretases and inhibiting α-secretase, it also causes tau hyperphosphorylation by activating protein kinases, such as glycogen synthase kinase-3β (GSK-3β), cyclin-dependent protein kinase-5 (CDK5), mitogenactivated protein kinases (MAPKs), etc., and inhibiting protein phosphatase 2A (PP2A). The metal ions imbalances can also directly or indirectly disrupt organelles, causing endoplasmic reticulum (ER) stress; mitochondrial and autophagic dysfunctions, which can cause or aggravate Aβ and tau aggregation/accumulation, and impair synaptic functions. Even worse, the metal ions imbalance-induced alterations can reversely exacerbate metal ions misdistribution and deposition. The vicious cycles between metal ions imbalances and Aβ/tau abnormalities will eventually lead to a chronic neurodegeneration and cognitive deficits, such as seen in AD patients. Conclusion: The metal ions imbalance induces Aβ and tau pathologies by directly or indirectly affecting multiple cellular/ subcellular pathways, and the disrupted homeostasis can reversely aggravate the abnormalities of metal ions transportation/ deposition. Therefore, adjusting metal balance by supplementing or chelating the metal ions may be potential in ameliorating AD pathologies, which provides new research directions for AD treatment.

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Section: Coppermentioning

confidence: 99%

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Wang

Yin

Liu

et al. 2020

Transl Neurodegener

296

188

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“…ATP7B is normally expressed in liver hepatocytes and operates in maintaining copper homeostasis in the body. In response to Cu overload, ATP7B moves from the Golgi to endo-lysosomal structures where it sequesters excess Cu and promotes its excretion into the bile [10,11]. Loss-of-function mutations prevent ATP7B from sequestering Cu and its removal from cells leading to severe Cu toxicosis, which is known as Wilson disease [12].…”

Section: Introductionmentioning

confidence: 99%

Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overcome ATP7B-Mediated Tolerance of Tumor Cells to Cisplatin

Mariniello

Petruzzelli

Wanderlingh

et al. 2020

Cancers

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Tumor resistance to chemotherapy represents an important challenge in modern oncology. Although platinum (Pt)-based drugs have demonstrated excellent therapeutic potential, their effectiveness in a wide range of tumors is limited by the development of resistance mechanisms. One of these mechanisms includes increased cisplatin sequestration/efflux by the copper-transporting ATPase, ATP7B. However, targeting ATP7B to reduce Pt tolerance in tumors could represent a serious risk because suppression of ATP7B might compromise copper homeostasis, as happens in Wilson disease. To circumvent ATP7B-mediated Pt tolerance we employed a high-throughput screen (HTS) of an FDA/EMA-approved drug library to detect safe therapeutic molecules that promote cisplatin toxicity in the IGROV-CP20 ovarian carcinoma cells, whose resistance significantly relies on ATP7B. Using a synthetic lethality approach, we identified and validated three hits (Tranilast, Telmisartan, and Amphotericin B) that reduced cisplatin resistance. All three drugs induced Pt-mediated DNA damage and inhibited either expression or trafficking of ATP7B in a tumor-specific manner. Global transcriptome analyses showed that Tranilast and Amphotericin B affect expression of genes operating in several pathways that confer tolerance to cisplatin. In the case of Tranilast, these comprised key Pt-transporting proteins, including ATOX1, whose suppression affected ability of ATP7B to traffic in response to cisplatin. In summary, our findings reveal Tranilast, Telmisartan, and Amphotericin B as effective drugs that selectively promote cisplatin toxicity in Pt-resistant ovarian cancer cells and underscore the efficiency of HTS strategy for identification of biosafe compounds, which might be rapidly repurposed to overcome resistance of tumors to Pt-based chemotherapy.

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“…Low expression of CTR1 has been associated with poor clinical outcome in NSCLC patients who had received platinum-based chemotherapy (Kim et al, 2014). Interestingly, the copper transporting ATPases, ATP7A and ATP7B, have been suggested to chelate and/or promote the cellular efflux of platinum-based drugs (Dolgova et al, 2009;Gupta and Lutsenko, 2009;Katano et al, 2004;Polishchuk and Polishchuk, 2016;Safaei and Howell, 2005). Studies have revealed a correlation between elevated ATP7B expression and reduced effectiveness of cisplatin chemotherapy in cancer patients (Miyashita et al, 2003;Nakayama et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Mammalian copper homeostasis requires retromer-dependent recycling of the high-affinity copper transporter 1 (CTR1/SLC31A1)

Curnock

Cullen

2020

Preprint

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The mammalian cell surface is decorated with a plethora of integral membrane proteins including those required for the transport of micronutrients, such as copper, which are essential to cellular health. The concentration of micronutrients within the cell is tightly regulated to avoid their adverse deficiency and toxicity effects. The sorting and recycling of nutrients transporters within the endo-lysosomal network is recognised as an essential process in regulating nutrient balance. The evolutionarily conserved endosomal sorting complex, retromer, coordinates integral membrane protein recognition and retrieval. Cellular copper homeostasis is regulated primarily by two transporters: the major copper influx transporter copper transporter 1 (CTR1/SLC31A1), which controls the uptake of copper from the extracellular environment and is essential for early embryonic development, and the established retromer cargo, the copper-transporting ATPase, ATP7A. Here, we show that in response to fluctuating extracellular copper the retromer complex controls the delivery of CTR1 to the cell surface. Following copper exposure, CTR1 is endocytosed to prevent excessive copper uptake. We reveal that internalised CTR1 localises on retromer-positive endosomes and in response to decreased extracellular copper retromer controls the recycling of CTR1 back to the cell surface to maintain copper homeostasis. In addition to copper, CTR1 plays a central role in platinum uptake. Significantly, the efficacy of platinumbased cancer drugs has been correlated with CTR1 expression. Consistent with this, we demonstrate that retromer-deficient cells show reduced sensitivity to the platinum-based drug, cisplatin. . A molecular code for endosomal recycling of phosphorylated cargos by the SNX27-retromer complex. Nat Struct Mol Biol 23, 921-932. Clifford, R. J., Maryon, E. B. and Kaplan, J. H. (2016). Dynamic internalization and recycling of a metal ion transporter: Cu homeostasis and CTR1, the human Cu+ uptake system. A. (2009). The Arp2/3 activator WASH controls the fission of endosomes through a large multiprotein complex. Dev Cell 17, 712-23. Dolgova, N. V., Olson, D., Lutsenko, S. and Dmitrlev, O. Y. (2009). The soluble metal-binding domain of the copper transporter ATP7B binds and detoxifies cisplatin. Biochemical Journal 419, 51-56.Eisses, J. F. and Kaplan, J. H. (2005). The mechanism of copper uptake mediated by human CTR1 -A mutational analysis. . A unique PDZ domain and arrestin-like fold interaction reveals mechanistic details of endocytic recycling by SNX27-retromer.

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The emerging role of lysosomes in copper homeostasis

Cited by 76 publications

References 90 publications

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overcome ATP7B-Mediated Tolerance of Tumor Cells to Cisplatin

Mammalian copper homeostasis requires retromer-dependent recycling of the high-affinity copper transporter 1 (CTR1/SLC31A1)

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