Copper homeostasis and copper-induced cell death in the pathogenesis of cardiovascular disease and therapeutic strategies

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Abstract

Copper is a vital mineral, and an optimal amount of copper is required to support normal physiologic processes in various systems, including the cardiovascular system. Over the past few decades, copper-induced cell death, named cuproptosis, has become increasingly recognized as an important process mediating the pathogenesis and progression of cardiovascular disease (CVD), including atherosclerosis, stroke, ischemia-reperfusion injury, and heart failure. Therefore, an in-depth understanding of the regulatory mechanisms of cuproptosis in CVD may be useful for improving CVD management. Here, we review the relationship between copper homeostasis and cuproptosis-related pathways in CVD, as well as therapeutic strategies addressing copper-induced cell death in CVD.

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The NLRP3 inflammasome: molecular activation and regulation to therapeutics

Karen V. Swanson, Meng Deng, Jenny P.-Y. Ting (2019)

NLRP3 (NACHT, LRR and PYD domains-containing protein 3) is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase-1-dependent release of the proinflammatory cytokines, IL-1β and IL-18, as well as to gasdermin D-mediated pyroptotic cell death. Recent studies have revealed new regulators of the NLRP3 inflammasome, including new interacting or regulatory proteins, metabolic pathways and a regulatory mitochondrial hub. In this Review, we present the molecular, cell biological and biochemical basis of NLRP3 activation and regulation, and describe how this mechanistic understanding is leading to potential therapeutics that target the NLRP3 inflammasome.

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Copper induces cell death by targeting lipoylated TCA cycle proteins

Peter Tsvetkov, Shannon Coy, Boryana Petrova … (2022)

Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper induces cell death, however, is unknown. Here, we show in human cells that copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. We show that copper-dependent death occurs by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms. Cell death is an essential, finely tuned process that is critical for the removal of damaged and superfluous cells. Multiple forms of programmed and nonprogrammed cell death have been identified, including apoptosis, ferroptosis, and necroptosis. Tsvetkov et al . investigated whether abnormal copper ion elevations may sensitize cells toward a previously unidentified death pathway (see the Perspective by Kahlson and Dixon). By performing CRISPR/Cas9 screens, several genes were identified that could protect against copper-induced cell killing. Using genetically modified cells and a mouse model of a copper overload disorder, the researchers report that excess copper promotes the aggregation of lipoylated proteins and links mitochondrial metabolism to copper-dependent death. —PNK Lipoylation determines sensitivity to copper-induced cell death.

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The development of the concept of ferroptosis

Tal Hirschhorn, Brent Stockwell (2019)

The term ferroptosis was coined in 2012 to describe an iron-dependent regulated form of cell death caused by the accumulation of lipid-based reactive oxygen species; this type of cell death was found to have molecular characteristics distinct from other forms of regulated cell death. Features of ferroptosis have been observed periodically over the last several decades, but these molecular features were not recognized as evidence of a distinct form of cell death until recently. Here, we describe the history of observations consistent with the current definition of ferroptosis, as well as the advances that contributed to the emergence of the concept of ferroptosis. We also discuss recent implications and applications of manipulations of the ferroptotic death pathway.

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Author and article information

Contributors

Peng Yu:

ORCID: http://orcid.org/0000-0002-9405-7686

zhangyuteam2022@163.com

Ao Shi:

ORCID: http://orcid.org/0000-0002-2970-4832

m1701040@sgul.ac.uk

Journal

Journal ID (nlm-ta): Cell Death Dis

Journal ID (iso-abbrev): Cell Death Dis

Title: Cell Death & Disease

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-4889

Publication date (Electronic): 11 February 2023

Publication date PMC-release: 11 February 2023

Publication date Collection: February 2023

Volume: 14

Issue: 2

Electronic Location Identifier: 105

Affiliations

[1 ]GRID grid.412455.3, ISNI 0000 0004 1756 5980, The Second Clinical Medical College of Nanchang University, , The Second Affiliated Hospital of Nanchang University, ; Nanchang, Jiangxi China

[2 ]GRID grid.194645.b, ISNI 0000000121742757, Food and Nutritional Sciences, School of Biological Sciences, , The University of Hong Kong, ; Pokfulam Road, Hong Kong, China

[3 ]GRID grid.412536.7, ISNI 0000 0004 1791 7851, Department of Cardiovascular Medicine, , The Second Affiliated Hospital of Sun Yat-Sen University, ; Guangzhou, Guangdong China

[4 ]GRID grid.412455.3, ISNI 0000 0004 1756 5980, Department of Endocrinology and Metabolism, , The Second Affiliated Hospital of Nanchang University, ; Nanchang, Jiangxi China

[5 ]GRID grid.416470.0, ISNI 0000 0004 4656 4290, Wafic Said Molecular Cardiology Research Laboratory, , The Texas Heart Institute, ; Houston, TX USA

[6 ]GRID grid.224260.0, ISNI 0000 0004 0458 8737, Division of Cardiology, Pauley Heart Center, , Virginia Commonwealth University, ; Richmond, VA USA

[7 ]GRID grid.264200.2, ISNI 0000 0000 8546 682X, Faculty of Medicine, , St. George University of London, ; London, UK

[8 ]GRID grid.413056.5, ISNI 0000 0004 0383 4764, University of Nicosia Medical School, , University of Nicosia, ; Nicosia, Cyprus

Author information

Xinyue Chen http://orcid.org/0000-0002-5439-2295

Peng Yu http://orcid.org/0000-0002-9405-7686

Ao Shi http://orcid.org/0000-0002-2970-4832

Article

Publisher ID: 5639

DOI: 10.1038/s41419-023-05639-w

PMC ID: 9922317

PubMed ID: 36774340

SO-VID: 150804cd-bfd5-4f2d-9cec-b2542d076850

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 25 October 2022

Date revision received : 26 January 2023

Date accepted : 1 February 2023

Funding

Funded by: FundRef https://doi.org/10.13039/501100004479, Natural Science Foundation of Jiangxi Province (Jiangxi Province Natural Science Foundation);

Award ID: 20212BAB216047

Award ID: 202004BCJL23049

Award Recipient : Peng Yu

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ScienceOpen disciplines: Cell biology

Keywords: cell death,cardiovascular diseases

Data availability:

ScienceOpen disciplines: Cell biology

Keywords: cell death, cardiovascular diseases

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Copper homeostasis and copper-induced cell death in the pathogenesis of cardiovascular disease and therapeutic strategies

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Cardiovascular Innovations and Applications

Most cited references 145

The NLRP3 inflammasome: molecular activation and regulation to therapeutics

Copper induces cell death by targeting lipoylated TCA cycle proteins

The development of the concept of ferroptosis

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