Copper-dependent cell death (cuproptosis): perspectives for pharmacological correction in human diseases

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Аннотация

In 2022, researchers from China identified a novel form of copper-dependent cell death, termed cuproptosis, which is distinct from all previously known types of cell death. Cuproptosis is initiated by the binding of copper ions to lipoated enzymes within the Krebs cycle, leading to protein aggregation, proteotoxic stress, and, ultimately, cell death. Copper, as an essential trace element, plays a critical role in numerous physiological processes across nearly all cell types. However, intracellular copper overload can cause oxidative stress and disrupt cellular functions, necessitating tight regulation of copper homeostasis. This article provides a comprehensive summary of current knowledge on copper metabolism, copper-related diseases, and the unique characteristics and regulatory mechanisms of cuproptosis. Furthermore, it explores the role of cuproptosis in the pathogenesis of conditions such as Wilson’s disease, Menkes disease, neurodegenerative disorders, cancer, and cardiovascular diseases, alongside its potential as a therapeutic target for pharmacological intervention.

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Авторлар туралы

Vladimir Vashchenko

Kirov Military Medical Academy

Хат алмасуға жауапты Автор.
Email: vladimir-vaschenko@yandex.ru

Dr. Sci. (Biology)

Ресей, 194044 Saint Petersburg, Academician Lebedev str., 6

Alexey Chuklovin

Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation

Email: alexei.chukh@mail.ru
SPIN-код: 3050-7030

MD, Dr. Sci. (Medicine)

Ресей, Saint Petersburg

Petr Shabanov

Kirov Military Medical Academy

Email: pdshabanov@mail.ru
ORCID iD: 0000-0003-1464-1127
SPIN-код: 8974-7477

MD, Dr. Sci. (Medicine), professor

Ресей, 194044 Saint Petersburg, Academician Lebedev str., 6

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2. Fig. 1. Copper ion cellular and mitochondrial metabolic transport pathways (adapted from Chen et al. [50]). CP — ceruloplasmin; MT — metallothionein; CTR1 — copper ion transmembrane transporter; CCS and SOD1 — copper chaperones delivering copper ions to subcellular compartments, including mitochondria, nucleus, and Golgi apparatus; CCO — mitochondrial complex containing COX17, COX11, SCO1, SCO2 (intramitochondrial copper ion transporters); GSN — glutathione; ATOX1 — Cu+ ion transporter [183]

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3. Fig. 2. Mechanism of elesclomol-induced cuproptosis (adapted from Chen et al. [51]). TTM — tetrathiomolybdate; FDX1 — ferredoxin; LIAS — lipoate synthase, regulator of Krebs cycle protein lipoylation; LPK — mitochondrial lipoylation enzyme [261]

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4. Fig. 3. Mitochondrial disruptions in cuproptosis (adapted from Zheng et al. [297]). FDX1 — ferredoxin 1; LA — lipoic acid; DLAT — dihydrolipoamide S-acetyltransferase; LIAS — lipoate synthase; PDH — pyruvate dehydrogenase complex; Cyt c — cytochrome C; Fe-S — iron-sulfur protein clusters; CoQ — coenzyme Q; ETC — electron transport chain

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5. Fig. 4. Lipoylation scheme of pyruvate dehydrogenase complex subunits in the krebs cycle (adapted from Mayr et al. [165]). CoA — coenzyme A; LA — lipoic acid; SH — sulfide bonds; TPP — thiamine pyrophosphate

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6. Fig. 5. Ubiquitin-proteasome protein degradation system (adapted from Aliabady et al. [14]). Ub — ubiquitin; PPi — pyrophosphate; E1 — ubiquitin-activating enzymes; E2 — ubiquitin-conjugating enzymes; E3 — ubiquitin-ligating enzymes

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7. Fig. 6. Structural formula of the elesclomol-copper complex

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8. Fig. 7. Therapeutic strategies using cuproptosis modulators for cancer treatment (adapted from Kang et al. [125]). DSF — disulfiram; Cu — copper; CuET — Cu-diethyldithiocarbamate

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