Cuproptosis (copper-induced cell death) module

A decomposition of cuproptosis: the regulated cell-death program in which excess intracellular copper, reduced to Cu(I) by the mitochondrial ferredoxin FDX1, binds the lipoyl moieties of lipoylated tricarboxylic-acid-cycle enzymes (chiefly the pyruvate dehydrogenase E2 subunit DLAT), driving their disulfide-dependent oligomerization/aggregation while destabilizing iron-sulfur cluster proteins. The resulting proteotoxic stress kills the cell. Cuproptosis is mechanistically distinct from apoptosis, necroptosis, ferroptosis, and pyroptosis, and was defined in human/mammalian cells, so this module is framed for the mammalian implementation with concrete human gene products grounded to UniProt. Design intent: the module is organized as an upstream copper-homeostasis layer that sets the death threshold (importer, chaperone, exporters), a copper- reduction trigger (FDX1), the protein-lipoylation machinery that builds the copper "bait", the lipoylated TCA-cycle targets/effectors (the pyruvate dehydrogenase complex, with DLAT as the aggregation-prone effector), and the execution node (cuproptosis proper). Protective and modulatory regulators (MTF1, GLS, CDKN2A) and the non-substituting paralog FDX2 are kept as an optional regulatory sub-module. Genes are grounded to UniProt only where verified; GO ids are grounded only to verified, non-obsolete terms in the matching aspect (MF in function, BP in processes/concepts, CC in locations).

MODULE:cuproptosisDRAFTBiological Processmodules/cuproptosis.yaml

cuproptosisGO:0160119

GO:0160119

cuproptosis

The module is grounded in the GO biological-process term for cuproptosis.

PMID:35298263

Copper induces cell death by targeting lipoylated TCA cycle proteins

Genome-wide CRISPR screens defined cuproptosis: FDX1 and the protein- lipoylation pathway are required, copper binds lipoylated DLAT causing its oligomerization, and iron-sulfur cluster proteins are destabilized, producing proteotoxic-stress cell death (erratum PMID:36356160).

PMID:31133756

Mitochondrial metabolism promotes adaptation to proteotoxic stress

Identified FDX1 as the target of the copper ionophore elesclomol and established the FDX1-copper axis upstream of copper-dependent cell death.

PMID:35594843

Cuproptosis: Cellular and molecular mechanisms underlying copper-induced cell death

Review placing cuproptosis among the regulated-cell-death pathways and summarizing the lipoylation/FDX1 mechanism and its therapeutic relevance.

file:projects/CUPROPTOSIS.md

Cuproptosis project page

The sibling gene-by-gene cuproptosis curation project that this module generalizes into a recursively decomposable mechanistic plan.

Copper handling sets the cuproptosis threshold but is upstream physiology: the importer raises sensitivity, the exporters and chaperone-buffering lower it. FDX1 has a dual role (reduces Cu2+ to Cu+ AND is required for protein lipoylation); both are represented. The death-executing event is the copper- induced oligomerization of lipoylated DLAT plus Fe-S protein loss, modelled as a process-level effect at the execution node rather than as a distinct MF (there is no exact GO MF for "copper-induced protein aggregation"). FDX2 is the FDX1 paralog that does NOT substitute in cuproptosis and is included only as a specificity control. Scope boundaries: copper acquisition/distribution pathways, cytosolic copper buffering by metallothioneins and GSH, and the general TCA cycle and pyruvate dehydrogenase catalytic biology are upstream or adjacent and are treated here only insofar as they gate or supply cuproptosis.

7Nodes

6Parts

0Variant Sets

0Variants

15Annotons

8Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:cuproptosis deep-research report alongside the module YAML.

Leaf nodes lacking representative members

1 leaf node(s) with no concrete protein grounding:

Cuproptosis execution ANY_PARTICIPANT

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Gene-review completeness (1/16 grounded genes reviewed)

1 complete review(s) · 1 with deep research · 15 missing review · 0 reviewed but lacking deep research

Gene	Review	Complete	Deep research
LIPT2 A6NK58	✗	—	—
ATP7B P35670	✓	✓	✓
ATOX1 O00244	✗	—	—
SLC31A1 (CTR1) O15431	✗	—	—
LIAS O43766	✗	—	—
GLS O94925	✗	—	—
PDHA1 P08559	✗	—	—
DLD P09622	✗	—	—
FDX1 P10109	✗	—	—
DLAT P10515	✗	—	—
PDHB P11177	✗	—	—
CDKN2A P42771	✗	—	—
ATP7A Q04656	✗	—	—
MTF1 Q14872	✗	—	—
FDX2 Q6P4F2	✗	—	—
LIPT1 Q9Y234	✗	—	—

Tree

CuproptosisBiological Processcuproptosis

Parts
1. 1. copper acquisition and homeostasis (sets the death threshold)
2. Copper acquisition and homeostasisBiological Processcopper_homeostasis
  
  Annotons
  - SLC31A1 (CTR1) high-affinity copper import Gene Product: SLC31A1 (CTR1)
  - ATOX1 cytosolic copper chaperone Gene Product: ATOX1
  - Copper-exporting P-type ATPases (ATP7A / ATP7B) Family: Cu(I)-transporting P-type ATPase (ATP7A/ATP7B)
3. 2. copper reduction trigger
4. FDX1-mediated Cu(II) reduction (master trigger)Molecular Functionfdx1_trigger
  
  Annotons
  - FDX1 ferredoxin / Cu(II)-reducing electron transfer Gene Product: FDX1
  - FDX1 requirement for protein lipoylation Gene Product: FDX1
5. 3. protein lipoylation machinery (builds the copper bait)
6. Mitochondrial protein-lipoylation machineryBiological Processlipoylation_machinery
  
  Annotons
  - LIAS lipoyl synthase (sulfur insertion) Gene Product: LIAS
  - LIPT2 lipoyl/octanoyltransferase (octanoyl loading) Gene Product: LIPT2
  - LIPT1 lipoyl(amido)transferase Gene Product: LIPT1
  - DLD (E3) dihydrolipoyl dehydrogenase Gene Product: DLD
7. 4. lipoylated TCA-cycle targets and aggregation effector
8. Lipoylated pyruvate dehydrogenase complex (copper targets)Protein Complexlipoylated_targets
  
  Annotons
  - Pyruvate dehydrogenase complex (lipoylated) Protein Complex: pyruvate dehydrogenase complex
9. 5. execution of cuproptosis (proteotoxic-stress death)
10. Cuproptosis executionBiological Processcuproptosis_execution
  
  Annotons
  - Copper-induced proteotoxic-stress cell death Any Participant: Cell-level outcome integrating lipoylated-protein aggregation and Fe-S cluster protein loss; not a single gene product.
11. 6. regulators and specificity controls optional
12. Cuproptosis regulators and specificity controlsRegulatory Stepcuproptosis_regulation
  
  Annotons
  - MTF1 metal-responsive transcription factor (protective) Gene Product: MTF1
  - GLS glutaminase (sensitivity modulator) Gene Product: GLS
  - CDKN2A (sensitivity modulator) Gene Product: CDKN2A
  - FDX2 (non-substituting paralog; specificity control) Gene Product: FDX2

Details

Context

mammals (defined in human cell lines)

mitochondrionGO:0005759

CuproptosisBiological Processcuproptosis

cuproptosisGO:0160119

Context

mammals (defined in human cell lines)

mitochondrionGO:0005759

Connections

copper_homeostasis -> fdx1_trigger Provides Input For

The labile copper pool set by import/export/chaperoning is the Cu(II) substrate reduced by FDX1.

copper_exporting_atpase -> cuproptosis_execution Negatively Regulates

Copper export lowers intracellular copper and protects against cuproptosis.

fdx1_trigger -> lipoylation_machinery Positively Regulates

FDX1 is required for the protein lipoylation that produces the copper bait.

fdx1_trigger -> lipoylated_targets Provides Input For

FDX1-generated Cu(I) is the species that binds lipoylated DLAT.

lipoylation_machinery -> lipoylated_targets Provides Input For

The lipoylation machinery installs the lipoyl groups on DLAT that copper attacks.

lipoylated_targets -> cuproptosis_execution Causes

Copper-bound lipoylated DLAT oligomerization, with Fe-S protein loss, executes cuproptosis.

Part 1: copper acquisition and homeostasis (sets the death threshold)

Copper acquisition and homeostasisBiological Processcopper_homeostasis

Copper entry, chaperone-mediated buffering, and export together set the labile copper pool available to trigger cuproptosis. High import raises sensitivity; chaperoning and export lower it.

Annotons

SLC31A1 (CTR1) high-affinity copper import

ctr1_copper_import

Participant: Gene Product: SLC31A1 (CTR1)

Gene Product:

SLC31A1 (CTR1)UniProtKB:O15431

Function

copper ion transmembrane transporter activityGO:0005375

Substrates: Cu(I) (extracellular)

Products: Cu(I) (cytosolic)

Processes

copper ion import across plasma membraneGO:0098705

Locations

plasma membrane

Principal route of cellular copper uptake; higher CTR1 activity increases the labile copper pool and sensitizes cells to cuproptosis.

ATOX1 cytosolic copper chaperone

atox1_copper_chaperone

Participant: Gene Product: ATOX1

Gene Product:

ATOX1UniProtKB:O00244

Function

copper chaperone activityGO:0016531

Targets: ATP7A ATP7B

Locations

cytosol

Buffers and delivers cytosolic Cu(I) to the secretory-pathway export ATPases; part of the homeostatic system that limits free copper.

Copper-exporting P-type ATPases (ATP7A / ATP7B)

copper_exporting_atpase

Participant: Family: Cu(I)-transporting P-type ATPase (ATP7A/ATP7B)

Family:

Cu(I)-transporting P-type ATPase (ATP7A/ATP7B) The two human copper-exporting P1B-type ATPases; ATP7B (Wilson disease) predominates in liver, ATP7A (Menkes disease) in most other tissues. They pump Cu(I) into the secretory pathway / out of the cytosol, lowering the copper available for cuproptosis.

Representative Members: ATP7AUniProtKB:Q04656 ATP7BUniProtKB:P35670

Function

P-type monovalent copper transporter activityGO:0140581

Substrates: Cu(I) (cytosolic) ATP

Products: Cu(I) (secretory pathway / extracellular) ADP phosphate

Locations

trans-Golgi network / plasma membrane

Export copper and lower the intracellular copper load; loss of export (e.g. ATP7B mutation in Wilson disease) raises copper and the cuproptosis risk, while their activity is protective.

Part 2: copper reduction trigger

FDX1-mediated Cu(II) reduction (master trigger)Molecular Functionfdx1_trigger

The mitochondrial ferredoxin FDX1 is the single strongest genetic dependency of cuproptosis. It reduces Cu(II) to the more reactive Cu(I) and is also required for protein lipoylation, coupling the trigger to the production of the copper "bait".

Annotons

FDX1 ferredoxin / Cu(II)-reducing electron transfer

fdx1_reductase

Participant: Gene Product: FDX1

Gene Product:

FDX1UniProtKB:P10109

Function

electron transfer activity (Cu(II) -> Cu(I) reduction)GO:0009055

Substrates: Cu(II)

Products: Cu(I)

Cofactors: [2Fe-2S] cluster

Locations

mitochondrial matrixGO:0005759

Reduces Cu(II) to Cu(I); the rate-limiting upstream regulator whose loss confers strong cuproptosis resistance. No exact GO MF term for cupric-reductase activity is asserted, so electron transfer activity is used as the grounded function.

FDX1 requirement for protein lipoylation

fdx1_lipoylation_support

Participant: Gene Product: FDX1

Gene Product:

FDX1UniProtKB:P10109

Function

positive regulation of protein lipoylation FDX1 is required for lipoylation of the TCA-cycle E2 enzymes (loss of FDX1 abolishes DLAT/DLST lipoylation); modelled as a regulatory role rather than a direct catalytic MF.

Processes

protein lipoylationGO:0009249

Couples the copper-reduction trigger to production of the lipoyl moieties that copper attacks.

Part 3: protein lipoylation machinery (builds the copper bait)

Mitochondrial protein-lipoylation machineryBiological Processlipoylation_machinery

The lipoic-acid post-translational modification on TCA-cycle E2/H proteins is the moiety that Cu(I) binds. Loss of any step confers cuproptosis resistance, defining this machinery as essential.

protein lipoylationGO:0009249

Annotons

LIAS lipoyl synthase (sulfur insertion)

Pyruvate dehydrogenase complex (lipoylated)

pdh_complex

Participant: Protein Complex: pyruvate dehydrogenase complex

Protein Complex:

pyruvate dehydrogenase complexGO:0045254

Active units:

DLAT (E2; lipoylated copper target/effector)

Participant: Gene Product: DLAT

Gene Product:

DLATUniProtKB:P10515

Role: Lipoylated E2 acetyltransferase; Cu(I) binds its lipoyl groups and drives oligomerization/aggregation that executes cuproptosis.

Function:

dihydrolipoyllysine-residue acetyltransferase activityGO:0004742

PDH E1 component (PDHA1 + PDHB)

Participant: Family: pyruvate dehydrogenase E1 (PDHA1/PDHB)

Family:

pyruvate dehydrogenase E1 (PDHA1/PDHB)

Representative Members: PDHA1UniProtKB:P08559 PDHBUniProtKB:P11177

Role: Decarboxylating E1 core of the complex.

Function:

pyruvate dehydrogenase (acetyl-transferring) activityGO:0004739

E3 component (DLD)

Participant: Gene Product: DLD

Gene Product:

DLDUniProtKB:P09622

Role: Shared dihydrolipoyl dehydrogenase E3 (see lipoylation machinery).

Locations

mitochondrial matrixGO:0005759

The lipoylated complex is the molecular target of copper; DLAT is the effector whose copper-induced aggregation links the trigger to death.

PMID:35298263

Copper binds lipoylated DLAT and induces its oligomerization; lipoylation-pathway and FDX1 loss prevent cuproptosis.

Part 5: execution of cuproptosis (proteotoxic-stress death)

Cuproptosis executionBiological Processcuproptosis_execution

Copper-bound lipoylated DLAT oligomerizes/aggregates and iron-sulfur cluster proteins are destabilized and lost; the combined proteotoxic stress executes cell death.

Annotons

Copper-induced proteotoxic-stress cell death

cuproptosis_death

Participant: Any Participant: Cell-level outcome integrating lipoylated-protein aggregation and Fe-S cluster protein loss; not a single gene product.

Cell-level outcome integrating lipoylated-protein aggregation and Fe-S cluster protein loss; not a single gene product.

Function

cuproptosis (execution) Process-level death execution; no exact GO MF for "copper-induced protein aggregation" exists, so only the BP is grounded.

Processes

cuproptosisGO:0160119

Integrates DLAT aggregation and Fe-S protein destabilization into proteotoxic-stress-driven death.

PMID:35298263

Aggregation of lipoylated proteins and loss of Fe-S cluster proteins accompany copper-induced proteotoxic-stress death.

Part 6: regulators and specificity controls (optional)

Cuproptosis regulators and specificity controlsRegulatory Stepcuproptosis_regulation

Genetic modifiers that tune cuproptosis sensitivity, plus the FDX1 paralog FDX2 that does not substitute in cuproptosis.

Annotons

MTF1 metal-responsive transcription factor (protective)

mtf1_protective

Participant: Gene Product: MTF1

Gene Product:

MTF1UniProtKB:Q14872

Function

DNA-binding transcription factor activityGO:0003700

Processes

cellular response to copper ionGO:0071280

Locations

nucleus

Induces metallothioneins and copper-buffering genes; a protective (negative) regulator whose loss sensitizes cells to cuproptosis.

GLS glutaminase (sensitivity modulator)

gls_modulator

Participant: Gene Product: GLS

Gene Product:

GLSUniProtKB:O94925

Function

glutaminase activityGO:0004359

A negative-regulator hit in the cuproptosis screens; modulates sensitivity.

CDKN2A (sensitivity modulator)

cdkn2a_modulator

Participant: Gene Product: CDKN2A

Gene Product:

CDKN2AUniProtKB:P42771

A negative-regulator hit in the cuproptosis screens; mechanism not fully defined.

FDX2 (non-substituting paralog; specificity control)

fdx2_specificity

Participant: Gene Product: FDX2

Gene Product:

FDX2UniProtKB:Q6P4F2

Function

2 iron, 2 sulfur cluster bindingGO:0051537

FDX1 paralog that does NOT substitute for FDX1 in cuproptosis; included to mark the specificity of the FDX1 dependency.

Connections

mtf1_protective -> cuproptosis_execution Negatively Regulates

MTF1-driven copper buffering protects against cuproptosis.

gls_modulator -> cuproptosis_execution Negatively Regulates

GLS loss sensitizes cells; GLS activity modulates cuproptosis.