Cuproptosis (Copper-Dependent Cell Death) Project
Overview
Cuproptosis is a recently defined form of regulated cell death driven by the
direct binding of copper to lipoylated proteins of the mitochondrial
tricarboxylic acid (TCA) cycle. It is mechanistically distinct from apoptosis,
necroptosis, ferroptosis, and pyroptosis. When intracellular Cu²⁺ is reduced to
Cu⁺ by the ferredoxin FDX1, copper binds lipoylated DLAT (the E2
component of the pyruvate dehydrogenase complex), triggering its disulfide-bond–
dependent oligomerization/aggregation, alongside destabilization of Fe–S cluster
proteins. The resulting proteotoxic stress kills the cell. Because cuproptosis
sensitivity tracks with reliance on mitochondrial respiration, it has rapidly
become a focus in cancer therapy and copper-overload disease.
The pathway was named and mechanistically defined by Tsvetkov et al. in 2022
(building on their 2019 identification of FDX1 as the target of the copper
ionophore elesclomol), so the literature — and the corresponding GO
annotations — are still young and incomplete. This makes it a good candidate for
focused review, and it parallels the existing Ferroptosis project as a
metal-dependent regulated-cell-death pathway.
Model Species
Primary: Homo sapiens (human)
- UniProt species code: HUMAN
- The pathway was defined in human cell lines (genome-wide CRISPR screens)
- Direct disease relevance: Wilson disease / Menkes disease (copper handling),
and cancer therapy (copper-ionophore strategies)
Core Pathway Architecture
1. Copper Delivery and Homeostasis
Copper must enter the cell and reach mitochondria for cuproptosis to occur;
exporters and chaperones set the threshold:
- SLC31A1 (CTR1) — high-affinity copper importer; raises cuproptosis sensitivity
- ATP7A — copper-exporting P-type ATPase (Menkes disease); lowers intracellular Cu
- ATP7B — copper-exporting P-type ATPase (Wilson disease); lowers intracellular Cu
- ATOX1 — cytosolic copper chaperone delivering Cu to ATP7A/ATP7B
2. Copper Reduction — the Trigger
- FDX1 — reduces Cu²⁺ → Cu⁺ and is the upstream master regulator of
cuproptosis; also required for protein lipoylation. The single strongest hit
in the defining CRISPR screens.
3. Protein Lipoylation Machinery
The lipoic acid post-translational modification on TCA-cycle E2 enzymes is the
"bait" that copper attacks; loss of this machinery confers resistance:
- LIAS — lipoyl synthase (inserts sulfur into the lipoyl moiety)
- LIPT1 — lipoyl(amido)transferase 1
- LIPT2 — lipoyl/octanoyl transferase 2
- DLD — dihydrolipoamide dehydrogenase (E3; shared component)
4. Lipoylated Targets — the Death Effectors
- DLAT — dihydrolipoamide S-acetyltransferase (PDH E2); copper-bound
lipoylated DLAT oligomerizes/aggregates — a hallmark of cuproptosis - PDHA1 / PDHB — pyruvate dehydrogenase E1 α/β subunits
- GCSH — glycine cleavage system H protein (lipoylated)
5. Regulators and Specificity Controls
- MTF1 — metal-regulatory transcription factor 1; induces metallothioneins
and is protective (negative regulator) - GLS — glutaminase; modulates sensitivity (negative regulator hit)
- CDKN2A — modulates sensitivity (negative regulator hit)
- FDX2 — FDX1 paralog that does not substitute for FDX1 in cuproptosis;
useful specificity control
Genes for Review (Priority Order)
Priority 1: Core Execution Machinery (~7 genes)
| Gene | UniProt | Function |
|---|---|---|
| FDX1 | P10109 | Cu²⁺→Cu⁺ reduction; master regulator; promotes lipoylation |
| LIAS | O43766 | Lipoyl synthase |
| LIPT1 | Q9Y234 | Lipoyltransferase 1 |
| DLD | P09622 | Dihydrolipoamide dehydrogenase (E3) |
| DLAT | P10515 | Lipoylated PDH E2; copper-induced aggregation effector |
| PDHA1 | P08559 | Pyruvate dehydrogenase E1 alpha |
| PDHB | P11177 | Pyruvate dehydrogenase E1 beta |
Priority 2: Copper Handling and Regulation (~6 genes)
| Gene | UniProt | Function |
|---|---|---|
| SLC31A1 | O15431 | Copper importer (CTR1) |
| ATP7A | Q04656 | Copper exporter (Menkes) |
| ATP7B | P35670 | Copper exporter (Wilson) |
| ATOX1 | O00244 | Cytosolic copper chaperone |
| MTF1 | Q14872 | Metal-responsive TF; protective regulator |
| GLS | O94925 | Glutaminase; sensitivity modulator |
Priority 3: Supporting / Specificity Genes (~4 genes)
| Gene | UniProt | Function |
|---|---|---|
| LIPT2 | A6NK58 | Lipoyl/octanoyl transferase 2 |
| GCSH | P23434 | Lipoylated glycine cleavage H protein |
| CDKN2A | P42771 | Sensitivity modulator |
| FDX2 | Q6P4F2 | FDX1 paralog; non-redundant specificity control |
Key Recent Discoveries
- FDX1 as the target of the copper ionophore elesclomol (Tsvetkov et al.,
Nat Chem Biol 2019, PMID:31133756) — established the FDX1–copper axis in
regulated cell death. - Definition of cuproptosis (Tsvetkov et al., Science 2022,
PMID:35298263; erratum PMID:36356160) — genome-wide CRISPR screens identified
FDX1 and the lipoylation pathway; showed copper binds lipoylated DLAT causing
aggregation and Fe–S cluster protein loss. - Mechanistic/therapeutic syntheses (e.g. Tang, Chen & Kang, Mol Cell
2022, PMID:35594843) — placed cuproptosis among regulated-cell-death pathways
and outlined cancer-therapy implications.
Disease and Therapeutic Relevance
- Copper-handling disorders: Wilson disease (ATP7B loss → copper overload)
and Menkes disease (ATP7A loss → copper deficiency) frame the homeostatic
thresholds for cuproptosis. - Cancer therapy: copper ionophores (elesclomol, disulfiram–Cu) selectively
kill cells dependent on mitochondrial respiration / high lipoylation; copper
chelators (e.g. tetrathiomolybdate) block cuproptosis. - Biomarker biology: FDX1 and lipoylation status are emerging predictors of
cuproptosis susceptibility across tumor types.
Curation Focus / Open Questions
- Is there (or should there be) a GO biological-process term for cuproptosis,
analogous to GO:0097707 ferroptosis? Scope the ontology gap. - Are FDX1's two roles (Cu²⁺ reduction vs. promoting protein lipoylation)
captured by distinct, appropriately specific MF/BP terms, or over-/under-annotated? - DLAT: distinguish its canonical acetyltransferase MF from its
cuproptosis-effector behavior (copper-induced aggregation) — the latter is a
process role, not a new MF. - Watch for over-annotation of every lipoylation/TCA gene with a generic
"cell death" process term where the experimental support is indirect.
Slides
- Slides (Marp source: CUPROPTOSIS-slides.md) — AI generated
Key References
- Tsvetkov P et al. (2019) Nat Chem Biol — FDX1/elesclomol (PMID:31133756)
- Tsvetkov P et al. (2022) Science — Cuproptosis definition (PMID:35298263; erratum PMID:36356160)
- Tang D, Chen X, Kang R (2022) Mol Cell — Mechanisms review (PMID:35594843)
Project Status
- [ ] Stub — needs gene folder setup (
just fetch-gene human <GENE>) - [ ] Priority 1 genes reviewed (0/7)
- [ ] Priority 2 genes reviewed (0/6)
- [ ] Priority 3 genes reviewed (0/4)
- [ ] Pathway summary + ontology-gap assessment