Cuproptosis (Copper-Dependent Cell Death) Project

Bottom line: cuproptosis is a form of regulated cell death, defined in 2022,
in which copper reduced by the ferredoxin FDX1 binds lipoylated TCA-cycle
enzymes such as DLAT and makes them aggregate. Scoped, not yet started as a
review campaign: this page selects 17 human genes in three priority tiers
(copper handling, the FDX1 trigger, the lipoylation machinery and its
lipoylated targets, and regulators), and a draft
cuproptosis module grounded in the GO term
GO:0160119 cuproptosis was built alongside it. We chose it because the
pathway is young, so its GO annotations are likely incomplete, and it pairs
with the Ferroptosis project as a second metal-dependent death pathway. Seven
of the 17 genes (DLD, DLAT, PDHA1, PDHB, ATP7B, GLS, GCSH) already have
reviewed annotations from other work (no pending rows, though DLD, DLAT, PDHA1,
PDHB and GLS are still flagged status: INITIALIZED), none of which mentions
cuproptosis. Of the other ten, LIPT1 has been fetched but not reviewed and nine
have no gene folder yet.

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)

Priority 2: Copper Handling and Regulation (~6 genes)

Priority 3: Supporting / Specificity Genes (~4 genes)

Key Recent Discoveries

1. 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.
2. 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.
3. 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

• [ ] Gene folder setup (just fetch-gene human <GENE>) — done for the reviewed
  genes below; FDX1, LIAS, SLC31A1, ATP7A, ATOX1, MTF1, LIPT2, CDKN2A and FDX2 still
  need folders (LIPT1 has only a UniProt record)
• [ ] Priority 1 genes reviewed (4/7: DLD, DLAT, PDHA1, PDHB; FDX1, LIAS, LIPT1 pending)
• [ ] Priority 2 genes reviewed (2/6: GLS, ATP7B; SLC31A1, ATP7A, ATOX1, MTF1 pending)
• [ ] Priority 3 genes reviewed (1/4: GCSH; LIPT2, CDKN2A, FDX2 pending)
• [ ] Pathway summary + ontology-gap assessment