Fascinating link between gene biosynthesis and cuproptosis

Lipoylation inhibition enhances radiation control of lung cancer by suppressing homologous recombination DNA damage repair Genetic screen finds lipoylation as a target to improve radiation success in lung cancer by blocking DNA damage repair.

1/Happy to share a new paper reporting a metabolic approach to radiosensitization in lung cancer, from Rachel Chiang, Faith Zhang and colleagues at UT Southwestern Radiation Oncology and @cri-utsw.bsky.social
www.science.org/doi/10.1126/...

Spearheaded by
@jeffreychsiao.bsky.social and Doug Warui 🙌 . Huge thanks to Jason Kwon for the computational analysis , Tamra, @maggiedreishpoon.bsky.social , Nolan Bick and
Squire Booker for making this possible.
@bidmc-cancercenter.bsky.social @broadinstitute.org

Key take-home points:
1.The acidic α-helix 3 is a crucial regulatory interface on FDX1
2. The roles of FDX1 in cuproptosis and lipoylation couldn't be uncoupled, suggesting they are a single, structurally linked function
3.DLD is a newly discovered upstream reductase for FDX1

Indeed, DLD bound FDX1 more strongly than FDXR in cells, and this interaction was lost with the D136R/D139R mutants. DLD could also replace FDXR in an FDX1-dependent lipoylation assay in vitro .

This hinted that FDX1 might need or have another electron donor in cells (which is not FDXR). Based on structural homology, we tested if DLD (dihydrolipoamide dehydrogenase), the E3 subunit of lipoylated complexes, could also serve as an FDX1 electron donor.

But there was a twist. Cells with D136R or D139R mutants were also completely deficient in lipoylation. Yet in vitro these mutants stayed fully functional — supporting LIAS-mediated lipoylation and also binding FDXR/LIAS with similar affinities as WT.

This analysis highlighted two residues — D136 and D139 on FDX1’s α-helix 3.

Mutating them to alanine left cuproptosis intact, but flipping their charge (Asp → Arg) made cells resistant to elesclomol–Cu–induced death.

This let us filter out mutations predicted to disrupt overall folding. We focused on variants that blocked FDX1-driven cuproptosis while predicted to remain structurally intact.

We paired the DMS data with an in silico FoldX analysis, which predicts the mean free-energy change (ΔΔG) for each residue in FDX1.

To find out, we performed deep mutational scanning (DMS), mutating every amino acid in FDX1 and testing its ability to promote cuproptosis in two cell line models.

So FDX1 has two roles: 1. Directly reducing Cu(II) bound to elesclomol, freeing Cu(I) and 2. Promoting protein lipoylation, the copper target in cuproptosis.
We set out to explore if these functions could be structurally uncoupled.

FDX1 regulates cellular protein lipoylation through direct binding to LIAS Ferredoxins are a family of iron–sulfur (Fe-S) cluster proteins that serve as essential electron donors in numerous cellular processes that are conserved through evolution. The promiscuous nature of f...

Later, we found FDX1 is also the key upstream regulator of protein #lipoylation, the very target of copper in cuproptosis. www.jbc.org/article/S002...

Copper induces cell death by targeting lipoylated TCA cycle proteins Lipoylation determines sensitivity to copper-induced cell death.

We previously showed that #FDX1 is essential for #cuproptosis , a copper-dependent cell death pathway where Cu targets lipoylated enzymes & Fe–S cluster proteins. www.science.org/doi/10.1126/...

New preprint out!
Deep Mutational Scanning of FDX1 Identifies Key Structural Determinants of Lipoylation and Cuproptosis
A quick twitorial 🧵
www.biorxiv.org/content/10.1...

Radiotherapy promotes cuproptosis and synergizes with cuproptosis inducers to overcome tumor radioresistance Lei et al. reveal that radiotherapy (RT) elevates mitochondrial copper and induces cuproptosis by upregulating CTR1 and depleting mitochondrial glutathione. Furthermore, BACH1 downregulation confers radioresistance by upregulating MT1E/X-mediated cuproptosis defense. Correspondingly, copper-loaded copper ionophores restore RT sensitivity by enhancing cuproptosis, highlighting a therapeutic strategy to overcome tumor radioresistance.

Radiotherapy promotes cuproptosis and synergizes with cuproptosis inducers to overcome tumor radioresistance

Isocitrate dehydrogenase 1 primes group-3 medulloblastomas for cuproptosis Dang et al. report that group-3 medulloblastomas (MBs) show c-MYC-driven high DLAT expression. In these tumors, wild-type IDH1 epigenetically regulates c-MYC, and inhibiting IDH1 lowers c-MYC and DLAT expression. Further, DLAT sensitizes group-3 MBs to cuproptosis. Notably, the copper ionophore elesclomol is toxic to multiple group-3 MB models, underscoring its therapeutic potential.

Isocitrate dehydrogenase 1 primes group-3 medulloblastomas for cuproptosis

When essential metal elements become culprits—Cuproptosis in focus Recently, a copper-dependent form of cell death called cuproptosis has been described, distinct from apoptosis, ferroptosis, and other known pathways. Cuproptosis is defined by excessive copper binding to lipoylated proteins, causing their aggregation and leading to cell death. Here, we discuss recent advances in understanding cuproptosis, focusing on its molecular mechanisms, physiological regulators, and therapeutic potential in cancer.

When essential metal elements become culprits—Cuproptosis in focus

Structural basis for catalysis by human lipoyl synthase | Nature Communications Lipoic acid is an essential cofactor in five mitochondrial multiprotein complexes. In each complex, it is tethered in an amide linkage to the side chain of a conserved lysyl residue on a lipoyl carrier protein or lipoyl domain to afford the lipoyl cofactor. Lipoyl synthase catalyzes the last step in the biosynthesis of the lipoyl cofactor, the addition of two sulfur atoms to carbons 6 and 8 of an octanoyllysyl residue of the H protein, the lipoyl carrier protein of the glycine cleavage system. Lipoyl synthase, a member of the radical S-adenosylmethionine superfamily, contains two [Fe4S4] clusters, one of which is sacrificed during catalysis to supply the appended sulfur atoms. Herein, we use X-ray crystallography to characterize several stages in lipoyl synthase catalysis and present a structure of an intermediate wherein the enzyme is cross-linked to the H protein substrate through a 6-mercaptooctanoyl ligand to a [Fe3S4] cluster. LipCo biosynthesis in humans depends exclusively on a

Unveiling lipoyl synthase action: adds sulfur to carbons 6 & 8 of octanoyl-lysyl in the H protein. Essential for 5 mitochondrial complexes! 🌟 PMID:40640146, Nat Commun 2025, @NatureComms https://doi.org/10.1038/s41467-025-61393-x #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Lipoyl deglutarylation by ABHD11 regulates mitochondrial and T cell metabolism Nature Chemical Biology - Glutarate rewires cell metabolism through conjugation to proteins or fatty acids, but how glutarylation is regulated is unclear. ABHD11 was identified as a...

Delighted to share our latest work on ABHD11 as a novel deglutarylating enzyme, and its role in T cell metabolism @natchembio.nature.com rdcu.be/ewiYZ. Many congratulations to co-first authors Guine Grice, Eleanor Minogue and @hudsonwilco.bsky.social! Great team effort with Randall Johnson's lab.

Image credit: Deqiang Kong, Yue Wang and Tianxing Yan. Cover design: Bethany Vukomanovic

❤️Our May issue is out❤️Read our three articles focused on atherosclerosis, describing TLO-like structures within plaques, FDX1’s protective role, and how gut microbiota-derived bile acids suppress platelet activation, and more!
www.nature.com/natcardiovas...

Just had exactly the same experience - went to watch wicked with my girls -with the exact opposite outcome, so boring. lucky they had beer in the theater 😂 .

chalk + chalkboard with diagrams

lab group silly picture

Wow - bluesky! 📈 🦠

Please help me amplify a special faculty search. We're looking for someone in "Microbial Systems Biology" to join me and @kreynoldslab.bsky.social at UTSW Sys Bio / Bioinformatics.

There is an empty lab space right next to us waiting for you!

apply.interfolio.com/154339

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Join us in Boston! The Department of Molecular Metabolism (MET) at the Harvard T.H. Chan School of Public Health has just opened a Jr. Faculty search. Apply by January 15, 2025 at academicpositions.harvard.edu/postings/14371