Genetic screen finds lipoylation as a target to improve radiation success in lung cancer by blocking DNA damage repair.

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.

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.

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.

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

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...

The Department of Molecular Metabolism (MET) at the Harvard T.H. Chan School of Public Health invites applications for the level of assistant professor. The shared interest of MET faculty is to explor...