Cell research: human cell lines and yeast (not human) · in vitro
Dreishpoon 2023 et al., J Biol Chem 2023; J Biol Chem 2023; PNAS 2023
Landmark T01 #1, what came after (1): mechanism follow-ups (still not human proof). Three primary studies I read in full confirmed and refined the FDX1->lipoylation step, all in human cell lines and yeast only (none did new zebrafish or mouse work). (1) Dreishpoon MB et al., J Biol Chem 2023 (PMC10462841): FDX1 directly binds the lipoyl-synthase enzyme LIAS and promotes lipoylation rather than acting only through iron-sulfur-cluster biosynthesis; LIAS protein is actually stabilised (rises), not lost, when FDX1 is lost; FDX1 loss causes loss of respiration and sensitivity to mild glucose starvation. (2) Joshi PR et al., J Biol Chem 2023 (PMC10470009): FDX1 (not FDX2) is required for lipoic-acid synthesis, but FDX1-knockout cells grow under 1% oxygen without lipoylation being rescued, arguing against a hypoxic salvage pathway. (3) Zulkifli M et al., PNAS 2023 (PMC10013847): FDX1 reduces elesclomol-bound copper inside mitochondria to release it to cytochrome c oxidase, with a separate FDX1-independent release outside mitochondria. These extend the landmark's mechanism; none is a human treatment study.
Source: Copper induces cell death by targeting lipoylated TCA cycle proteins. Tsvetkov P, Coy S, Petrova B, Dreishpoon M, Verma A, Abdusamad M, Rossen J, Joesch-Cohen L, Humeidi R, Spangler RD, Eaton JK, Frenkel E, Kocak M, Corsello SM, Lutsenko S, Kanarek N, Santagata S, Golub TR. Science. 2022;375(6586):1254-1261. doi:10.1126/science.abf0529. PMID 35298263; PMC9273333 (NIH author manuscript). Published 2022-03-17. Erratum: Science 2022;376(6591):eabq4855.
Verified research card EL-LM-T01-01-c-R2