LIAS

LIAS is a mitochondrial radical SAM enzyme that catalyzes the final step of lipoic acid biosynthesis and is required for lipoylation of key mitochondrial enzymes, with loss of function causing deficient protein lipoylation, reduced pyruvate dehydrogenase activity, and variant nonketotic hyperglycinemia rescuable by wild-type LIAS (PMID:24334290). The human enzyme harbors two [4Fe-4S] clusters — a reducing cluster and an auxiliary cluster — whose assembly can be reconstituted in vitro by [2Fe-2S]-bound ISCU and ISCA2, with the auxiliary cluster added before the reducing cluster (PMID:33562493). Beyond carrying its cofactors, LIAS function is gated by direct binding of ferredoxin FDX1, which promotes LIAS's productive engagement of the lipoyl carrier protein GCSH to drive cellular protein lipoylation independently of Fe-S cluster biosynthesis (PMID:37453661, PMID:36778498). The integrity of its [4Fe-4S] clusters renders LIAS sensitive to iron overload, which strips the clusters, impairs lipoylation, and triggers cuproptosis (PMID:40753758), and LIAS activity protects mitochondrial function and antioxidant capacity in vivo (PMID:33263565).

1. 2013 High

   Establishing whether LIAS is genuinely required for human mitochondrial protein lipoylation, this work linked loss-of-function mutations to a defined biochemical and clinical phenotype with rescue.

   Evidence Patient mutation identification, lipoylation and enzyme activity assays, complementation by transfection of native LIAS

   PMID:24334290

   Open questions at the time

   • Did not resolve the enzymatic mechanism or cofactor requirements
   • Spectrum of affected lipoylated enzymes only partially defined
2. 2021 High

   To define the catalytic machinery, this work showed human LIAS uses two distinct [4Fe-4S] clusters and identified the Fe-S donors and assembly order needed for activity.

   Evidence In vitro reconstitution, LC-MS activity assay, EPR spectroscopy, and cluster-site mutagenesis

   PMID:33562493

   Open questions at the time

   • No high-resolution structure of holo-LIAS
   • In vivo relevance of the reconstitution order not tested
3. 2021 Medium

   Addressing whether LIAS activity is protective at the organismal level, gain-of-function in mice showed enhanced antioxidant capacity and improved mitochondrial function in metabolic disease.

   Evidence Transgenic Lias-overexpression mice crossed to Leprdb/db, histopathology, mitochondrial and oxidative stress assays

   PMID:33263565

   Open questions at the time

   • Single lab
   • Mechanism connecting lipoylation to antioxidant capacity not dissected
4. 2023 High

   To explain how lipoylation is controlled beyond cofactor supply, this work showed FDX1 directly binds LIAS and promotes its functional engagement of GCSH, a regulatory role separable from Fe-S biosynthesis.

   Evidence Co-immunoprecipitation, metabolite and transcriptional profiling, loss-of-function studies

   PMID:36778498 PMID:37453661

   Open questions at the time

   • Structural basis of the FDX1-LIAS interface unresolved
   • Stoichiometry and electron-transfer kinetics not quantified
5. 2023 Medium

   Extending LIAS into disease signaling, this work reported a direct PCSK9-LIAS interaction driving cardiomyocyte cuproptosis in ischemia-reperfusion injury.

   Evidence Co-immunoprecipitation, protein docking, in vivo mouse I/R model with echocardiography and histopathology

   PMID:39930254

   Open questions at the time

   • Single Co-IP and docking without reciprocal structural validation
   • Mechanistic basis of how the interaction promotes cuproptosis not dissected
6. 2023 Medium

   To validate pathogenicity of specific human variants, yeast complementation confirmed that a missense LIAS variant abolishes function.

   Evidence Yeast lip5Δ complementation growth assay and exome sequencing

   PMID:36680912

   Open questions at the time

   • Single method, single ortholog system
   • Residue-level mechanism of dysfunction not defined
7. 2025 Medium

   Connecting iron homeostasis to LIAS activity, this work showed iron overload strips LIAS [4Fe-4S] clusters to impair lipoylation and induce cuproptosis, reversible by restoring assembly machinery or chelating iron.

   Evidence Loss/gain-of-function in cell and mouse I/R models, Fe-S integrity, lipoylation, and cuproptosis assays

   PMID:40753758

   Open questions at the time

   • No direct in vitro reconstitution of cluster loss
   • Single lab, no structural confirmation

• How FDX1-LIAS-GCSH assembly, cofactor delivery, and iron-sensitive cluster loss are integrated structurally and kinetically remains unresolved.
• No high-resolution structure of the LIAS-FDX1-GCSH assembly
• Quantitative coupling between cluster integrity and lipoylation output not established