DLST mutations in pheochromocytoma and paraganglioma cause proteome hyposuccinylation and metabolic remodeling

• Published in: Cancer communications (London, England) Vol. 43; no. 7; pp. 838 - 843
• Main Authors: Mellid, Sara, García, Fernando, Leandro‐García, Luis Javier, Díaz‐Talavera, Alberto, Martínez‐Montes, Ángel Mario, Gil, Eduardo, Calsina, Bruna, Monteagudo, María, Letón, Rocío, Roldán‐Romero, Juan María, Santos, María, Lanillos, Javier, Valdivia, Carlos, Martínez‐Puente, Natalia, Nicolás‐Hernández, Javier, Jiménez, Scherezade, Pérez‐Martínez, Manuel, Honrado, Emiliano, Coloma, Javier, Cerezo, Ana, Santiveri, Clara María, Esteller, Manel, Campos‐Olivas, Ramón, Caleiras, Eduardo, Montero‐Conde, Cristina, Rodríguez‐Antona, Cristina, Muñoz, Javier, Robledo, Mercedes, Cascón, Alberto
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.07.2023; John Wiley and Sons Inc; Wiley
• Subjects: Acids; Dehydrogenases; DNA methylation; Encyclopedias; Enzymes; Genes; Genomes; Hypoxia; Kinases; Letter to the Editor; Letters to the Editor; Metabolism; Mitochondria; Mutation; Proteins; Tumorigenesis; Tumors
• ISSN: 2523-3548; 2523-3548
• DOI: 10.1002/cac2.12427

Abbreviations PPGL pheochromocytoma and paraganglioma TCA tricarboxylic acid OGDH 2-oxoglutarate dehydrogenase OGDHc oxoglutarate dehydrogenase complex SucCoA succinyl-coenzyme A PTM post-translational modification KEGG Kyoto Encyclopedia of Genes and Genomes DLD dihydrolipoamide dehydrogenase NADH nicotinamide adenine dinucleotide reduced RNA-Seq RNA sequencing LCL lymphoblastoid cell line SDH succinate dehydrogenase NES normalized enrichment scores DLST dihydrolipoamide S-succinyltransferase KEGG Kyoto Encyclopedia of Genes and Genomes KO knockout WT wild-type Dear Editor, Of all human tumors, pheochromocytomas and paragangliomas (PPGLs) have the highest heritability rate. Abbreviations: PPGL, pheochromocytoma and paraganglioma; SucCoA, succinyl coenzyme A; TCAc, tricarboxylic acid cycle; DAPI, 4’,6-diamidino-2-phenylindole, dihydrochloride; NES, normalized enrichment score; GSEA, gene set enrichment analysis; LCL, lymphoblastoid cell line; Succ-K IHC, succinylated lysine immunohistochemistry; Log2FC, Log2 fold change. To determine whether DLST alterations may affect the cellular succinylome, mass spectrometry was applied to previously generated DLST knockout (KO) H838 cell lines into which DLST constructs, including the wild-type (WT), the two aforementioned PPGL-causing mutants, and the catalytically dead p.H424A mutant [ 2] were stably introduced (Supplementary Figure S3A-B). The number of hyposuccinylated lysines differed between proteins, ranging from 1 to 20 (Supplementary Figure S3D). [...]hyposuccinylated proteins were involved in multiple pathways and mapped to all cellular compartments (Supplementary Figure S3E, Supplementary Table S2), indicating a widespread down-regulation of succinylation.