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

Dear Editor, Of all human tumors, pheochromocytomas and paragangliomas (PPGLs) have the highest heritability rate. Over 15% of PPGLs harbor mutations in genes encoding tricarboxylic acid (TCA) cycle-related enzymes that cause oncometabolite accumulation and drive tumorigenesis via metabolic adaptation to hypoxia and global hypermethylation [1]. The dihydrolipoamide S-succinyltransferase (DLST) gene was recently described as a new PPGL susceptibility gene [2]. DLST is a component of the 2oxoglutarate dehydrogenase (OGDH) complex (OGDHc) that catalyzes the conversion of alpha-ketoglutarate to succinyl-coenzyme A (SucCoA) in the TCA cycle. It also plays an understudied role in protein succinylation, a highly conserved post-translational modification (PTM) involving succinyl group transfer from SucCoA to protein lysine residues [3]. Succinylation causes major chemical and structural changes to proteins and has been linked to the development of diseases, including cancer [4, 5]. Here, we further characterized DLST-mutated PPGLs, explored the molecular mechanisms underlying their tumorigenesis, and examined the impact of DLST mutations on the succinylome. Transcriptome analysis was performed for PPGLs carrying the recurrent DLST-p.G374Emutation and a PPGL carrying the DLST-p.Y422C variant, whose deleterious effect was supported by a comprehensive study (Supplementary Figure S1). Hierarchical clustering revealed that DLST-