title: Alpha-ketoglutarate dehydrogenase complex-dependent succinylation of proteins in neurons and neuronal cell lines.
abstract: Reversible post-translation modifications of proteins are common in all cells and appear to regulate many processes. Nevertheless, the enzyme(s) responsible for the alterations and the significance of the modification are largely unknown. Succinylation of proteins occurs and causes large changes in the structure of proteins; however, the source of the succinyl groups, the targets, and the consequences of these modifications on other proteins remain unknown. These studies focused on succinylation of mitochondrial proteins. The results demonstrate that the α-ketoglutarate dehydrogenase complex (KGDHC) can serve as a trans-succinylase that mediates succinylation in an α-ketoglutarate-dependent manner. Inhibition of KGDHC reduced succinylation of both cytosolic and mitochondrial proteins in cultured neurons and in a neuronal cell line. Purified KGDHC can succinylate multiple proteins including other enzymes of the tricarboxylic acid cycle leading to modification of their activity. Inhibition of KGDHC also modifies acetylation by modifying the pyruvate dehydrogenase complex. The much greater effectiveness of KGDHC than succinyl-CoA suggests that the catalysis owing to the E2k succinyltransferase is important. Succinylation appears to be a major signaling system and it can be mediated by KGDHC. Reversible post-translation modifications of proteins are common and may regulate many processes. Succinylation of proteins occurs and causes large changes in the structure of proteins. However, the source of the succinyl groups, the targets, and the consequences of these modifications on other proteins remains unknown. The results demonstrate that the mitochondrial α-ketoglutarate dehydrogenase complex (KGDHC) can succinylate multiple mitochondrial proteins and alter their function. Succinylation appears to be a major signaling system and it can be mediated by KGDHC.
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, Burke Medical Research Institute, White Plains, New York, USA.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Gibson
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, Burke Medical Research Institute, White Plains, New York, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, Burke Medical Research Institute, White Plains, New York, USA.
authors.forename: Huan-Lian
authors.initials: HL
authors.lastname: Chen
authors.affiliation: Proteomics and Mass Spectrometry Facility, Institute of Biotechnology, Cornell University, Ithaca, New York, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: College of Pharmacy, Washington State University, Spokane, Washington, USA.
authors.forename: Travis T
authors.initials: TT
authors.lastname: Denton
authors.affiliation: Proteomics and Mass Spectrometry Facility, Institute of Biotechnology, Cornell University, Ithaca, New York, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D037761:Sirtuins / Q000378:metabolism
chemical_list: D000214:Acyl Coenzyme A; D009419:Nerve Tissue Proteins; C012046:succinyl-coenzyme A; D007655:Ketoglutarate Dehydrogenase Complex; D037761:Sirtuins
keywords: Alzheimer's disease; acetylation; brain metabolism; mitochondria; succinylation; α-ketoglutarate dehydrogenase complex