Work

Calcium-insensitive splice variants of mammalian E1 subunit of 2-oxoglutarate dehydrogenase complex with tissue-specific patterns of expression

Year: 2016

Type: article

Abstract: The 2-oxoglutarate dehydrogenase (OGDH) complex is an important control point in vertebrate mitochondrial oxidative metabolism, including in the citrate cycle and catabolism of alternative fuels including glutamine. It is subject to allosteric regulation by NADH and the ATP/ADP ratio, and by Ca(2+) through binding to the E1 subunit. The latter involves a unique Ca(2+)-binding site which includes D(114)ADLD (site 1). Here, we describe three splice variants of E1 in which either the exon expressing this site is replaced with another exon (loss of site 1, LS1) or an additional exon is expressed leading to the insertion of 15 amino acids just downstream of site 1 (Insert), or both changes occur together (LS1/Insert). We show that all three variants are essentially Ca(2+)-insensitive. Comparison of massive parallel sequence (RNA-Seq) databases demonstrates predominant expression of the Ca(2+)-sensitive archetype form in heart and skeletal muscle, but substantial expression of the Ca(2+)-insensitive variants in brain, pancreatic islets and other tissues. Detailed proteomic and activity studies comparing OGDH complexes from rat heart and brain confirmed the substantial difference in expression between these tissues. The evolution of OGDH variants was explored using bioinformatics, and this indicated that Ca(2+)-sensitivity arose with the emergence of chordates. In all species examined, this was associated with the co-emergence of Ca(2+)-insensitive variants suggesting a retained requirement for the latter in some settings. Tissue-specific expression of OGDH splice variants may thus provide a mechanism that tunes the control of the enzyme to the specialized metabolic and signalling needs of individual cell types.

Source: Biochemical Journal

DOI: 10.1042/bcj20160135

Authors: Richard M. Denton, Timothy J. Pullen, Craig T. Armstrong, Kate J. Heesom, Guy A. Rutter

Institutions: University of Bristol, Imperial College London

Language: English

Topic: Biochemical Acid Research Studies

Subfield: Biochemistry

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: green

Funders: Wellcome Trust, Diabetes UK, Medical Research Council, Biotechnology and Biological Sciences Research Council

Awards: Roles of GWA genes in controlling pancreatic beta cell function and mass., Control of glucagon secretion by AMPK and related kinases., Role of mitochondrial calcium transport in the regulation of insulin secretion, G3555667338, The impact of long non-coding RNA at the Pax6 locus on beta cell identity and function