Mitochondrial alpha-ketoacid dehydrogenase complexes (OADHCs)

Mitochondrial alpha-ketoacid dehydrogenase complexes (OADHCs) are a family of high-molecular-weight multienzyme assemblies located within the mitochondrial matrix that play a central role in energy metabolism (Zhou et al., 2014, PMID: 24561261). This family includes the pyruvate dehydrogenase complex (PDC), the alpha-ketoglutarate dehydrogenase complex (OGDC), and the branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) (Bunik & Fernie, 2009, PMID: 19403471). These complexes catalyze the oxidative decarboxylation of alpha-ketoacids into their respective acyl-CoA derivatives, linking glycolysis and amino acid catabolism to the tricarboxylic acid (TCA) cycle (Reed, 1974, PMID: 4610354). Dysregulation of these complexes is linked to various metabolic disorders, such as maple syrup urine disease and lactic acidosis, as well as chronic conditions like diabetes and cancer (Pardeshi et al., 2020, PMID: 32824144). In cancer, drugs like devimistat (CPI-613) target the E2 subunit of PDC and OGDC to disrupt the altered metabolic pathways of tumor cells (Zachar et al., 2013, PMID: 23641219). Additionally, the BCKDC is a target for phenylbutyrate, which promotes its activity by inhibiting the regulatory kinase BCKDK to treat maple syrup urine disease (Brunetti-Pierri et al., 2011, PMID: 21324289). Therapeutic strategies often focus on modulating the activity of these complexes using small molecule inhibitors or activators to restore metabolic balance or selectively disrupt energy production in malignant cells (Neuburger et al., 2021, PMID: 33547244).

Other names

2-oxoacid dehydrogenase complexesAlpha-ketoacid dehydrogenase complexesMitochondrial 2-oxoacid dehydrogenase complexes

Modulation of enzyme activity through inhibition of regulatory kinases (e.g., PDK, BCKDK) or direct inhibition of the E2 subunit to disrupt mitochondrial metabolism.