The α‐Ketoglutarate Dehydrogenase Complex

Abstract

The alpha-ketoglutarate dehydrogenase complex (KGDHC) is an important mitochondrial constituent, and deficiency of KGDHC is associated with a number of neurological disorders. KGDHC is composed of three proteins, each encoded on a different and well-characterized gene. The sequences of the human proteins are known. The organization of the proteins into a large, ordered multienzyme complex (a "metabolon") has been well studied in prokaryotic and eukaryotic species. KGDHC catalyzes a critical step in the Krebs tricarboxylic acid cycle, which is also a step in the metabolism of the potentially excitotoxic neurotransmitter glutamate. A number of metabolites modify the activity of KGDHC, including inactivation by 4-hydroxynonenal and other reactive oxygen species (ROS). In human brain, the activity of KGDHC is lower than that of any other enzyme of energy metabolism, including phosphofructokinase, aconitase, and the electron transport complexes. Deficiencies of KGDHC are likely to impair brain energy metabolism and therefore brain function, and lead to manifestations of brain disease. In general, the clinical manifestations of KGDHC deficiency relate to the severity of the deficiency. Several such disorders have been recognized: infantile lactic acidosis, psychomotor retardation in childhood, intermittent neuropsychiatric disease with ataxia and other motor manifestations, Friedreich's and other spinocerebellar ataxias, Parkinson's disease, and Alzheimer's disease (AD). A KGDHC gene has been associated with the first two and last two of these disorders. KGDHC is not uniformly distributed in human brain, and the neurons that appear selectively vulnerable in human temporal cortex in AD are enriched in KGDHC. We hypothesize that variations in KGDHC that are not deleterious during reproductive life become deleterious with aging, perhaps by predisposing this mitochondrial metabolon to oxidative damage.

Proteomic profiling of the hypothalamus in a mouse model of cancer-induced anorexia-cachexia

“…An inducible effect of α -ketoglutarate and glutamate on the expression of the oxoglutarate dehydrogenase gene has been described (Sheu and Blass, 1999) and could be the cause of the upregulation of oxoglutarate dehydrogenase in the hypothalami of tumour-bearing mice that was seen in the present study. No such upregulation was seen in pair-fed mice, and although the difference in expression between tumour-bearing mice and the food-restricted pair-fed mice did not reach statistical significance, it was borderline ( P =0.0502), potentially indicating a selective effect in the tumour-bearing mice.…”

The TCA cycle transferase DLST is important for MYC-mediated leukemogenesis

“…DLST is a TCA cycle transferase functioning in the KGDHC that catalyzes the conversion of α-KG to succinyl-CoA for energy production and macromolecule synthesis. 32 Our studies implicate DLST as an important mediator of MYC-mediated leukemogenesis. Interestingly, we observed elevated DLST protein levels in zebrafish Myc -overexpressing T-ALL cells as well as in primary T-ALL patient samples, compared with their respective thymus controls.…”

“…DLST functions as a transferase in the α-ketoglutarate (α-KG) dehydrogenase complex (KGDHC), which is critical for energy production and macromolecule synthesis in the TCA cycle. 32 Taken together, our studies identify DLST as an important mediator of MYC-driven leukemogenesis and provide compelling evidence for the metabolic dependence of T-ALL cells on the TCA cycle. Importantly, these studies provide strong rationale to develop and test therapeutic strategies that target DLST and other TCA cycle enzymes for T-ALL treatment.…”

Interaction of Glutaric Aciduria Type 1-Related glutaryl-CoA Dehydrogenase with Mitochondrial Matrix Proteins

“…OGDC catalyzes the rate-limiting step of oxidative decarboxylation of both α-ketoglutarate and α-ketoadipate to succinyl- and glutaryl-CoA, respectively, in the tricarboxylic acid (TCA) cycle [25], [26]. In addition to OGDC, pyruvate dehydrogenase (PDC) and branched-chain α-ketoacid dehydrogenase complex (BCKDC) belong to the family of α-ketoacid dehydrogenase multienzyme complexes containing homologous DLST-E2 subunits and may explain the 55 and 69 kDa DLST immunoreactive bands detected in the elution fraction.…”