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Reductions in metabolism and excess oxidative stress are prevalent in multiple neurodegenerative diseases. The activity of the mitochondrial enzyme α-ketoglutarate dehydrogenase complex (KGDHC) appears central to these abnormalities. KGDHC is diminished in multiple neurodegenerative diseases. KGDHC can not only be rate limiting for NADH production and for substrate level phosphorylation, but is also a source of reactive oxygen species (ROS). The goal of these studies was to determine how changes in KGDHC modify baseline ROS, the ability to buffer ROS, baseline glutathionylation, calcium modulation and cell death in response to external oxidants. In vivo, reducing KGDHC with adeno virus diminished neurogenesis and increased oxidative stress. In vitro, treatments of short duration increased ROS and glutathionylation and enhanced the ability of the cells to diminish the ROS from added oxidants. However, long-term reductions lessened the ability to diminish ROS, diminished glutathionylation and exaggerated oxidant-induced changes in calcium and cell death. Increasing KGDHC enhanced the ability of the cells to diminish externally added ROS and protected against oxidant-induced changes in calcium and cell death. The results suggest that brief periods of diminished KGDHC are protective, while prolonged reductions are harmful. Furthermore, elevated KGDHC activities are protective. Thus, mitogenic therapies that increase KGDHC may be beneficial in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

This Editorial highlights a study by Gibson et al. published in this issue of JNeurochem, in which the authors reveal a novel role for the α‐ketoglutarate dehydrogenase complex (KGDHC) in post‐translational modification of proteins. KGDHC may catalyze post‐translational modification of itself as well as several other proteins by succinylation of lysine residues. The authors' report of an enzyme responsible for succinylation of key mitochondrial enzymes represents a major step toward our understanding of the complex functional metabolome. TCA, tricarboxylic acid; KG, α‐ketoglutarate; KGDHC, α‐ketoglutarate dehydrogenase complex; FUM, fumarase; MDH, malate dehydrogenase; ME, malic enzyme; GDH, glutamate dehydrogenase; AAT, aspartate aminotransferase; GS, glutamine synthetase; PAG, phosphate‐activated glutaminase; SIRT3, silent information regulator 3; SIRT5, silent information regulator 5. This Editorial highlights a study by Gibson et al. published in this issue of JNeurochem, in which the authors reveal a novel role for the α‐ketoglutarate dehydrogenase complex (KGDHC) in post‐translational modification of proteins. KGDHC may catalyze post‐translational modification of itself as well as several other proteins by succinylation of lysine residues. The authors' report of an enzyme responsible for succinylation of key mitochondrial enzymes represents a major step toward our understanding of the complex functional metabolome. TCA, tricarboxylic acid; KG, α‐ketoglutarate; KGDHC, α‐ketoglutarate dehydrogenase complex; FUM, fumarase; MDH, malate dehydrogenase; ME, malic enzyme; GDH, glutamate dehydrogenase; AAT, aspartate aminotransferase; GS, glutamine synthetase; PAG, phosphate‐activated glutaminase; SIRT3, silent information regulator 3; SIRT5, silent information regulator 5. Read the full article ‘Alpha‐ketoglutarate dehydrogenase complex‐dependent succinylation of proteins in neurons and neuronal cell lines’ on page 86. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Read the highlighted article ‘Reductions in the mitochondrial enzyme α-ketoglutarate dehydrogenase complex in neurodegenerative disease – beneficial or detrimental?’ on page 823. Mitochondrial dysfunctions that occur in parallel to an exacerbated production of reactive oxygen species (ROS) affect energy metabolism in neurodegenerative disorders. The activity of the mitochondrial metabolic tricarboxylic acid cycle enzyme 2‐oxoglutarate dehydrogenase complex (KGDHC) is an important regulator of these abnormalities. This Editorial highlights a study by Chen et al. () in the current issue of the Journal of Neurochemistry in which the authors show that transient up‐ or down‐modulation of KGDHC activity can play a protective role against exogenously excess ROS. The findings suggest that perturbation in metabolism, caused by transient reductions in KGDHC, activates cellular antioxidant systems to overcome a prospective increase in ROS. The study adds novel functions to the long list of metabolic tasks of KGDHC, thus raising the possibility to consider the pharmacological control of KGDHC activity as a therapeutic strategy against the bioenergetics deficiency of neurodegenerative disorders. Read the highlighted article ‘Reductions in the mitochondrial enzyme α-ketoglutarate dehydrogenase complex in neurodegenerative disease – beneficial or detrimental?’ on page 823. [ABSTRACT FROM AUTHOR]