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The alpha-ketoglutarate dehydrogenase complex
1Dementia Research Service, Burke Medical Research Institute, Weill Medical College of Cornell University, White Plains, New York 10605, USA.
Insights
Alpha-ketoglutarate dehydrogenase complex (KGDHC) deficiency impairs brain energy metabolism, leading to neurological disorders. Variations in KGDHC may cause age-related brain diseases due to oxidative damage.
Area of Science:
- Biochemistry
- Neuroscience
- Genetics
Background:
- The alpha-ketoglutarate dehydrogenase complex (KGDHC) is a key mitochondrial enzyme in the Krebs cycle.
- KGDHC plays a role in glutamate metabolism and is sensitive to oxidative stress.
- Lower KGDHC activity in the brain compared to other energy metabolism enzymes suggests its critical role in neuronal function.
Purpose of the Study:
- To investigate the association between KGDHC and neurological disorders.
- To explore the hypothesis that KGDHC variations become detrimental with aging, potentially due to oxidative damage.
Main Methods:
- Analysis of KGDHC gene associations with neurological conditions.
- Examination of KGDHC distribution in human brain tissue.
- Review of existing literature on KGDHC function and deficiency.
Main Results:
- KGDHC deficiency is linked to various neurological disorders, including infantile lactic acidosis, psychomotor retardation, ataxia, Parkinson's, and Alzheimer's disease.
- Specific KGDHC gene variations are associated with several of these conditions.
- Neurons vulnerable in Alzheimer's disease show enrichment in KGDHC, suggesting regional susceptibility.
Conclusions:
- KGDHC deficiency significantly impacts brain energy metabolism and function, manifesting as diverse neurological diseases.
- Age-related oxidative damage may exacerbate the effects of KGDHC variations, contributing to neurodegeneration.
- Understanding KGDHC's role is crucial for diagnosing and potentially treating age-related neurological conditions.
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.