title: Reductions in the mitochondrial enzyme α-ketoglutarate dehydrogenase complex in neurodegenerative disease - beneficial or detrimental?
abstract: 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. Read the Editorial Highlight for this article on Page 689.
authors: Brain and Mind Research Institute, Weill Cornell Medical College, Burke Medical Research Institute, White Plains, New York, USA.
authors: Huanlian
authors: H
authors: Chen
authors: Department of Pharmaceutical Sciences, Washington State University, College of Pharmacy, Spokane, Washington, USA.
authors: Travis T
authors: TT
authors: Denton
authors: Brain and Mind Research Institute, Weill Cornell Medical College, Burke Medical Research Institute, White Plains, New York, USA.
authors: Hui
authors: H
authors: Xu
authors: Brain and Mind Research Institute, Weill Cornell Medical College, York Avenue, New York, USA.
authors: Noel
authors: N
authors: Calingasan
authors: Brain and Mind Research Institute, Weill Cornell Medical College, York Avenue, New York, USA.
authors: M Flint
authors: MF
authors: Beal
authors: Brain and Mind Research Institute, Weill Cornell Medical College, Burke Medical Research Institute, White Plains, New York, USA.
authors: Gary E
authors: GE
authors: Gibson
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D007655:Ketoglutarate Dehydrogenase Complex / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D007655:Ketoglutarate Dehydrogenase Complex
keywords: cell death; mitochondria; oxidative stress; α-ketoglutarate dehydrogenase complex