Molecular Neurobiology

, Volume 31, Issue 1–3, pp 43–63 | Cite as

The α-ketoglutarate-dehydrogenase complex

A mediator between mitochondria and oxidative stress in neurodegeneration
  • Gary E. Gibson
  • John P. Blass
  • M. Flint Beal
  • Victoria Bunik
Article

Abstract

Damage from oxidative stress and mitochondrial dysfunction occur together in many common neurodegenerative diseases. The enzymes that form the mitochondrial α-ketoglutarate-dehydrogenase complex (KGDHC), a key and arguably rate-limiting enzyme system of the tricarboxylic acid cycle, might mediate the interaction of these processes. KGDHC activity is reduced in numerous age-related neurodegenerative diseases and is diminished by oxidative stress. In Alzheimer’s disease (AD), the reduction correlates highly to diminished mental performance. Thus, research has focused on the mechanisms by which select oxidants reduce KGDHC and the consequences of such a reduction. Diminished KGDHC in cells is associated with apoptosis without changes in the mitochondrial membrane potential. Studies of isolated mitochondria and of animal models suggest that a reduction in KGDHC can predispose to damage by other toxins that promote neurodegeneration. Diminished oxidative metabolism can be plausibly linked to pathological features of neurodegenerative diseases (e.g., reduced mental function, the plaques and tangles in AD). Thus, reductions in KGDHC might be central to the pathophysiology of these diseases. Studies of proteins, cells, animal models, and humans suggest that treatments to diminish, or bypass, the reduction in KGDHC might be beneficial in age-related neurodegenerative disorders.

Index Entries

Oxidative stress Alzheimer’s disease α-ketoglutarate dehydrogenase neurodegeneration 

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Copyright information

© Humana Press Inc 2005

Authors and Affiliations

  • Gary E. Gibson
    • 1
    • 2
  • John P. Blass
    • 1
    • 2
  • M. Flint Beal
    • 1
  • Victoria Bunik
    • 3
  1. 1.Department of Neurology and NeuroscienceWeill Medical College of Cornell UniversityNew York
  2. 2.Burke Medical Research InstituteWhite Plains
  3. 3.A.N. Belozersky Institute of Physico-Chemical BiologyMoscow State UniversityMoscowRussia

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