alpha-keto-beta-methyl-n-valeric acid diminishes reactive oxygen species and alters endoplasmic reticulum Ca(2+) stores.

Mitochondrial dysfunction and oxidative stress occur in neurodegenerative diseases. Other results show that bombesin-releasable calcium stores (BRCS) from the endoplasmic reticulum (ER) are exaggerated in fibroblasts from patients with Alzheimer's disease (AD) compared with controls and in fibroblasts from a young control treated with H(2)O(2). We hypothesize that alterations in oxidative stress underlie the exaggeration in BRCS in AD, and that appropriate antioxidants may be useful in treating this abnormality.

Inhibition of alpha-ketoglutarate dehydrogenase complex promotes cytochrome c release from mitochondria, caspase-3 activation, and necrotic cell death.

Mitochondrial dysfunction has been implicated in cell death in many neurodegenerative diseases. Diminished activity of the alpha-ketoglutarate dehydrogenase complex (KGDHC), a key and arguably rate-limiting enzyme of the Krebs cycle, occurs in these disorders and may underlie decreased brain metabolism. The present studies used alpha-keto-beta-methyl-n-valeric acid (KMV), a structural analogue of alpha-ketoglutarate, to inhibit KGDHC activity to test effects of reduced KGDHC on mitochondrial function and cell death cascades in PC12 cells.