J Neurochem. 2008 May 5 [Epub ahead of print]

The Ketogenic Diet Increases Mitochondrial Glutathione Levels.

Jarrett SG, Milder JB, Liang LP, Patel M.

Department of Pharmaceutical Sciences, University of Colorado Denver,
Denver, CO 80262, USA.

The ketogenic diet (KD) is a high-fat, low carbohydrate diet that is
used as a therapy for intractable epilepsy. However, the mechanism(s)
by which the KD achieves neuroprotection and/or seizure control are
not yet known. We sought to determine whether the KD improves
mitochondrial redox status. Adolescent Sprague-Dawley rats (P28) were
fed a KD or control diet for 3 weeks and ketosis was confirmed by
plasma levels of beta-hydroxybutyrate (BHB). KD-fed rats showed a 2-
fold increase in hippocampal mitochondrial glutathione (GSH) and GSH/
GSSG ratio compared to control diet-fed rats. To determine whether
elevated mitochondrial GSH was associated with increased de novo
synthesis, the enzymatic activity of glutamate cysteine ligase (GCL)
(the rate limiting enzyme in GSH biosynthesis) and protein levels of
the catalytic (GCLC) and modulatory (GCLM) subunits of GCL were
analyzed. Increased GCL activity, as well as upregulated protein
levels of GCL subunits in KD-fed, but not control rats, was observed.
Reduced coenzyme A (CoASH), an indicator of mitochondrial redox
status, and lipoic acid, a thiol antioxidant, were also significantly
increased in the hippocampus of KD-fed rats compared to controls.
Since GSH is a major mitochondrial antioxidant that protects
mitochondrial DNA (mtDNA) against oxidative damage, we measured
mitochondrial hydrogen peroxide (H(2)O(2)) production and H(2)O(2)-
induced mtDNA damage. Isolated hippocampal mitochondria from KD-fed
rats showed functional consequences consistent with the improvement of
mitochondrial redox status i.e. decreased H(2)O(2) production and
mtDNA damage. Together, the results demonstrate that the KD
upregulates GSH biosynthesis, enhances mitochondrial antioxidant
status, and protects mtDNA from oxidant-induced damage.

PMID: 18466343 [PubMed - as supplied by publisher]

--

Steve