Modulation of oxidative stress and mitochondrial function by the ketogenic diet

Abstract

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. The broad efficacy of the KD in diverse epilepsies coupled with its profound influence on metabolism suggests that mitochondrial functions may be critical in its mechanism(s) of seizure control. Mitochondria subserve important cellular functions that include the production of cellular ATP, control of apoptosis, maintenance of calcium homeostasis and the production and elimination of reactive oxygen species (ROS). This review will focus on recent literature reporting the regulation of mitochondrial functions and redox signaling by the KD. The review highlights a potential mechanism of the KD involving the production of low levels of redox signaling molecules such as H2O2 and electrophiles e.g. 4-hydroxynonenal (4-HNE), which in turn activate adaptive pathways such as the protective transcription factor, NF E2-related factor 2 (Nrf2). This can ultimately result in increased production of antioxidants (e.g. GSH) and detoxification enzymes which may be critical in mediating the protective effects of the KD.

Ketogenic diets, mitochondria, and neurological diseases

“…In addition to enhancing energy reserves, ATP levels, and the expression of many enzymes involved in multiple metabolic pathways in the mitochondria, the KD has also been shown to increase mitochondrial biogenesis in the hippocampus ( 48 ). Additionally, multiple studies have demonstrated elevated antioxidant activity, diminished production of ROS, and decreased ROS-induced damage with the KD ( 6,14,94 ). Figure 3 summarizes the substrates and pathways linking mitochondrial redox changes to the TCA and astrocytes from Bad Ϫ / Ϫ or Bad S155A mice exhibited reduced mitochondrial oxidative metabolism of glucose, but enhanced mitochondrial respiration in the presence of BHB ( 87 ).…”

“…However, it is important to recognize that much of the data discussed herein remain preliminary in nature. Nevertheless, the therapeutic potential for dietary therapies for neurological disorders remains almost limitless when viewed from the perspective of salvaging neuronal bioenergetic dysfunction ( 6,8,14 ).…”

Ketogenic diet and its impact on mental processes of working population

“…Mitochondria do not only supply cells with energy; they control the apoptosis, calcium levels and production and elimination of reactive oxygen species (ROS) (Milder et al, 2012). Nutrition based therapies are not only an option for rare mitochondriopathies but also for a spectrum of ND associated with aging (Procaccio et al, 2014).…”

“…Both roles make KB highly neuroprotective agents (Cahill, 2006). KB mediate their antioxidative properties by activation of protective transcription factors (like Nrf2) that increase the production of antioxidants like glutathione and other enzymes (Milder et al, 2012).…”

Nrf2 to the Rescue

“…diet profoundly alters redox processes, in part by increasing cellular glutathione levels via activation of the Nrf2 pathway (5,6). Therefore, a clear rationale exists for validating the Nrf2 pathway as antiepileptic or antiepileptogenic therapies.…”