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Review
. 2014 Nov;55(11):2211-28.
doi: 10.1194/jlr.R048975. Epub 2014 May 20.

Ketogenic diets, mitochondria, and neurological diseases

Lindsey B Gano  1 , Manisha Patel  1 , Jong M Rho  2
Affiliations
Review

Ketogenic diets, mitochondria, and neurological diseases

Lindsey B Gano et al. J Lipid Res. 2014 Nov.

Abstract

The ketogenic diet (KD) is a broad-spectrum therapy for medically intractable epilepsy and is receiving growing attention as a potential treatment for neurological disorders arising in part from bioenergetic dysregulation. The high-fat/low-carbohydrate "classic KD", as well as dietary variations such as the medium-chain triglyceride diet, the modified Atkins diet, the low-glycemic index treatment, and caloric restriction, enhance cellular metabolic and mitochondrial function. Hence, the broad neuroprotective properties of such therapies may stem from improved cellular metabolism. Data from clinical and preclinical studies indicate that these diets restrict glycolysis and increase fatty acid oxidation, actions which result in ketosis, replenishment of the TCA cycle (i.e., anaplerosis), restoration of neurotransmitter and ion channel function, and enhanced mitochondrial respiration. Further, there is mounting evidence that the KD and its variants can impact key signaling pathways that evolved to sense the energetic state of the cell, and that help maintain cellular homeostasis. These pathways, which include PPARs, AMP-activated kinase, mammalian target of rapamycin, and the sirtuins, have all been recently implicated in the neuroprotective effects of the KD. Further research in this area may lead to future therapeutic strategies aimed at mimicking the pleiotropic neuroprotective effects of the KD.

Keywords: cellular signaling; fatty acids; ketone; oxidative stress.

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Figures

Fig. 1.
Fig. 1.
Metabolic pathways involved in KD treatment. CAT, carnitine-acylcarnitine translocase; GLUT-1, glucose transporter-1; BBB, blood-brain barrier; CPT-1, carnitine palmitoyl transferase; numbered black circle 1, 3-hydroxybutyrate dehydrogenase; numbered black circle 2, succinyl-CoA3-oxoacid CoA transferase; numbered black circle 3, mitochondrial acetoacetyl-CoA thiolase; MRC, mitochondrial respiratory complex. Reprinted with permission (180).
Fig. 2.
Fig. 2.
Comparison of four major KDs. Pie-charts depict relative proportion of calories provided by fat, protein, and carbohydrates for the classic KD (4:1 ratio by weight of fats to carbohydrate plus protein), the MCT diet, the MAD, and the LGIT.
Fig. 3.
Fig. 3.
Mitochondrial function and neuronal excitability. Various aspects of the mitochondria can lead to impairment of its bioenergetic capacity affecting neuronal excitability, apoptosis, and an increase in seizure susceptibility. O2·, production by complex I and III of the ETC leads to the production of ONOO−, in a reaction with NO, and H2O2 through dismutation by the antioxidant MnSOD (SOD2). H2O2 is membrane-permeable and able to diffuse out of the mitochondria causing widespread oxidative damage. Excessive O2·, production also damages Fe-S-containing enzymes involved in the TCA cycle such as aconitase. OH· can be formed from H2O2 through Fenton chemistry and lead to further oxidative damage of macromolecules such as ETC complexes and mtDNA. Oxidative damage to mtDNA can lead to increased mutation rates and a decrease in ETC subunit expression encoded by the mitochondrial genome. Alterations in the redox status of GSH/GSSG and CoASH/CoASSG can cause an inability to protect against the deleterious effects of ROS. Modification of NT biosynthesis within the mitochondria can affect levels of neuronal excitability/inhibition. Oxidative damage to these targets can result in increased neuronal excitability resulting from decreased ΔΨ and ATP levels affecting the Na+/K+-ATPase and the release of cytochrome C, leading to apoptosis. mNa+C2+E, mitochondrial sodium calcium exchanger; mCU, mitochondrial calcium uniporter; mNICE, mitochondrial sodium independent calcium exchanger; CoASSG, CoA glutathione disulfide; GR, glutathione reductase; GPx, glutathione peroxidase; cytoC, cytochrome C; Suc, succinate; Fum, fumarate. Reprinted with permission (181).
Fig. 4.
Fig. 4.
Proposed mechanisms for the neuroprotective effects of the KD and its variants. The dietary interventions are shown in orange; the metabolic effects of the diets are shown in blue; the energy-sensing pathways that may mediate the effects of the dietary alterations are shown in red; the cellular effects resulting from the diets and/or the energy-sensing pathways are shown in green; and the broad protective effects of the diets and the resulting cellular effects are in shown cyan. Solid black lines indicate links proven in the literature; dashed black lines represent possible, but as yet unproven, links. Further details are provided in the text.
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