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. 2016 Sep;36(9):1603-13.
doi: 10.1177/0271678X15610584. Epub 2015 Oct 13.

Ketogenic diet decreases oxidative stress and improves mitochondrial respiratory complex activity

Tiffany Greco  1 , Thomas C Glenn  2 , David A Hovda  3 , Mayumi L Prins  4
Affiliations

Ketogenic diet decreases oxidative stress and improves mitochondrial respiratory complex activity

Tiffany Greco et al. J Cereb Blood Flow Metab. 2016 Sep.

Abstract

Cerebral metabolism of ketones after traumatic brain injury (TBI) improves neuropathology and behavior in an age-dependent manner. Neuroprotection is attributed to improved cellular energetics, although other properties contribute to the beneficial effects. Oxidative stress is responsible for mitochondrial dysfunction after TBI. Ketones decrease oxidative stress, increase antioxidants and scavenge free radicals. It is hypothesized that ketogenic diet (KD) will decrease post-TBI oxidative stress and improve mitochondria. Postnatal day 35 (PND35) male rats were given sham or controlled cortical impact (CCI) injury and placed on standard (STD) or KD. Ipsilateral cortex homogenates and mitochondria were assayed for markers of oxidative stress, antioxidant expression and mitochondrial function. Oxidative stress was significantly increased at 6 and 24 h post-injury and attenuated by KD while inducing protein expression of antioxidants, NAD(P)H dehydrogenase quinone 1 (NQO1) and superoxide dismutase (SOD1/2). Complex I activity was inhibited in STD and KD groups at 6 h and normalized by 24 h. KD significantly improved Complex II-III activity that was reduced in STD at 6 h. Activity remained reduced at 24 h in STD and unchanged in KD animals. These results strongly suggest that ketones improve post-TBI cerebral metabolism by providing alternative substrates and through antioxidant properties, preventing oxidative stress-mediated mitochondrial dysfunction.

Keywords: Traumatic brain injury; juvenile; ketogenic diet; mitochondria; oxidative stress.

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Figures

Figure 1.
Figure 1.
Cytosolic expression of 3NT in PND35 rats on STD or KD diet for 6 or 24 h after TBI. (a) Representative image of 3NT in different treatment groups and time points. (b) Average (± SEM) densitometric ratios for 3NT/total protein, *p < 0.05.
Figure 2.
Figure 2.
Mitochondrial expression of 4HNE in PND35 rats on STD or KD diet for 6 or 24 h after TBI. (a) Representative image of 4HNE. (b) Average (± SEM) densitometric ratios for 4HNE, 27 kDa/total protein, *p < 0.05. (c) Average (± SEM) densitometric ratios for 4HNE, 25 kDa/total protein, *p < 0.05.
Figure 3.
Figure 3.
Cytosolic expression of NQO1 and SOD1 in PND35 rats on STD or KD diet for 6 or 24 h after TBI. (a) Representative image of NQO1 and SOD1. (b) Average (± SEM) densitometric ratios for SOD1/total protein, *p < 0.05. (c) Average (± SEM) densitometric ratios for NQO1/total protein, *p < 0.05.
Figure 4.
Figure 4.
Mitochondrial expression of SOD2 in PND35 rats on STD or KD diet for 6 or 24 h after TBI. (a) Representative image of SOD2. (b) Average (± SEM) densitometric ratios for SOD2/total protein, *p < 0.05.
Figure 5.
Figure 5.
Mitochondrial Complex I activity in PND35 rats on STD or KD diet for 6 or 24 h after TBI. Average (± SEM) activity for Complex I, *p < 0.05.
Figure 6.
Figure 6.
Mitochondrial Complex II/III activity in PND35 rats on STD or KD diet for 6 or 24 h after TBI. Average (± SEM) activity for Complex II/III, *p < 0.05.
Figure 7.
Figure 7.
Representative mechanism of ketogenic diet actions. Injury-induced activation of NMDA receptors causes an influx of Ca2+ into the cell. Increased concentrations of Ca2+ and injury lead to increased cytosolic ROS/RNS production that inhibit mitochondrial function. Ca2+ is also taken up by the mitochondria and inhibits Complex I resulting in further ROS production. Despite mitochondrial inhibition, ATP concentrations are initially maintained through increased lactate production and phosphocreatine breakdown. By 24 h, both decreased glycolysis and mitochondrial function lead to decreased ATP function. KD decreases oxidative stress at 6 h and maintains ATP by increasing succinate and improving Complex II/III activity allowing flux of succinate through Complex II. KD is able to prevent decreases in ATP at 24 h from diminished glycolysis by increasing Acetyl-CoA production.
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