D-β-Hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease
Kim Tieu, Celine Perier, Casper Caspersen, Peter Teismann, Du-Chu Wu, Shi-Du Yan, Ali Naini, Miquel Vila, Vernice Jackson-Lewis, Ravichandran Ramasamy, Serge Przedborski
Kim Tieu, Celine Perier, Casper Caspersen, Peter Teismann, Du-Chu Wu, Shi-Du Yan, Ali Naini, Miquel Vila, Vernice Jackson-Lewis, Ravichandran Ramasamy, Serge Przedborski
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Article Neuroscience

D-β-Hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease

Abstract

Parkinson disease (PD) is a neurodegenerative disorder characterized by a loss of the nigrostriatal dopaminergic neurons accompanied by a deficit in mitochondrial respiration. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that causes dopaminergic neurodegeneration and a mitochondrial deficit reminiscent of PD. Here we show that the infusion of the ketone body D-β-hydroxybutyrate (DβHB) in mice confers partial protection against dopaminergic neurodegeneration and motor deficits induced by MPTP. These effects appear to be mediated by a complex II–dependent mechanism that leads to improved mitochondrial respiration and ATP production. Because of the safety record of ketone bodies in the treatment of epilepsy and their ability to penetrate the blood-brain barrier, DβHB may be a novel neuroprotective therapy for PD.

Authors

Kim Tieu, Celine Perier, Casper Caspersen, Peter Teismann, Du-Chu Wu, Shi-Du Yan, Ali Naini, Miquel Vila, Vernice Jackson-Lewis, Ravichandran Ramasamy, Serge Przedborski

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DβHB increases oxygen consumption in purified brain mitochondria. Mitoch...
DβHB increases oxygen consumption in purified brain mitochondria. Mitochondria (300 μg) were incubated in the absence or presence of MPP+ (5 minutes; a) or rotenone (2.5 minutes; b) at 30°C, and then 5 mM DβHB was added to induce oxygen consumption. DβHB attenuated inhibition of mitochondrial respiration induced by MPP+ (a) or rotenone (b) at indicated concentrations, which blocked about 25–90% of oxygen consumption when glutamate and malate were used as NADH-linked substrates (data not shown). (c) The improvement of oxygen consumption by DβHB is stereospecific and is blocked by 10 mM 3-NP, a complex II inhibitor. (d) DβHB increases oxygen consumption in a dose-dependent and saturable fashion as seen with succinate, a complex II substrate, although not as efficiently as succinate does on an equimolar basis. n = 3–4.