The ketogenic diet as a therapeutic intervention strategy in mitochondrial disease.

Changbo Qu,Tom Schirris,Yihang Pan,Werner J.H Koopman,Merel J.W Adjobo-Hermans,Clara Van Karnebeek,Jaap Keijer,Melissa Van De Wal

doi:10.1016/j.biocel.2021.106050

Abstract

Classical mitochondrial disease (MD) represents a group of complex metabolic syndromes primarily linked to dysfunction of the mitochondrial ATP-generating oxidative phosphorylation (OXPHOS) system. To date, effective therapies for these diseases are lacking. Here we discuss the ketogenic diet (KD), being a high-fat, moderate protein, and low carbohydrate diet, as a potential intervention strategy. We concisely review the impact of the KD on bioenergetics, ROS/redox metabolism, mitochondrial dynamics and mitophagy. Next, the consequences of the KD in (models of) MD, as well as KD adverse effects, are described. It is concluded that the current experimental evidence suggests that the KD can positively impact on mitochondrial bioenergetics, mitochondrial ROS/redox metabolism and mitochondrial dynamics. However, more information is required on the bioenergetic consequences and mechanistic mode-of-action aspects of the KD at the cellular level and in MD patients.

Highlights

Mitochondria are double-membrane organelles residing in the cytosol of virtually every eukaryotic cell
Evidence obtained in various cellular and organismal models, sup ports the conclusion that the ketogenic diet (KD) affects mitochondrial bioenergetics, mitochondrial reactive oxygen species (ROS)/redox metabolism, and mitochondrial dynamics
The information in the previous section illustrates that our current understanding of the bioenergetic consequences and mechanistic aspects of the KD in mitochondrial disease (MD) patients is still insufficient

Summary

Introduction

Mitochondria are double-membrane organelles residing in the cytosol of virtually every eukaryotic cell. 2. Normally, the majority of pyruvate enters mitochondria, where it is converted into acetyl coenzyme A (AcCoA) to fuel ATP production by the integrated action of the tricarboxylic acid (TCA) cycle and the oxidative phosphorylation (OXPHOS) system (see below). ETC action is linked to ATP pro duction by the FoF1-ATPase (CV) by a chemiosmotic coupling mecha nism (Mitchell and Moyle, 1967) This involves the ETC-mediated creation of an inward-directed trans-MIM proton motive force. Mitochondria can produce reactive oxygen species (ROS) as “by-products” of ETC action, in particular during pathological conditions (Murphy, 2009) These ROS can act as messenger molecules in physiological cell control and induce antioxi dant signaling (Fig. 1D), but, when reaching too high levels, can induce oxidative stress (Halliwell and Gutteridge, 2015). Under non-pathological conditions too high ROS levels are prevented by the action of various interlocked antioxidant pathways including the nico tinamide nucleotide transhydrogenase (NNT), glutathione (GSH), glutathione peroxidase (GPX) and superoxide dismutase (SOD) enzymes (Fig. 1D)

The KD impacts on mitochondrial energy metabolism

The KD impacts on mitochondrial redox metabolism

The KD impacts on mitochondrial dynamics and mitophagy

Adverse effects of the KD

Findings

Summary and future perspectives