Brain Lipotoxicity of Phytanic Acid and Very Long-chain Fatty Acids. Harmful Cellular/Mitochondrial Activities in Refsum Disease and X-Linked Adrenoleukodystrophy.

Georg Reiser,Peter Schönfeld

doi:10.14336/ad.2015.0823

Abstract

It is increasingly understood that in the aging brain, especially in the case of patients suffering from neurodegenerative diseases, some fatty acids at pathologically high concentrations exert detrimental activities. To study such activities, we here analyze genetic diseases, which are due to compromised metabolism of specific fatty acids, either the branched-chain phytanic acid or very long-chain fatty acids (VLCFAs). Micromolar concentrations of phytanic acid or of VLCFAs disturb the integrity of neural cells by impairing Ca2+ homeostasis, enhancing oxidative stress or de-energizing mitochondria. Finally, these combined harmful activities accelerate cell death. Mitochondria are more severely targeted by phytanic acid than by VLCFAs. The insertion of VLCFAs into the inner membrane distorts the arrangement of membrane constituents and their functional interactions. Phytanic acid exerts specific protonophoric activity, induces reactive oxygen species (ROS) generation, and reduces ATP generation. A clear inhibition of the Na+, K+-ATPase activity by phytanic acid has also been reported. In addition to the instantaneous effects, a chronic exposure of brain cells to low micromolar concentrations of phytanic acid may produce neuronal damage in Refsum disease by altering epigenetic transcriptional regulation. Myelin-producing oligodendrocytes respond with particular sensitivity to VLCFAs. Deleterious activity of VLCFAs on energy-dependent mitochondrial functions declines with increasing the hydrocarbon chain length (C22:0 > C24:0 > C26:0). In contrast, the reverse sequence holds true for cell death induction by VLCFAs (C22:0 < C24:0 < C26:0). In adrenoleukodystrophy, the uptake of VLCFAs by peroxisomes is impaired by defects of the ABCD1 transporter. Studying mitochondria from ABCD1-deficient and wild-type mice proves that the energy-dependent functions are not altered in the disease model. Thus, a defective ABCD1 apparently exerts no obvious adaptive pressure on mitochondria. Further research has to elucidate the detailed mechanistic basis for the failures causing fatty acid-mediated neurodegeneration and should help to provide possible therapeutic interventions.

Highlights

It is increasingly understood that in the aging brain, especially in the case of patients suffering from neurodegenerative diseases, some fatty acids at pathologically high concentrations exert detrimental activities
Synthetic PPARα and PPARγ ligands initiate neuroprotective activity. In this context it is important to note that PPARβ/δ activation emerged as the focus of a novel approach for the treatment of a wide range of neurodegenerative diseases
We propose that PPARβ/δ has a central control of the peroxisome proliferator activated receptors (PPARs) triad

Summary

Introduction

It is increasingly understood that in the aging brain, especially in the case of patients suffering from neurodegenerative diseases, some fatty acids at pathologically high concentrations exert detrimental activities. Phytanic and very long-chain fatty acids brain toxicity mitochondrial dysfunction is considered to be the main causal factor in the pathogenesis of several neurodegenerative diseases (for recent review, see [3]).

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