Fifty years of research on mitochondrial fatty acid oxidation disorders: The remaining challenges

Abstract

Since the identification of the first disorder of mitochondrial fatty acid oxidation (FAOD) in 1973, more than twenty defects have been identified. Although there are some differences, most FAOD have similar clinical signs, which are mainly due to energy depletion and toxicity of accumulated metabolites. However, some of them have an unusual clinical phenotype or specific clinical signs. This manuscript focuses on what we have learnt so far on the pathophysiology of these disorders which present with clinical signs that are not typical of categorical FAOD. It also highlights that some disorders have not yet been identified and tries to make assumptions to explain why. It also deals with new treatments under consideration in FAOD, including triheptanoin and similar anaplerotic substrates, ketone body treatments, RNA and gene therapy approaches. Finally, it suggests challenges for the diagnosis of FAOD in the coming years, both for symptomatic patients and for those diagnosed through newborn screening. The ultimate goal would be to identify all the patients born with FAOD and ensure for them the best possible quality of life.Take home messageTentative hypotheses to improve the diagnosis and the treatment of fatty acid oxidation defects.This article is protected by copyright. All rights reserved.

PCYT1A deficiency disturbs fatty acid metabolism and induces ferroptosis in the mouse retina

“…These results suggested that the FFA utilization of the cellular mitochondria was impaired. After the uptake of FFAs, cells activate the carnitine cycle and β-oxidation (FAO), which ultimately provides energy through the tricarboxylic acid cycle (TCA cycle) and oxidative phosphorylation [ 34 ]. Therefore, we further examined the expression of the key enzymes fatty acid transporter 3 (FATP3, a member of the FATP family) and carnitine palmitoyltransferase 1 (CPT1, a rate-limiting enzyme) during the fatty acid uptake and FAO processes.…”

One substrate many enzymes virtual screening uncovers missing genes of carnitine biosynthesis in human and mouse

“…Carnitine supply is crucial for energy metabolism as it enables the transport of fatty acids into the mitochondria, where they are oxidized to generate ATP. Although not essential to the body’s supply of carnitine, nutritional sources are very important in humans, with about 75% of total body carnitine originating from food sources, at least in the presence of an omnivorous diet 72 , 73 . The results of our study suggest that humans and some other mammals, having lost a gene coding for an enzyme with efficient HTMLA activity, may have a lower output from the biosynthetic pathway and a higher dietary requirement for carnitine.…”