Abstract

Fatty acids in mitochondria, in sensu stricto, arise either as β-oxidation substrates imported via the carnitine shuttle or through de novo synthesis by the mitochondrial fatty acid synthesis (mtFAS) pathway. Defects in mtFAS or processes involved in the generation of the mtFAS product derivative lipoic acid (LA), including iron-sulfur cluster synthesis required for functional LA synthase, have emerged only recently as etiology for neurodegenerative disease. Intriguingly, mtFAS deficiencies very specifically affect CNS function, while LA synthesis and attachment defects have a pleiotropic presentation beyond neurodegeneration. Typical mtFAS defect presentations include optical atrophy, as well as basal ganglia defects associated with dystonia. The phenotype display of patients with mtFAS defects can resemble the presentation of disorders associated with coenzyme A (CoA) synthesis. A recent publication links these processes together based on the requirement of CoA for acyl carrier protein maturation. MtFAS defects, CoA synthesis- as well as Fe-S cluster-deficiencies share lack of LA as a common symptom.