Mitochondrial medicine in fatty acid oxidation disorders: insights from genetic discoveries and patient cell models

Mitochondrial fatty acid oxidation (mFAO) disorders are caused by genetic variants in mFAO enzymes, their electron transporters, and cofactors. The clinical spectrum is heterogeneous, ranging from multi-organ failure and early death to milder neuromuscular forms that often are triggered or exacerbated during catabolic stress. Advances in genetics and the inclusion of mFAO disorders in newborn screening programs have allowed timely diagnosis and dietary interventions to prevent tissue damage and even death. Current dietary treatment aims to prevent energy deficiency and reduce toxic metabolites, but does not significantly prevent neurological, cardiac, and skeletal muscular abnormalities, including rhabdomyolysis. This review summarizes the present knowledge obtained from human studies showing that disruption of mitochondrial bioenergetics and redox homeostasis may represent relevant mechanisms for understanding long-term tissue damage and the stress-induced disease pathology of mFAO disorders. Sources and mechanisms of reactive oxygen species (ROS) production are discussed, including knowledge gained from mutations in the Electron Transfer Flavoprotein (ETF) and ETF-Ubiquinone Oxidoreductase (ETF-QO) proteins. The ETF/ETF-QO site serves as a biophysical and biochemical linker between mFAO and OXPHOS, and its high capacity for ROS production makes it a key component of the respiratory chain and a source of ROS in mFAO disorders. Understanding mitochondrial disturbances and how secondary disturbances in mFAO cofactors integrate with redox regulation at the ETF/ETF-QO site will advance our understanding of not only mFAO disorders but also the many diseases entailing OXPHOS and mFAO deficiencies, such as neurological and cardiovascular diseases, and as such, be enlightening for mitochondrial medicine in general.