From genome to phenome—Simple inborn errors of metabolism as complex traits

• Oxidative phosphorylation is biochemically tightly linked to fatty acid oxidation.
• Patients with defects in OXPHOS sporadically show signs of impaired FAO and vice versa.
• Nutrient sensing signaling networks emerge as essential for coupling.
• Targeting nutrient sensing signaling networks offers new therapeutic possibilities.
• The study of secondary cellular reponses calls for the more integrative approach of systems medicine.

Sporadically, patients with a proven defect in either mFAO or OXPHOS are described presenting with a metabolic profile and clinical phenotype expressing concurrent defects in both pathways. Biochemical linkages between both processes are tight. Therefore, it is striking that concurrent dysfunction of both systems occurs so infrequent. In this review, the linkages between OXPHOS and mFAO and the hypothesized processes responsible for concurrent problems in both systems are reviewed, both from the point of view of primary biochemical connections and secondary cellular responses, i.e. signaling pathways constituting nutrient-sensing networks. We propose that affected signaling pathways may play an important role in the phenomenon of concurrent defects. Recent data indicate that interference in the affected signaling pathways may resolve the pathological phenotype even though the primary enzyme deficiency persists. This offers new (unexpected) prospects for treatment of these inborn errors of metabolism. This article is part of a Special Issue entitled: From Genome to Function.