Bezafibrate activation of PPAR drives disturbances in mitochondrial redox bioenergetics and decreases the viability of cells from patients with VLCAD deficiency

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is the most common inborn fatty acid oxidation (FAO) disorder. VLCAD characterized by distinct phenotypes. The severe phenotypes are potentially life-threatening and affect heart or liver, with a comparatively milder phenotype myopathic symptoms. There an unmet clinical need for effective treatment options phenotype. molecular mechanisms driving gradual decrease in mitochondrial function associated alterations of muscle fibers unclear. peroxisome proliferator-activated receptor (PPAR) pan-agonist bezafibrate potent modulator FAO multiple other functions has been proposed as potential medication cases disorders. In vitro experiments have demonstrated ability to increase expression activity. However, outcome small-scale trials controversial. We found deficient patient fibroblasts increased oxidative stress burden deranged bioenergetic capacity, compared controls. Applying heat under fasting conditions pretreated cells, caused marked further superoxide levels. Patient cells failed maintain levels essential thiol peptide antioxidant glutathione experienced cellular viability. Our findings indicate that chronic PPAR activation plausible initiator long-term pathogenesis deficiency. implicate disruption redox homeostasis key pathogenic mechanism support notion metabolism might be important factor