Lund, M, Andersen, KG, Heaton, R, Hargreaves, IP, Gregersen, N and Olsen, RKJ (2021) Bezafibrate activation of PPAR drives disturbances in mitochondrial redox bioenergetics and decreases the viability of cells from patients with VLCAD deficiency. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. ISSN 0925-4439

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Abstract

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

Item Type:	Article
Uncontrolled Keywords:	0601 Biochemistry and Cell Biology, 1101 Medical Biochemistry and Metabolomics, 1103 Clinical Sciences
Subjects:	Q Science > QH Natural history > QH301 Biology R Medicine > RM Therapeutics. Pharmacology
Divisions:	Pharmacy & Biomolecular Sciences
Publisher:	Elsevier BV
Date Deposited:	10 Feb 2021 10:11
Last Modified:	05 Feb 2022 00:50
DOI or ID number:	10.1016/j.bbadis.2021.166100
URI:	https://researchonline.ljmu.ac.uk/id/eprint/14422

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