A mitochondrial-targeted electron scavenger and a cardiolipin binding peptide decrease superoxide generation and improve mitochondrial respiration in ACAD9- deficient fibroblasts


Guilhian  Leipnitz,  PhD1,2*,  Bianca  Seminotti,  PhD1,  Al-Walid  Mohsen,  PhD1,

Anuradha Karunanidhi, MS1, Vera Y. Roginskaya, MS3, Peter Wipf, PhD4,  Bennett Van Houten, PhD3, Jerry Vockley, MD, PhD1.

1Division    Medical    Genetics,    Department    Pediatrics,    University   of Pittsburgh,

Pittsburgh, PA, USA

2PPG Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

3Department   of   Pharmacology   and   Chemical   Biology,   University   of Pittsburgh,

Pittsburgh, PA, USA

4Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA

*e-mail: guilhian@ufrgs.br / Phone: +5551996958682

Background: Acyl-CoA dehydrogenase 9 (ACAD9) is a flavoprotein that catalyzes the first step in long-chain fatty acid β-oxidation and acts as an assembly factor for mitochondrial respiratory chain complex I. Individuals with ACAD9 deficiency present with progressive encephalomyopathy, recurrent Reye syndrome, and cardiomyopathy that can be fatal. Although some patients are responsive to riboflavin therapy, there are limited treatment options for this disorder.

Objective: Evaluating the effect of potential protective compounds on superoxide generation and mitochondrial respiration in fibroblasts of an ACAD9-deficient patient.

Methods: Patient fibroblasts were cultured in medium without glucose for 48-72 hr to assess the ability of ACAD9-deficient cells to accommodate the shift of energy source from glucose, and the effect of JP4-039, a mitochondrial targeting free radical scavenger, as well as a novel cardiolipin targeting peptide on superoxide production and oxygen consumption.

Results: Superoxide generation was increased, whereas basal respiration and reserve capacity were decreased in ACAD9-deficient cells, compared to normal cells. While either JP4-039 or the cardiolipin targeting peptide decreased superoxide levels, the antioxidants N-acetylcysteine, trolox, resveratrol, and mitoQ, and the pan-PPAR agonist bezafibrate did not reduce superoxide levels. JP4-039 and the peptide increased basal respiration and reserve capacity in deficient cells as well.

Conclusion: These findings suggest that some of the presumed damaging biochemical abnormalities caused by ACAD9 deficiency can be alleviated by JP4-039 and the novel cardiolipin targeting peptide, in addition to improving bioenergetics in ACAD9- deficient fibroblasts. This provides the impetus for further evaluation of these molecules as potential therapeutics for this disorder.

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