Study Finds Potential New Target, Drug Candidate to Treat Patients with Barth Syndrome

Recent research published in Nature Metabolism discusses a potential new target and a small-molecule drug candidate for treating the Barth syndrome, an incurable genetic disease that is rare and life-threatening. Those with the condition often have weak muscles and hearts as well as chronic fatigue and recurrent infections.¹

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In individuals without Barth syndrome, the lipid cardiolipin (CL) undergoes a series of transformations—or remodeling—within the mitochondria. In those with Barth syndrome, an important gene in the mitochondria, tafazzin (TAZ), is mutated, causing the remodeling of CL to stop and harmful lipids to accumulate.¹

“We found that lyso-CL, an intermediate accumulating in mutant TAZ-deficient cells, interacts with the mitochondrial protein cytochrome c (cyt c), converting it to a demon enzyme that oxidizes everything around it,” said Valerian Kagan, PhD, DSc, professor of environmental and occupational health at the University of Pittsburgh School of Public Health, in a press release.¹

The study authors hypothesized that the accumulation of mono-lysol-CL (MLCL) influences the formation of anomalous MLCL-cyt c peroxidase complexes and peroxidation of polyunsaturated fatty acid phospholipids as the primary Barth syndrome pathogenic mechanism. Using genetic, biochemical and biophysical, redox lipidomic, and computational approaches, the authors revealed mechanisms of peroxidase-competent MLCL-cyt c complexation and increased phospholipid peroxidation in different TAZ-deficient cells in animal models and pre-transplant biopsies from the hearts of patients with Barth syndrome.^1,2

The investigators found that a specific mitochondria-targeted anti-peroxidase agent had inhibited MLCL-cyt c peroxidase activity and excessive oxidation in TAZ-deficient cells, therefore preventing phospholipid peroxidation and improving mitochondrial respiration of TAZ-deficient myoblasts, restoring exercise endurance in Barth syndrome models. The compound, known as imidazole-substituted oleic acid, could potentially block the formation of those complexes and improve motor function and endurance in those with Barth syndrome.²

In addition, faulty mitochondria are partly to blame and the researchers expect a molecular component could potentially be targeted to reverse the disease course in the future. The study authors suggest that future research should focus on the correction of genetic TAZ deficiency and improving mitochondrial function through small-molecule therapeutics.^1,2

References

1. University of Pittsburgh. Potential new target and drug candidate for Barth syndrome. News release. November 23, 2023. Accessed November 29, 2023. https://www.eurekalert.org/news-releases/1008802

2. Kagan, V.E., Tyurina, Y.Y., Mikulska-Ruminska, K. et al. Anomalous peroxidase activity of cytochrome c is the primary pathogenic target in Barth syndrome. Nat Metab (2023). https://doi.org/10.1038/s42255-023-00926-4