Targeting cytochrome c peroxidase activity for Barth Syndrome

Inhibiting the peroxidase activity of the mitochondrial protein cytochrome c could help treat Barth Syndrome, which is caused by a mutation in the lipid metabolism enzyme TAFAZZIN, and leads to accumulation of a variant of the TAFAZZIN substrate cardiolipin that complexes with cytochrome c and drives aberrant oxidation of polyunsaturated fatty acid-containing lipids.

Expression of the cardiolipin variant MLCL was higher in a Barth Syndrome patient-derived lymphoblast cell line than in a similar cell line from a healthy control, and TAFAZZIN knockout in mouse myoblast and cardiac cell lines increased MLCL levels compared with normal expression. Biochemical, chemical and computational studies showed MLCL bound cytochrome c and caused it to act as a lipid peroxidase. ...