Kagan, V.E., Tyurina, Y.Y., Mikulska-Ruminska, K., Damschroder, D., Vieira Neto, E., Lasorsa, A., Kapralov, A.A., Tyurin, V.A., Amoscato, A.A., Samovich, S.N., Souryavong, A.B., Dar, H.H., Ramim, A., Liang, Z., Lazcano, P., Ji, J., Schmidtke, M.W., Kiselyov, K., Korkmaz, A., Vladimirov, G.K., Artyukhova, M.A., Rampratap, P., Cole, L.K., Niyatie, A., Baker, E.K., Peterson, J., Hatch, G.M., Atkinson, J., Vockley, J., Kühn, B., Wessells, R., van der Wel, P.C.A., Bahar, I., Bayir, H., Greenberg, M.L. (2023). Anomalous peroxidase activity of cytochrome c is the primary pathogenic target in Barth syndrome.  Nat Metab 5(12): 2184--2205.

FBrf0258401

Research paper

Barth syndrome (BTHS) is a life-threatening genetic disorder with unknown pathogenicity caused by mutations in TAFAZZIN (TAZ) that affect remodeling of mitochondrial cardiolipin (CL). TAZ deficiency leads to accumulation of mono-lyso-CL (MLCL), which forms a peroxidase complex with cytochrome c (cyt c) capable of oxidizing polyunsaturated fatty acid-containing lipids. We hypothesized that accumulation of MLCL facilitates formation of anomalous MLCL-cyt c peroxidase complexes and peroxidation of polyunsaturated fatty acid phospholipids as the primary BTHS pathogenic mechanism. Using genetic, biochemical/biophysical, redox lipidomic and computational approaches, we reveal mechanisms of peroxidase-competent MLCL-cyt c complexation and increased phospholipid peroxidation in different TAZ-deficient cells and animal models and in pre-transplant biopsies from hearts of patients with BTHS. A specific mitochondria-targeted anti-peroxidase agent inhibited MLCL-cyt c peroxidase activity, prevented phospholipid peroxidation, improved mitochondrial respiration of TAZ-deficient C2C12 myoblasts and restored exercise endurance in a BTHS Drosophila model. Targeting MLCL-cyt c peroxidase offers therapeutic approaches to BTHS treatment.

PMC11213643 (PMC) (EuropePMC)