Anomalous peroxidase activity of cytochrome c is the primary pathogenic target in Barth syndrome.

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.

A rare cause of secondary hemophagocytic lymphohistiocytosis: systemic loxoscelism.

BACKGROUND: Loxoscelism is caused by the bite of a specific spider type called the Loxosceles genus. In Turkey, most cases are seen after L. rufescens bites. Clinical manifestation of the bites ranges from local cutaneous reaction to severe ulcerative necrosis. Systemic loxoscelism may also occur. CASE: Herein, we report a previously healthy five-year-old male patient who developed a secondary hemophagocytic lymphohistiocytosis after a presumed brown spider bite. He was treated with dexamethasone. Within the following 14 days, hemophagocytic syndrome resolved. Local hyperbaric oxygen therapy was applied to the necrotic areas. CONCLUSION: Secondary hemophagocytic lymphohistiocytosis may develop after systemic loxoscelism. In the presence of persistent fever, hepatosplenomegaly and laboratory findings this clinical entity should be kept in mind.