TY - JOUR
T1 - Anomalous peroxidase activity of cytochrome c is the primary pathogenic target in Barth syndrome
AU - Kagan, Valerian E.
AU - Tyurina, Yulia Y.
AU - Mikulska-Ruminska, Karolina
AU - Damschroder, Deena
AU - Vieira Neto, Eduardo
AU - Lasorsa, Alessia
AU - Kapralov, Alexander A.
AU - Tyurin, Vladimir A.
AU - Amoscato, Andrew A.
AU - Samovich, Svetlana N.
AU - Souryavong, Austin B.
AU - Dar, Haider H.
AU - Ramim, Abu
AU - Liang, Zhuqing
AU - Lazcano, Pablo
AU - Ji, Jiajia
AU - Schmidtke, Michael W.
AU - Kiselyov, Kirill
AU - Korkmaz, Aybike
AU - Vladimirov, Georgy K.
AU - Artyukhova, Margarita A.
AU - Rampratap, Pushpa
AU - Cole, Laura K.
AU - Niyatie, Ammanamanchi
AU - Baker, Emma Kate
AU - Peterson, Jim
AU - Hatch, Grant M.
AU - Atkinson, Jeffrey
AU - Vockley, Jerry
AU - Kühn, Bernhard
AU - Wessells, Robert
AU - van der Wel, Patrick C.A.
AU - Bahar, Ivet
AU - Bayir, Hülya
AU - Greenberg, Miriam L.
N1 - Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85177576548
U2 - 10.1038/s42255-023-00926-4
DO - 10.1038/s42255-023-00926-4
M3 - Article
C2 - 37996701
AN - SCOPUS:85177576548
SN - 2522-5812
VL - 5
SP - 2184
EP - 2205
JO - Nature Metabolism
JF - Nature Metabolism
IS - 12
ER -