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

Autor: Kagan VE; Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, School of Public Health, Children's Neuroscience Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. kagan@pitt.edu., Tyurina YY; Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, School of Public Health, Children's Neuroscience Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Mikulska-Ruminska K; Institute of Physics, Faculty of Physics, Astronomy and Informatics, Nicolaus Copernicus University in Toruń, Toruń, Poland., Damschroder D; Department of Physiology, Wayne State University School of Medicine, Detroit, MI, USA., Vieira Neto E; Department of Pediatrics, Genetic and Genomic Medicine Division, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA., Lasorsa A; Zernike Institute for Advanced Materials, University of Groningen, Groningen, The Netherlands., Kapralov AA; Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, School of Public Health, Children's Neuroscience Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Tyurin VA; Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, School of Public Health, Children's Neuroscience Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Amoscato AA; Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, School of Public Health, Children's Neuroscience Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Samovich SN; Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, School of Public Health, Children's Neuroscience Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Souryavong AB; Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, School of Public Health, Children's Neuroscience Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Dar HH; Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, School of Public Health, Children's Neuroscience Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Ramim A; Department of Biological Sciences, Wayne State University, Detroit, MI, USA., Liang Z; Department of Biological Sciences, Wayne State University, Detroit, MI, USA., Lazcano P; Department of Biological Sciences, Wayne State University, Detroit, MI, USA., Ji J; Department of Biological Sciences, Wayne State University, Detroit, MI, USA., Schmidtke MW; Department of Biological Sciences, Wayne State University, Detroit, MI, USA., Kiselyov K; Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA., Korkmaz A; Department of Pediatrics, Division of Critical Care and Hospital Medicine, Redox Health Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA., Vladimirov GK; Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, School of Public Health, Children's Neuroscience Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Artyukhova MA; Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, School of Public Health, Children's Neuroscience Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Rampratap P; Zernike Institute for Advanced Materials, University of Groningen, Groningen, The Netherlands., Cole LK; Department of Pharmacology and Therapeutics, University of Manitoba, Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada., Niyatie A; Department of Pediatrics, Pediatric Institute for Heart Regeneration and Therapeutics, University of Pittsburgh, Pittsburgh, PA, USA., Baker EK; Department of Chemistry & Centre for Biotechnology, Brock University, St Catharines, Ontario, Canada., Peterson J; Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, School of Public Health, Children's Neuroscience Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Hatch GM; Department of Pharmacology and Therapeutics, University of Manitoba, Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada., Atkinson J; Department of Chemistry & Centre for Biotechnology, Brock University, St Catharines, Ontario, Canada., Vockley J; Department of Pediatrics, Genetic and Genomic Medicine Division, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA., Kühn B; Department of Pediatrics, Pediatric Institute for Heart Regeneration and Therapeutics, University of Pittsburgh, Pittsburgh, PA, USA., Wessells R; Department of Physiology, Wayne State University School of Medicine, Detroit, MI, USA., van der Wel PCA; Zernike Institute for Advanced Materials, University of Groningen, Groningen, The Netherlands., Bahar I; Laufer Center for Physical Quantitative Biology and Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, New York, NY, USA., Bayir H; Department of Pediatrics, Division of Critical Care and Hospital Medicine, Redox Health Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. hb2753@cumc.columbia.edu., Greenberg ML; Department of Biological Sciences, Wayne State University, Detroit, MI, USA. mgreenberg@wayne.edu.
Jazyk: angličtina
Zdroj: Nature metabolism [Nat Metab] 2023 Dec; Vol. 5 (12), pp. 2184-2205. Date of Electronic Publication: 2023 Nov 23.
DOI: 10.1038/s42255-023-00926-4
Abstrakt: 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.
(© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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