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

Journal

Nature metabolism

ISSN: 2522-5812

Titre abrégé: Nat Metab

Pays: Germany

ID NLM: 101736592

Informations de publication

Date de publication:
23 Nov 2023

Historique:

received: 08 08 2022

accepted: 10 10 2023

medline: 24 11 2023

pubmed: 24 11 2023

entrez: 23 11 2023

Statut: aheadofprint

Résumé

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.

Identifiants

DOI: 10.1038/s42255-023-00926-4 PMID: 37996701

pubmed: 37996701

doi: 10.1038/s42255-023-00926-4

pii: 10.1038/s42255-023-00926-4

doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Subventions

Organisme : U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)

ID : GM134715

Organisme : U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)

ID : GM134715

Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)

ID : NS076511

Organisme : U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)

ID : AG059683

Organisme : U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)

ID : HL117880

Informations de copyright

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