Integrated multi-omics mapping of mitochondrial dysfunction and substrate preference in Barth syndrome cardiac tissue
Barth syndrome (BTHS) is a rare X-linked recessively inherited disorder caused by variants in the TAFAZZIN gene, leading to impaired conversion of monolysocardiolipin (MLCL) into mature cardiolipin (CL). Accumulation of MLCL and CL deficiency are diagnostic markers for BTHS. Clinically, BTHS includes cardiomyopathy, skeletal myopathy, neutropenia, and growth delays. Severely affected patients may require early cardiac transplants due to unpredictable cardiac phenotypes. The pathophysiological mechanisms of BTHS are poorly understood, and treatments remain symptomatic. This study analyzed heart samples from five pediatric male BTHS patients (5 months-15 years) and compared them to tissues from 24 non-failing donors (19-71 years) using an integrated omics method combining metabolomics, lipidomics, and proteomics. The analysis confirmed changes in diagnostic markers (CL and MLCL), severe mitochondrial alterations, metabolic shifts, and elevated heart-failure markers. It also revealed significant interindividual differences among BTHS patients. This study describes a powerful analytical tool for the in-depth analysis of metabolic disorders and a solid foundation for the understanding of BTHS disease phenotypes in cardiac tissues.
Authors
- Yorrick Jaspers (ORCID: https://orcid.org/0000-0002-9153-5734)
- Jolanda van der Velden (ORCID: https://orcid.org/0000-0001-5224-5788)
- Frédéric M. Vaz (ORCID: https://orcid.org/0000-0002-9048-1041)
- Riekelt H. Houtkooper (ORCID: https://orcid.org/0000-0001-9961-0842)
- Sander R. Piersma (ORCID: https://orcid.org/0000-0001-7262-3395)
- Bauke V. Schomakers (ORCID: https://orcid.org/0000-0002-0242-9113)
- Michel van Weeghel (ORCID: https://orcid.org/0000-0002-4916-2866)
- Peter T. Simpson (ORCID: https://orcid.org/0000-0002-4816-8289)
- Signe Mosegaard (ORCID: https://orcid.org/0000-0002-4561-1978)
- Gajja Sophi Salomons (ORCID: https://orcid.org/0000-0003-2509-3648)
- Barry J. Byrne
- Paul M.L. Janssen (ORCID: https://orcid.org/0000-0002-9682-3014)
- Jan B. van Klinken (ORCID: https://orcid.org/0000-0002-9855-3548)
- Connie R. Jiménez (ORCID: https://orcid.org/0000-0002-3103-4508)
- Iman Man Hu
- Denise Cloutier
- Adriana S Passadouro
- Maria M. Trętowicz
- Cathelijne M. E. Lamboo
Institutions
- University of Florida (US)
- Center for Personalized Cancer Treatment (NL)
- Amsterdam Neuroscience (NL)
- Enveda Therapeutics (United States) (US)
- Amsterdam University Medical Centers (NL)
- Pro Persona (NL)
- The Ohio State University (US)
- Amsterdam University of Applied Sciences (NL)
- Vrije Universiteit Amsterdam (NL)
- University of Amsterdam (NL)
- Florida College (US)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2025-10-13
- DOI
- https://doi.org/10.1038/s44321-025-00320-5
- Citations
- 1
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 0.81