MitoSAM-dependent lipoylation controls postnatal heart development via metabolic remodeling
, is essential for this shift by sustaining the lipoylation of 2-oxoacid dehydrogenases, critical for TCA cycle activation. Proteomic and metabolomic profiling revealed that reduced mitoSAM availability impaired lipoylation, blocking TCA cycle function and restricting nucleotide synthesis, while mitochondrial gene expression and respiratory capacity remained largely intact. In vivo EdU labeling showed persistent cardiomyocyte proliferation imposing further strain on nucleotide pools. Supplementation with medium-chain triglycerides during the suckling-to-weaning transition restored metabolic function and normalized cardiac growth and morphology. Our data reveal a critical developmental window in which mitoSAM-dependent lipoylation ensures heart maturation.
Authors
- Marco F. Moedas (ORCID: https://orcid.org/0000-0001-5461-0320)
- Ralph J. DeBerardinis (ORCID: https://orcid.org/0000-0002-2705-7432)
- Ákos Végvári (ORCID: https://orcid.org/0000-0002-1287-0906)
- Linden Muellner-Wong (ORCID: https://orcid.org/0000-0003-0348-6408)
- Florian A. Rosenberger (ORCID: https://orcid.org/0000-0003-4604-6170)
- Anastasia Rumyantseva (ORCID: https://orcid.org/0000-0002-7847-6178)
- Thomas P. Mathews (ORCID: https://orcid.org/0000-0002-9355-8243)
- David Alsina (ORCID: https://orcid.org/0000-0003-0708-7391)
- Anna Wredenberg (ORCID: https://orcid.org/0000-0002-2500-6121)
- David Moore (ORCID: https://orcid.org/0000-0002-3748-0154)
- Daniel Andersson (ORCID: https://orcid.org/0000-0003-4548-702X)
- Lars H. Lund (ORCID: https://orcid.org/0000-0003-1411-4482)
- Trevor S. Tippetts (ORCID: https://orcid.org/0000-0002-1419-7057)
- Christoph Freyer (ORCID: https://orcid.org/0000-0003-0418-1673)
- Rolf Wibom (ORCID: https://orcid.org/0000-0001-6721-4642)
- Gianluigi Pironti (ORCID: https://orcid.org/0000-0001-9401-3029)
- Alissa Wilhalm
- William Carter (ORCID: https://orcid.org/0009-0007-5490-6499)
- Anna Wedell (ORCID: https://orcid.org/0000-0002-2612-6301)
- R. Winston
Institutions
- Children's Medical Center (US)
- Karolinska University Hospital (SE)
- Howard Hughes Medical Institute (US)
- Karolinska Institutet (SE)
- Southwestern Medical Center (US)
- Max Planck Institute for Biology of Ageing (DE)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-04-20
- DOI
- https://doi.org/10.64898/2026.04.20.719537
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Cancer Prevention and Research Institute of Texas
- Stiftelsen Promobilia
- Cancerfonden
- Hjärnfonden
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- National Heart, Lung, and Blood Institute
- National Cancer Institute