Loss of the mitochondrial SAM transporter reveals a lipoylation-dependent metabolic vulnerability in the postnatal heart
The neonatal heart experiences rapid metabolic growth after birth to meet increasing energetic and biosynthetic demands. How mitochondrial cofactor availability limits this transition remains unclear. Here, we demonstrate that mitochondrial S -adenosylmethionine (mitoSAM) import through SLC25A26 becomes limiting shortly after birth and specifically restricts protein lipoylation, although other mitoSAM-dependent processes are partially preserved. Loss of Slc25a26 impaired lipoylation-dependent flux through pyruvate and α-ketoglutarate dehydrogenases, restricting tricarboxylic acid cycle carbon entry and depleting aspartate and nucleotide pools. Conversely, mitochondrial gene expression remained intact, and respiratory chain enzyme activities showed partial impairment, indicating that lipoylation is the most mitoSAM-sensitive pathway during postnatal heart adaptation. These metabolic limitations were linked to sustained cardiomyocyte cell–cycle activity, delayed structural maturation, and early cardiomyopathy. Supplementing with medium-chain triglycerides during the suckling-to-weaning transition partially stabilized metabolism and prolonged survival. Overall, our findings identify a stage-specific metabolic vulnerability in the postnatal heart characterized by hierarchical mitoSAM utilization within the mitochondria.
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)
- Yvonne Hinze (ORCID: https://orcid.org/0000-0002-2966-9862)
- 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/0000-0002-8217-9707)
- 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
- Science Advances
- Published
- 2026-08-26
- DOI
- https://doi.org/10.1126/sciadv.aeg8792
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Howard Hughes Medical Institute
- Cancer Prevention and Research Institute of Texas
- Stiftelsen Promobilia
- Cancerfonden
- Hjärt-Lungfonden
- Karolinska Institutet
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- Stiftelsen Konung Gustaf V:s 80-årsfond
- Reumatikerförbundet
- Novo Nordisk Fonden
- Stockholm läns landsting
- National Heart, Lung, and Blood Institute
- National Cancer Institute