MitoSAM-dependent lipoylation controls postnatal heart development via metabolic remodeling

Area of Science:

• Cardiovascular physiology
• Mitochondrial metabolism
• Neonatal development

Background:

• The neonatal heart transitions from glycolysis to oxidative phosphorylation.
• The precise mechanisms governing this metabolic remodeling are not fully understood.

Purpose of the Study:

• To investigate the role of mitochondrial S-adenosylmethionine (mitoSAM) in neonatal heart metabolic adaptation.
• To identify the molecular targets and consequences of insufficient mitoSAM during this transition.

Main Methods:

• Proteomic and metabolomic profiling to assess lipoylation and TCA cycle function.
• In vivo EdU labeling to evaluate cardiomyocyte proliferation.
• Supplementation studies with medium-chain triglycerides (MCTs).

Main Results:

• Sufficient mitoSAM, imported via Slc25a26, is essential for lipoylation of 2-oxoacid dehydrogenases, enabling TCA cycle activation.
• Reduced mitoSAM impaired lipoylation, blocked TCA cycle function, and restricted nucleotide synthesis.
• MCT supplementation restored metabolic function and normalized cardiac growth and morphology during the suckling-to-weaning transition.

Conclusions:

• MitoSAM-dependent lipoylation is critical for neonatal heart maturation.
• This pathway represents a key developmental window for ensuring proper cardiac metabolic function and growth.