Mitochondria for a central hub in metabolism and involved in diverse pathways such as energy, lipid or amino acid metabolism, or iron-sulphur cluster formation. Dysfunction in this organelle is associated with rare inborn errors of metabolism, but numerous more common diseases show dysregulation in mitochondria. Classically, this has been attributed to changes in cellular respiration and aerobic ATP production, but recent advances show that an imbalance in different metabolites can also affect mitochondrial function. Around 30% of cellular S-adenosylmethionine reside inside mitochondria, but its role is there is only partially understood. We disrupted the mitochondrial SAM transporter, SAMC, in various murine tissues and demonstrate tissue-specific responses to a mitochondrial SAM depletion. For instance, while the skeletal muscle develops a progressive decline resembling other mitochondrial myopathies, cardiac-specific deletion causes a severe and sudden cardiac phenotype driven by a rapid loss of lipoylation of 2-oxoacid dehydrogenases. This collapse coincides with the transition from milk to solid food, causing a natural reduction in medium-chain fatty acids. Our data establish that octanoic acid becomes rate-limiting during this transition and indicate a direct route for octanoic acid into mitochondria, thus exposing a critical requirement for lipoic acid during cardiac maturation.