Loss of the Mitochondrial SAM Transporter Reveals a Lipoylation-Dependent Metabolic Vulnerability in the Postnatal Heart

ABSTRACT: SLC25A26 encodes the sole mitochondrial S-adenosylmethionine carrier (SAMC). Inside mitochondria, SAM functions as a methyl group donor for various methyltransferases and as a substrate for radical SAM enzymes. Variants in SAMC are associated with mitochondrial disease, and we previously demonstrated that the mitochondrial methylation potential links the one-carbon pool to energy metabolism, but tissue-specific responses are poorly understood. Here, we studied the physiological, molecular, and metabolic consequences of a SAMC deficiency in heart or skeletal muscle. While SAMC ablation in skeletal muscle causes 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. We demonstrate that octanoic acid becomes rate-limiting during this transition, exposing a critical requirement for lipoic acid during cardiac maturation.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart, Skeletal Muscle Fiber

SUBMITTER: Akos Vegvari  

LAB HEAD: Akos Vegvari

PROVIDER: PXD050486 | Pride | 2026-07-03

REPOSITORIES: Pride