Modelling mitochondrial SAM depletion in fruit flies and mice

S-adenosylmethionine (SAM) is the principle biological methyl group donor for a diverse range of substrates. It is synthesised in the cytosolic methionine cycle and shuttled throughout the cell. The mitochondrial SAM (mitoSAM) pool depends on import through the inner-membrane SAMC and supports the maturation of metabolites and mitochondrial RNAs. Mutations in SAMC in patients cause a severe metabolic crisis, however, the organellar regulation of mitoSAM and the protein methylation landscape within mitochondria are largely unknown. Using fly and mouse models, we demonstrate that titrating mitoSAM differentially effects mitochondrial function. Metabolite and iron-sulfur cluster biosynthesis are disrupted due to acutely decreased methylation potential, while prolonged mitoSAM deficiency affects fly longevity and OXPHOS stability. The herein uploaded raw data was used for total larvae and total cell proteome quantification in the established lines. Our results define the critical role of cytoplasmic SAM production for mitochondrial methylation events and highlight the indirect effect of one-carbon metabolism on cellular bioenergetics.