RESUMO
Sub-cellular compartmentalization of metabolism has important implications for the local production of metabolites and redox co-factors, as well as pathway regulation. 4'-phosphopantetheinyl (4'PP) groups are essential co-factors derived from coenzyme A and added to target proteins in both the cytoplasm and mitochondria by p hospho p antetheinyl transferase (PPTase) enzymes. Mammals express only one PPTase, thought to localize to the cytoplasm: aminoadipate semialdehyde dehydrogenase phosphopantetheinyl transferase (AASDHPPT); raising the question of how mitochondrial proteins are 4'PP-modified. We found that AASDHPPT is required for mitochondrial respiration and oxidative metabolism via the mitochondrial fatty acid synthesis (mtFAS) pathway. Moreover, we discovered that a pool of AASDHPPT localizes to the mitochondrial matrix via an N-terminal mitochondrial targeting sequence contained within the first 13 amino acids of the protein. Our data show that mitochondrial localization of AASDHPPT is required to support mtFAS function, and further identify two variants in Aasdhppt that are likely pathogenic in humans.