Heme synthesis and CSA. The intra-and extramitochondrial step in heme biosynthesis, as well as the inferred transport steps for heme precursors across the mitochondrial inner membrane, are depicted in relation to 2 heme-related causes of CSA: XLSA and SLC25A38 deficiency. 5-ALA is synthesized from succinyl-CoA and glycine by ALAS2. SLC25A38 likely imports glycine into mitochondria and might also export ALA to the cytosol. In the cytosol, ALA molecules are assembled into coproporphyrinogen III (CP'gen III) that is further modified to protoporphyrin IX (PPIX) in the mitochondrial intermembrane space and then transported into the mitochondria by an unknown transporter. Iron transported into mitochondria by MFRN1 is combined with PPIX to form heme by the enzyme FECH.