Drosophila delta-1-pyrroline-5-carboxylate dehydrogenase (P5CDh) is required for proline breakdown and mitochondrial integrity-Establishing a fly model for human type II hyperprolinemia

Delta-1-pyrroline-5-carboxylate dehydrogenase (P5CDh) is a nuclear-encoded mitochondrial enzyme that catalyzes the second step in proline degradation. Mutations in human P5CDh cause type II hyperprolinemia, a complex syndrome displaying increased serum proline and mental disabilities. Conceptual gene CG7145 in Drosophila melanogaster encodes the orthologous DmP5CDh1. The mutant allele CG7145f04633 contains a piggyBac transposon that truncates the enzyme by 83 residues. Heterozygous (CG7145f04633/TM3) individuals developed normally, while homozygous (CG7145f04633/CG7145f04633) individuals displayed proline levels twice that of normal, swollen mitochondria, and ultimately larval and pupal lethality. We believe this is the first correlation between the loss of P5CDh and morphological defects in mitochondria.