Acute intermittent porphyria (AIP), an inherited hepatic disorder, is due to a defect of
hydroxymethylbilane synthase (HMBS), an
enzyme involved in
heme biosynthesis. AIP is characterized by recurrent, life-threatening attacks at least partly due to the increased hepatic production of 5-aminolaevulinic
acid (ALA). Both the mitochondrial
enzyme, ALA synthase (ALAS) 1, involved in the first step of
heme biosynthesis, which is closely linked to mitochondrial bioenergetic pathways, and the promise of an ALAS1
siRNA hepatic
therapy in humans, led us to investigate hepatic energetic metabolism in Hmbs KO mice treated with
phenobarbital. The mitochondrial respiratory chain (RC) and the
tricarboxylic acid (TCA) cycle were explored in the Hmbs(-/-) mouse model. RC and TCA cycle were significantly affected in comparison to controls in mice treated with
phenobarbital with decreased activities of RC complexes I (-52%, (**)p<0.01), II (-50%, (**)p<0.01) and III (-55%, (*)p<0.05), and decreased activity of α-ketoglutarate
dehydrogenase (-64%, (*)p<0.05),
citrate synthase (-48%, (**)p<0.01) and
succinate dehydrogenase (-53%, (*)p<0.05). Complex II-driven
succinate respiration was also significantly affected. Most of these metabolic alterations were at least partially restored after the
phenobarbital arrest and
heme arginate administration. These results suggest a cataplerosis of the TCA cycle induced by
phenobarbital, caused by the massive withdrawal of
succinyl-CoA by ALAS induction, such that the TCA cycle is unable to supply the reduced cofactors to the RC. This profound and reversible impact of AIP on mitochondrial energetic metabolism offers new insights into the beneficial effect of
heme,
glucose and ALAS1
siRNA treatments by limiting the cataplerosis of TCA cycle.