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.