Acute intermittent porphyria causes hepatic mitochondrial energetic failure in a mouse model
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Published on: November 27, 2019
Chadi Homedan1, Jihane Laafi2, Caroline Schmitt3
1UMR INSERM 1063, Angers, France; Centre Hospitalier Universitaire, Département de Biochimie et Génétique, Angers, France.
Abstract:
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.
Insights
Acute intermittent porphyria (AIP) disrupts hepatic energy metabolism, impairing mitochondrial function. Treatments like heme arginate can reverse these AIP-induced metabolic changes.
Area of Science:
- Biochemistry
- Genetics
- Metabolic Disorders
Background:
- Acute intermittent porphyria (AIP) is an inherited hepatic disorder caused by a defect in hydroxymethylbilane synthase (HMBS).
- AIP attacks are linked to increased hepatic production of 5-aminolaevulinic acid (ALA).
- Mitochondrial enzyme ALA synthase 1 (ALAS1) is crucial for heme biosynthesis and linked to energy pathways, with ALAS1 siRNA therapy showing promise.
Purpose of the Study:
- To investigate the impact of AIP on hepatic energetic metabolism.
- To explore mitochondrial respiratory chain (RC) and tricarboxylic acid (TCA) cycle function in a mouse model of AIP.
- To understand the metabolic effects of phenobarbital treatment and potential therapeutic interventions.
Main Methods:
- Utilized Hmbs knockout (KO) mice as a model for AIP.
- Administered phenobarbital to induce AIP-like metabolic changes.
- Assessed activities of RC complexes (I, II, III), alpha-ketoglutarate dehydrogenase, citrate synthase, and succinate dehydrogenase.
- Examined the effects of phenobarbital withdrawal and heme arginate administration.
Main Results:
- Phenobarbital treatment significantly decreased activities of RC complexes I, II, and III in Hmbs KO mice.
- Key TCA cycle enzymes, including alpha-ketoglutarate dehydrogenase, citrate synthase, and succinate dehydrogenase, showed reduced activity.
- Complex II-driven succinate respiration was notably affected.
- These metabolic deficits were largely reversible upon cessation of phenobarbital and administration of heme arginate.
Conclusions:
- Phenobarbital induces TCA cycle cataplerosis in AIP by increasing succinyl-CoA withdrawal via ALAS1 induction.
- This cataplerosis impairs the TCA cycle's ability to supply cofactors to the RC, leading to mitochondrial dysfunction.
- The findings offer insights into the therapeutic benefits of heme, glucose, and ALAS1 siRNA by mitigating TCA cycle cataplerosis in AIP.
