Acute Intermittent Porphyria Causes Hepatic Mitochondrial Energetic Failure In A Mouse Model.

Acute Intermittent Porphyria Causes Hepatic Mitochondrial Energetic Failure In A Mouse Model. Int J Biochem Cell Biol. 2014 Apr 10; Authors: Homedan C, Laafi J, Schmitt C, Gueguen N, Lefebvre T, Karim Z, Desquiret-Dumas V, Wetterwald C, Deybach JC, Gouya L, Puy H, Reynier P, Malthièry Y 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-d...
Source: The International Journal of Biochemistry and Cell Biology - Category: Biochemistry Authors: Tags: Int J Biochem Cell Biol Source Type: research