Pilot study of mitochondrial bioenergetics in subjects with acute porphyrias

Publication date: Available online 20 May 2019Source: Molecular Genetics and MetabolismAuthor(s): Natalia Dixon, Ting Li, Brandon Marion, Denise Faust, Stephen Dozier, Anthony Molina, Sean Rudnick, Herbert L. BonkovskyAbstractBackground and aimsThe acute porphyrias are characterized by defects in heme synthesis, particularly in the liver. In some affected patients, there occurs a critical deficiency in a regulatory heme pool within hepatocytes that leads to up-regulation of 5-aminolevulinic acid [ALA] synthase-1, which is the first and normally rate-controlling enzyme in the pathway. In earlier work, we described defects in mitochondrial functions in cultured skin fibroblasts from patients with acute intermittent porphyria [AIP]. Others described defects in livers of murine models of AIP. Here, we explored mitochondrial energetics in peripheral blood mononuclear cells [PBMCs] and platelets in persons with AIP and hereditary coproporphyria [HCP]. Our hypotheses were that there are deficits in bioenergetic capacity in acute porphyrias and that subjects with more severe acute porphyria have more pronounced reductions in mitochondrial oxygen consumption rates [OCR].MethodsWe studied 17 subjects with acute hepatic porphyrias, 14 with classical AIP, one with severe AIP due to homozygous deficiency of hydroxymethylbilane synthase [HMBS], 2 with HCP, and 5 non-porphyric controls. We collected peripheral blood, isolated PBMCs, which we assayed either immediately or after frozen storag...

Source: Molecular Genetics and Metabolism - May 22, 2019 Category: Genetics & Stem Cells Source Type: research