Liebold Abstract Type A 2022

Acute porphyrias are rare metabolic disorders marked by episodes of severe abdominal pain,

neurological issues ranging from anxiety and confusion to seizures or paralysis, and extreme light sensitivity. These disease “attacks” are due to inherited mutations in enzymes of the heme biosynthesis pathway and the consequent accumulation of toxic heme precursors, including cyclic tetrapyrroles called porphyrins that generate free radicals when exposed to light. The basic science of acute porphyrias has primarily been studied in cultured cells and mouse models. However, the deep evolutionary conservation of the heme biosynthesis pathway as well as the photosensitizing effects of porphyrins also present opportunities to explore mechanisms of disease pathogenesis in nontraditional systems. We recently showed planarian flatworms generate porphyrins in the pigment cells of their skin, due to a physiological heme biosynthesis bottleneck. This leads to rapid ablation of the pigment cells in response to prolonged light exposure. In humans, dieting or fasting induces expression of the first and rate-limiting pathway enzyme, 5-aminolevulinic acid synthase (ALAS), thereby exacerbating the buildup of toxic intermediates in the presence of a downstream blockage. Remarkably, we found this effect is conserved in planarians, establishing a novel and experimentally tractable acute porphyria model. Here, we propose to use ultra performance liquid chromatography (UPLC) assays performed by the Center for Iron and Hematology Disorders (CIHD) at the University of Utah to gain further insight into the biochemistry of planarian porphyrins. Specifically, we will: 1) seek to identify the major porphyrin(s) and/or derivative(s) produced in two different planarian species; and 2) utilize defined laboratory diets to examine the impacts of changes in carbohydrate and protein consumption, as well as total caloric intake, on ALAS activity in tissue lysates. Together with another ongoing line of research in our lab, these experiments stand to provide new insight into nutrient-sensing pathways mediating dietary impacts on porphyrin/heme biosynthesis. In turn, this has the potential to advance our understanding of the pathophysiology of acute porphyrias and to reveal new avenues for treating these disorders.