# Metabolic control of porphyrin biosynthesis by mTOR signaling

> **NIH NIH R15** · KEENE STATE COLLEGE · 2021 · $412,148

## Abstract

PROJECT SUMMARY/ABSTRACT
 Acute porphyrias are potentially life-threatening disorders caused by inherited mutations in enzymes of
the evolutionarily conserved heme biosynthesis pathway. The resulting bottleneck effect leads to a buildup of
toxic heme precursors, including the neurotoxin 5-aminolevulinic acid (ALA) and molecules called porphyrins
that generate free radicals when exposed to light. Conditions that upregulate the first, and rate-limiting pathway
enzyme, 5-aminolevulinic acid synthase (ALAS), can trigger rapid accumulation of ALA and porphyrins, leading
to symptomatic “attacks” characterized by seizures, paralysis, and extreme light sensitivity. One common
trigger of acute attacks is dieting or fasting. The overall goal of this project is to characterize the molecular
mechanisms involved in metabolic control of porphyrin/heme biosynthesis, with an emphasis on determining
the role of the key cellular energy sensor mechanistic target of rapamycin (mTOR). The research plan utilizes
planarian flatworms as an experimentally tractable porphyria disease model. Planarians have a natural
bottleneck in the heme biosynthesis pathway, leading to porphyrin accumulation in the pigment cells of their
skin, and exhibit elevated ALAS expression, porphyrin levels, and light sensitivity in response to reduced
nutrient intake, just like many human patients. Preliminary results show knockdown of mTOR by RNA
interference (RNAi) also leads to an increase in porphyrins, raising the possibility that mTOR signaling in
response to feeding acts as a negative regulator of ALAS expression. This hypothesis will be tested in the first
aim, using RNAi, qRT-PCR, and a liquid chromatography assay for ALAS activity. Additional RNAi experiments
in planarians will identify upstream and downstream components of this signaling pathway, while studies
involving siRNA and drug treatments in cultured human hepatocytes will determine whether this mechanism is
evolutionarily conserved and amenable to pharmacological manipulation. Completion of these experiments will
improve our understanding of the pathogenesis of acute porphyrias and may reveal new avenues for treating
these disorders. Additionally, the work will provide high-level research experiences for undergraduate students
interested in pursuing biomedical career paths in the INBRE state of New Hampshire.

## Key facts

- **NIH application ID:** 10114624
- **Project number:** 1R15DK127370-01
- **Recipient organization:** KEENE STATE COLLEGE
- **Principal Investigator:** Jason Pellettieri
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $412,148
- **Award type:** 1
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10114624

## Citation

> US National Institutes of Health, RePORTER application 10114624, Metabolic control of porphyrin biosynthesis by mTOR signaling (1R15DK127370-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10114624. Licensed CC0.

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