# Regulation of heme synthesis by mitochondrial proteins

> **NIH NIH R35** · UNIVERSITY OF DELAWARE · 2020 · $400,000

## Abstract

ABSTRACT
The long-term goal of this project is to identify the mechanisms that regulate “housekeeping” mitochondrial
heme metabolism. Heme plays a central role in the redox reactions of life-essential processes such as
mitochondrial respiration. My research program is particularly interested in 1. identifying proteins that
regulate mitochondrial heme/porphyrin transport and 2. proteins that are part of the housekeeping
mitochondrial homeostasis machinery that structurally or functionally interact with the core enzymes of the
heme synthesis pathway. While the enzymes of the heme synthesis are well characterized and identical in all
tissues, the regulatory mechanisms that couple heme synthesis to cellular requirements are very poorly
understood. The importance of these regulatory mechanisms is underscored by the existence of disorders of
heme synthesis and iron metabolism that are caused by dysregulation of proteins that are commonly associated
with “housekeeping” homeostatic processes or mitochondrial respiration. Although all tissues require heme,
most of our studies on regulatory aspects of heme synthesis have focused on erythroid cells to the exclusion of
understanding heme synthesis in other cell types. This project uses our knowledge of erythroid heme synthesis
as a springboard to identify heme regulatory mechanisms that are required for housekeeping heme synthesis.
Project 1 aims to identify proteins that are required for mitochondrial porphyrin transport in non-erythroid
cells. Heme intermediates are photosensitive and cytotoxic, requiring mechanisms for cells to quickly and
efficiently transport heme intermediates across cell membranes, to the next enzyme in the heme synthetic
pathway. When efficient transport does not occur, cytotoxic porphyrins accumulate in cells, potentially causing
porphyria and heme deficiency. While TMEM14C is essential for porphyrin transport in erythroid cells,
TMEM14 proteins are not required for heme synthesis in non-erythroid cells. Using a combination of
proteomics and whole genome sequencing/RNAseq analysis of TMEM14C suppressor mutants, we will identify
novel mitochondrial proteins that regulate porphyrin transport in non-erythroid cells. The long-term goal of
Project 2 is to understand the regulation of the heme synthesis complex by proteins that regulate housekeeping
mitochondrial homeostasis. During this project period, we focus on the ubiquitous mitochondrial unfoldase,
CLPX, which plays an essential role in regulating the activity and protein stability of heme synthesis enzymes.
We show that the function of CLPX is highly tissue-specific, and propose to understand its role in the systemic
regulation of heme metabolism in the setting of “housekeeping” heme synthesis. These studies will provide
essential datasets that will be invaluable to the mitochondrial protein unfoldase community, but will also be
essential for determining how CLPX globally regulates mitochondrial homeostasis via tight regulation of ...

## Key facts

- **NIH application ID:** 10000941
- **Project number:** 5R35GM133560-02
- **Recipient organization:** UNIVERSITY OF DELAWARE
- **Principal Investigator:** Yvette Y Yien
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $400,000
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000941

## Citation

> US National Institutes of Health, RePORTER application 10000941, Regulation of heme synthesis by mitochondrial proteins (5R35GM133560-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10000941. Licensed CC0.

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