# NCOA4-Mediated Ferritinophagy in Iron-Dependent Brain Development

> **NIH NIH R21** · UNIVERSITY OF MINNESOTA · 2021 · $232,500

## Abstract

ABSTRACT: Developing neurons have high iron requirements to support their metabolism, growth, and
differentiation. Yet, free iron can produce oxidative stress and be cytotoxic. To avoid neurological damage from
iron deficiency (ID) and overload, neuronal iron levels must be tightly regulated. Ferritin protein complexes play
a critical role in regulating intracellular iron availability by storing iron that is not immediately used. During times
of high iron demand (e.g., development), ferritin iron release must be controlled to prevent ID. Ferritinophagy,
the process by which iron is released from ferritin and delivered to sites of high iron demand (e.g., mitochondria),
was recently characterized in developing red blood cells (RBCs). Nuclear receptor coactivator 4 (NCOA4) is the
specific cargo receptor that initiates mobilization of ferritin iron by directing ferritin to lysosomes via selective
autophagy. Ferritinophagy is critical for maintaining the supply of iron required for mitochondrial heme synthesis
in developing RBCs. There are currently no data on the role of NCOA4 or ferritinophagy during neuron
development, causing a significant gap in our understanding of how the release of iron stored in ferritin is
regulated during this highly iron-sensitive process. Dysregulation of neuronal ferritinophagy could result in severe
iron underload or overload with significant clinical ramifications. This proposal focuses on early-life ID because
it is prevalent throughout the world and permanently impairs neurobehavioral function (e.g., learning and
memory) in children. ID specifically within the developing hippocampal neuron accounts for a significant portion
of the learning/memory deficits. Basic principles of ferritin iron regulation discovered in this neuronal subtype will
likely apply to all rapidly developing neurons. We hypothesize that, similar to iron handling during RBC
development, iron released through NCOA4-mediated ferritinophagy forms an iron pool that is that is essential
for normal neuron development and function. Aim 1 uses our unique in vitro model of chronic early-life
hippocampal neuronal ID to test whether NCOA4 and ferritinophagy are required for optimal neuronal
development by regulating iron availability. We hypothesize that loss of NCOA4 will disrupt neuronal iron
homeostasis and impair critical neurodevelopmental processes (i.e., mitochondrial respiration, neuronal dendrite
and synapse formation). Aim 2 translates Aim 1’s in vitro findings to the in vivo brain to reveal the
developmental age-dependent role of NCOA4 and ferritinophagy in regulating hippocampal neuron iron
utilization. We hypothesize that NCOA4-mediated ferritinophagy provides a source of iron that is required during
the postnatal switch from iron storage to utilization and when neuronal iron supply is restricted (i.e., ID). We will
test this using two unique hippocampal-specific transgenic mouse lines that model disruptions to neuronal iron
uptake (Slc11a2 KO) ...

## Key facts

- **NIH application ID:** 10284640
- **Project number:** 1R21HD106043-01
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Thomas W. Bastian
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $232,500
- **Award type:** 1
- **Project period:** 2021-07-27 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10284640

## Citation

> US National Institutes of Health, RePORTER application 10284640, NCOA4-Mediated Ferritinophagy in Iron-Dependent Brain Development (1R21HD106043-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10284640. Licensed CC0.

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