# Lysosome remodeling mediates high zinc homeostasis

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $80,295

## Abstract

Abstract
 Zinc is an essential nutrient that profoundly affects human health, since ~10% of the proteome binds zinc.
A key to zinc homeostasis is storage during times of excess and release during periods of deficiency.
Lysosomes, which have a well-established role in the degradation of macromolecules, are emerging as a
conserved site of zinc storage. How lysosomes integrate the dual functions of zinc storage and degradation is
not well defined. Our data indicate that lysosomes mediate these dual functions in separate compartments.
 We used C. elegans to demonstrate excess zinc is stored in lysosomes of intestinal cells; CDF-2 (ZnT2 in
mammals) is the SLC30 family transporter that loads zinc into lysosomes, and ZIPT-2.3 is the SLC39 family
transporter that releases zinc. Reciprocal regulation of CDF-2 and ZIPT-2.3 regulates the direction of zinc flow;
in excess zinc, CDF-2 is upregulated to increase storage and ZIPT-2.3 is downregulated to decrease release.
 How do lysosomes rapidly change the composition of transporters on their surface? Using super-resolution
microscopy, we discovered that lysosomes have an expansion compartment connected to the acidified central
compartment. The expansion compartment is contracted in zinc-replete conditions, but grows dramatically in
response to high zinc. Our overall hypothesis is that the expansion compartment allows the rapid delivery of
CDF-2 to lysosomes to promote zinc homeostasis –without disturbing degradative processes in the acidified
compartment. This hypothesis is innovative, since we only observed the expansion compartment with the
recent availability of super-resolution microscopy. To determine if this mechanism is conserved, we examined
lysosome dynamics in mammalian cells; the ZnT2 zinc transporter alters its localization on lysosomes in
response to high zinc, consistent with lysosome remodeling. To test the predictions of our model, we will
characterize the molecular nature of the compartment, identify transcriptional changes during assembly and
disassembly, and validate our findings in mammalian cells.
Specific Aim 1, First, we will use TEM to determine whether lysosomes have a second membrane-bound
compartment that contains CDF-2. Second, we will use X-ray fluorescence microscopy to test whether zinc is
sequestered in this structure.
Specific Aim 2, we will extend these findings to mammalian cells. We will test whether the ZnT2 transporter is
required to store zinc, identify the ZIP protein that releases zinc, and test whether these transporters are
reciprocally regulated to remodel lysosomes.
Specific Aim 3, we will analyze the regulation of lysosome remodeling. We demonstrated that the lysosome
biogenesis regulator HLH-30 (TFEB in mammals) is required for remodeling. We will determine how the
transcriptional response to high zinc mediates lysosome remodeling. These studies will have a major impact by
defining a new aspect of lysosome biology that is critical for zinc homeostasis.

## Key facts

- **NIH application ID:** 11100619
- **Project number:** 3R01GM068598-15S1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Kerry Kornfeld
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $80,295
- **Award type:** 3
- **Project period:** 2003-06-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11100619

## Citation

> US National Institutes of Health, RePORTER application 11100619, Lysosome remodeling mediates high zinc homeostasis (3R01GM068598-15S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11100619. Licensed CC0.

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