# Discovery and Characterization of Novel Regulators of Mitochondrial Copper Homeostasis

> **NIH NIH F31** · TEXAS A&M AGRILIFE RESEARCH · 2020 · $35,050

## Abstract

Project Summary
Copper is an essential micronutrient required for normal cellular functions as evidenced by the finding that
copper deficiency and overload result in devastating human disorders. Despite the fundamental importance of
copper in cellular and organismal health, the intracellular copper trafficking and distribution is poorly
understood. For example, copper is required for the assembly and activity of the terminal enzyme of the
mitochondrial respiratory chain, however, how copper is delivered to the mitochondria is not known. To
address this gap in our understanding of intracellular copper trafficking to the mitochondria, a genome-wide
“copper-sensitized” screen was performed, which identified multiple proteins involved in vacuolar function as
putative regulators of mitochondrial copper homeostasis. The yeast vacuole has long been implicated in
maintaining cellular metal homeostasis, but exactly how vacuolar function impacts mitochondrial metal
homeostasis is not understood. The hits from the screen are likely to provide the molecular mechanism
underlying this connection. Top “hits” from our screen included multiple components of the adaptor protein 3
complex (AP-3), as regulators of respiratory growth and copper homeostasis. This is a novel finding because
AP-3 has not been linked to either metal homeostasis or mitochondrial respiratory function. Additionally, we
identified components of the pH-sensing pathway- Rim20 and Rim21, which like AP-3 impact vacuolar
function, as novel regulators of copper-dependent mitochondrial function. The loss of either Rim20 or Rim21
causes a decrease in the levels of a copper requiring subunit of the mitochondrial respiratory chain. This result
suggests that a perturbation in vacuolar function disrupts mitochondrial copper homeostasis. To investigate the
role of the vacuole in copper trafficking to mitochondria, I propose the following aims: (1) Determine the role of
AP-3 in intracellular metal homeostasis and mitochondrial function; and (2) Determine the mechanism by which
Rim20 and Rim21 promotes expression of copper-containing subunits of the mitochondrial respiratory chain.
Since mutations in genes encoding the subunits of AP-3 cause Hermansky-Pudlak syndrome (HPS) in
humans, I will experimentally test the hypothesis that like yeast mutants, copper supplementation can alleviate
biochemical defects observed in HPS patient cell lines. Thus, the proposed project will not only address a
fundamental question in cell biology of intracellular metal trafficking but may also provide new insights on the
pathology associated with a rare human disease.

## Key facts

- **NIH application ID:** 9930113
- **Project number:** 5F31GM128339-03
- **Recipient organization:** TEXAS A&M AGRILIFE RESEARCH
- **Principal Investigator:** Natalie Michelle Garza
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $35,050
- **Award type:** 5
- **Project period:** 2018-06-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9930113

## Citation

> US National Institutes of Health, RePORTER application 9930113, Discovery and Characterization of Novel Regulators of Mitochondrial Copper Homeostasis (5F31GM128339-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9930113. Licensed CC0.

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