# Investigating the Lysosome and Plasma Membrane Systems in Protecting Cells Against Age-induced Amino Acid Toxicity

> **NIH NIH F31** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $39,884

## Abstract

Project Summary
The incidence of age-related diseases such as Alzheimer’s disease and Parkinson’s disease continues to
increase as human lifespan continues to increase. Advancements in science and healthcare have resulted in
effective therapies for many diseases but treatments for these debilitating diseases remain elusive. Many studies
on aging focus on the dysfunction of basic cellular processes, or the hallmarks of aging. These include
mitochondrial dysfunction, abnormal nutrient signaling, telomere shortening, amongst many others. We recently
found that lysosomal (vacuole in yeast) deacidification is an early event in aging and precedes mitochondrial
dysfunction. Vacuole deacidification results in a loss of amino acid compartmentalization, particularly cysteine,
and this results in mitochondrial dysfunction. Amino acid restriction or supplementation with iron rescued
mitochondrial function. These previous findings demonstrate the importance of the vacuole in amino acid
homeostasis and aging. It should be noted that vacuole deacidification is a gradual process in aging and there
are likely systems that collaborate with the vacuole in maintaining cellular homeostasis. Thus, we performed a
screen to determine what genes are conditionally essential upon vacuole deacidification. We uncovered genes
involved in the ESCRT/MVB pathway as essential under these conditions. Furthermore, we also found several
genes involved in endocytosis to be conditionally essential too. The ESCRT pathway is a cellular trafficking
pathway that allows for the remodeling of the plasma membrane (PM) proteome, especially nutrient transporters.
When transporters are endocytosed, the ESCRT pathway recognizes ubiquitylated transporters and directs them
to the vacuole for degradation. The known function of the ESCRT pathway in conjunction with the vacuole’s role
in amino acid compartmentalization raises the idea that these two systems collaborate in maintaining cellular
amino acid homeostasis during the aging process. This is supported by our pilot study showing that amino acid
transporters (AATs) are indeed endocytosed upon vacuole deacidification. By using the budding yeast
Saccharomyces cerevisiae, we will determine how amino acid uptake and metabolite pools are affected under
conditions of vacuole deacidification. Furthermore, we will elucidate the signal that originates from dysfunctional
vacuoles that triggers AAT endocytosis and turnover. Finally, we will test the hypothesis that Aβ inhibits ESCRT-
mediated turnover of AATs and inhibits cell growth by causing amino acid toxicity. Aging remains an active field
of research but how the ESCRT pathway cooperates with the vacuole in the context of aging is understudied.
Furthermore, how Aβ expression affects cellular amino acid homeostasis is understudied. The goal of this
proposal is to elucidate a novel mechanism for cellular aging and increase our understanding of the pathogenesis
of Alzheimer’s disease.

## Key facts

- **NIH application ID:** 10820137
- **Project number:** 5F31AG082494-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Kevin Chui
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $39,884
- **Award type:** 5
- **Project period:** 2023-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10820137

## Citation

> US National Institutes of Health, RePORTER application 10820137, Investigating the Lysosome and Plasma Membrane Systems in Protecting Cells Against Age-induced Amino Acid Toxicity (5F31AG082494-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10820137. Licensed CC0.

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