# Endolysosomal Regulation of Amino Acid Homeostasis in Aging

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $456,564

## Abstract

PROJECT SUMMARY
Organelle deterioration is a common feature of aging, and contributes to a number of age-related diseases. A
major interest of my lab is to understand how organelles are functionally interconnected within cells, and uncover
mechanisms by which organelle dysfunction perturbs cellular homeostasis during aging. Our work in this area
during the previous project period focused on the lysosome (or vacuole in yeast), an acidic organelle that
functions in protein degradation as well as metabolite storage and signaling. Impaired lysosomal function is a
hallmark of aging across species and is a major contributor to age-related cellular dysfunction. Because many
pathways converge at the lysosome that rely on the acidification of the organelle, how perturbations in lysosome
acidity impact cell function has remained unclear. Answering this important question is a long-term goal of our
lab. In the previous project period, we employed budding yeast as a model system to interrogate how vacuole
dysfunction impacts cell health during aging, with a specific focus on dissecting the nature of its functional link
to another metabolic organelle, the mitochondrion. We found that the essential function of vacuoles in supporting
mitochondrial respiration is not linked to its well-known function in autophagy, but rather, it was tied to the role
of vacuoles in amino acid compartmentalization and storage. We found that cysteine, which is stored in vacuoles
in healthy cells, disrupts iron homeostasis when its vacuole compartmentation is perturbed during aging. Loss
of iron homeostasis in turn alters the function of mitochondria, as well as numerous other iron-dependent cellular
processes. Importantly, the connection between lysosome function, mitochondria, and iron homeostasis was
validated by two other groups in human cells. Altogether, these results raise a new hypothesis to explain how
loss of lysosome function causes age-related deterioration, and identify amino acids as potential drivers of
cellular decline during aging. In the next project period, we plan to build on this discovery and new preliminary
data by identifying pathways that coordinate with vacuoles to maintain amino acid homeostasis (Aim 1), and
dissecting cellular mechanisms of amino acid toxicity and their impact on cellular decline during aging (Aim 2).
The results of these studies will have a significant impact on our understanding of cellular pathways that
coordinate with vacuoles to maintain amino acid organization, and provide key insight into the degree to which
the 20 proteogenic amino acids act as toxic agents during aging when their organization is compromised.

## Key facts

- **NIH application ID:** 10883072
- **Project number:** 2R01AG061376-06
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Adam Hughes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $456,564
- **Award type:** 2
- **Project period:** 2018-09-30 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883072

## Citation

> US National Institutes of Health, RePORTER application 10883072, Endolysosomal Regulation of Amino Acid Homeostasis in Aging (2R01AG061376-06). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10883072. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*