# Tyrosine degradation pathway in mitochondrial dysfunction and aging

> **NIH NIH R03** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $79,500

## Abstract

Abstract
 Loss of metabolic homeostasis is a hallmark of aging that leads to increased susceptibility to diseases
and increased frailty. Although global metabolic reprogramming has been explored in different species, the
mechanisms driving this reprogramming are poorly understood. Through a deeper understanding of these
processes, the affected metabolic pathways can be directly targeted, paving the way to a delay or even a
reversal of aging in model organisms and ultimately in humans.
 We previously demonstrated that the levels of enzymes in the tyrosine degradation pathway increase
with age and that either whole-body or neuronal-specific downregulation of enzymes in the tyrosine
degradation pathway significantly extend Drosophila lifespan. Mechanistically, suppression of mitochondrial
Electron Transport Chain Complex I (mETC CI) phenocopies aging and drives the upregulation of enzymes in
the tyrosine degradation pathway. Although the augmentation of tyrosine catabolism was detrimental to health-
and lifespan in our studies, the mechanism driving this age-dependent upregulation is unknown. It is also
unknown whether a similar mechanism is responsible for the age-dependent decrease of tyrosine-derived
neurotransmitters in mammals including humans.
 Through our preliminary screen of potential transcription factors/regulators, we identified stonewall
(Stwl) as a prospective transcriptional regulator (TR) that is responsible for the upregulation of TAT in response
to mETC CI inhibition. Our central hypothesis is that inhibiting Stwl can prevent the augmented tyrosine
degradation associated with aging and mitochondrial dysfunction and that this process is conserved
in mammals.
 In this application, we propose to determine the impact of Stwl on the levels of enzymes in the tyrosine
degradation pathway, levels of tyrosine-derived neurotransmitters, and Drosophila health- and lifespan (Aim 1);
and to test whether the effect of aging/mitochondrial dysfunction on the activity of the tyrosine degradation
pathway is conserved in mammals (Aim 2). We expect that the insights we gain will allow us to establish a
novel link between aging, mitochondrial dysfunction, tyrosine metabolism, and the production of
neurotransmitters.

## Key facts

- **NIH application ID:** 10527038
- **Project number:** 1R03AG075651-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Andrey A Parkhitko
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $79,500
- **Award type:** 1
- **Project period:** 2022-09-30 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10527038

## Citation

> US National Institutes of Health, RePORTER application 10527038, Tyrosine degradation pathway in mitochondrial dysfunction and aging (1R03AG075651-01A1). Retrieved via AI Analytics 2026-06-16 from https://api.ai-analytics.org/grant/nih/10527038. Licensed CC0.

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