# Triphenylphosphonium-glutathione as a Protectant Against Mitochondrial Decay

> **NIH NIH R21** · OREGON STATE UNIVERSITY · 2020 · $185,417

## Abstract

Mitochondrial decay is an intrinsic part of aging and age-associated chronic diseases, especially
neurodegenerative pathologies such as Parkinson’s and Alzheimer’s diseases (AD). In particular, mitochondrial
matrix glutathione (mGSH), which is essential for normal mitochondrial function, declines with age and in
AD where mGSH loss has been identified as one of the earliest hallmarks associated with disease onset. The
reason mGSH is so vital is that mitochondria do not synthesize GSH; rather, mGSH is supplied from the
cytosol via slow facilitated transport. This lack of equilibrium with the cytosol severely challenges the cell's
ability to maintain sufficient mGSH levels when its rate of oxidation exceeds supply. Such constraints to
maintaining mGSH thus constitute a key barrier to creating an effective GSH-restoring treatment. There is no
current clinical therapy that remediates mGSH. Compounds that increase cellular GSH do not sustainably
affect the mitochondrial GSH pool. The lack of mitochondrial GSH remediators thus represents a distinct
barrier to limiting the degree of mitochondrial dysfunction during a variety of pathophysiological conditions
that occur in aging. We created a novel compound, triphenylphosphonium-GSH (TPP-GSH) in an attempt to
overcome the obstacles for a mGSH therapy. Our promising preliminary findings show that fully water soluble
TPP-GSH elevates mGSH levels in isolated rat hepatocytes, and restores mitochondrial structure and function
in transgenic mice that develop Alzheimer’s Disease-like pathology. We propose that TPP-GSH will supply
GSH to mitochondria and serve as a mGSH-restoring and -augmenting therapy. We will address this proposal
in two Aims where: Aim 1 will define the bioavailability and tissue distribution characteristics of TPP-GSH.
We will establish a non-toxic TPP-GSH dose-range (both ip and orally) for male and female C57BL/6J mice at
3-5 weeks (young) and 18 months (old) of age. Cohorts of young and old mice of both sexes will be treated with
isotopically labeled TPP-GSH at the Maximum Tolerated Dose (MTD) for each group prior to sacrifice and to
determine TPP-GSH tissue distribution by LC-mass spectrometry. The amount of TPP-GSH accumulating in
the mitochondrial matrix will also be defined. Aim 2 will determine whether TPP-GSH maintains or improves
mitochondrial function in 5xFAD mice. Presenilin-mutant mice (5xFAD) which rapidly develop A-mediated
mitochondrial damage followed by neurocognitive deficits will be used to test the extent that TPP-GSH
preserves hippocampal mitochondrial function. TPP-GSH will be given to both sexes of 5xFAD mice (&
wildtype [WT] controls) at the MTD starting at weaning. Treatment will continue up to 6 months when severe
mitochondrial decay and neurocognitive decline are typically evident. Throughout, mice will be tested for
memory and learning, and also mitochondrial function assessed (ultrastructure, bioenergetic reserve, &
oxidant leakage). Similar measures of functio...

## Key facts

- **NIH application ID:** 9989748
- **Project number:** 5R21AG060206-02
- **Recipient organization:** OREGON STATE UNIVERSITY
- **Principal Investigator:** TORY M HAGEN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $185,417
- **Award type:** 5
- **Project period:** 2019-08-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989748

## Citation

> US National Institutes of Health, RePORTER application 9989748, Triphenylphosphonium-glutathione as a Protectant Against Mitochondrial Decay (5R21AG060206-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9989748. Licensed CC0.

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