# Molecular components of the mitochondrial permeability transition pore and its role in neurodegenerative diseases

> **NIH NIH K01** · YALE UNIVERSITY · 2021 · $51,775

## Abstract

Project Summary/Abstract
 Mitochondrial and synaptic dysfunction are early pathological features of Alzheimer's
disease (AD) and other neurodegenerative diseases. The mitochondrial permeability transition
pore (mPTP) is a mitochondrial ion channel that plays a central role in cell death during age-
related neurodegeneration, therefore mPTP can serve as an important therapeutic target.
Studies show that the major mPTP inducer, the peptidylprolyl isomerase cyclophilin D (CypD),
interacts directly with the OSCP subunit of the stator arm of the mammalian ATP synthase. The
stator arm stabilizes the connection between the ATP synthase catalytic (F1) and membrane
(FO) portions. In AD, a complex of CypD and oligomeric Aβ peptide have been found to
potentiate mPTP opening, resulting in impaired mitochondrial function, neuronal injury and
death.
 We have recently suggested a novel role of the ATP synthase membrane embedded c-
subunit in forming the pore of mPT. We have found further that the F1 portion of the ATP
synthase gates the channel and that the loss of F1 components and OSCP during glutamate-
induced excitotoxicity is correlated with neuronal death. We suggest that disruptions in
interaction between the F1 and the stator arm during neuronal toxicity destabilize the ATP
synthase structure, making the mitochondria more susceptible to mPT and cell death.
 In this proposal, using mutagenesis, we will investigate the molecular mechanisms that
lead to the opening of the c-subunit leak channel, which converts the ATP synthase from an
energy-conserving to an energy-dissipating, cell death-inducing, device. In order to attempt to
enhance neuronal survival in the face of stress, we will perform mutations within the ATP
synthase that modify the conformation of the ATP synthase, preventing mPT channel gating and
decreasing channel conductance. Based on our mutagenesis findings we will design a
transgenic mouse on the background of the AD model (Tg mAPP) mouse to study if
neuroprotective ATP synthase mutations will protect the Tg mAPP mouse from the onset of AD-
like features. We will also introduce the same mutations in non transgenic mouse to study the
physiological roles of mPTP in the cell in general.
 Identifying molecular mechanisms underlying c-subunit gating will provide us with
increased understanding of the role of mPTP in aging and neurodegeneration. The findings will
lead to the design of specific and potent therapeutic compounds to target the mPTP directly,
resulting in preventative strategies for neurodegenerative disease.

## Key facts

- **NIH application ID:** 10134170
- **Project number:** 5K01AG054734-05
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Nelli Mnatsakanyan
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,775
- **Award type:** 5
- **Project period:** 2017-07-15 → 2022-01-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134170

## Citation

> US National Institutes of Health, RePORTER application 10134170, Molecular components of the mitochondrial permeability transition pore and its role in neurodegenerative diseases (5K01AG054734-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10134170. Licensed CC0.

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