# Molecular mechanisms of the mitochondrial permeability transition

> **NIH NIH R35** · NEW YORK UNIVERSITY · 2024 · $125,829

## Abstract

Research Summary
The overarching goal of my research program is to identify and characterize molecular mechanisms
responsible for stress-induced permeabilization of the mitochondrial inner membrane. In most eukaryotic
cells, mitochondria are the primary source of the energy that they provide in the form of ATP by
performing oxidative phosphorylation (OXPHOS). OXPHOS is a two-step process. First, substrate
oxidation by the respiratory chain results in the generation of the electrical potential on the mitochondrial
inner membrane. This potential energy drives the generation of ATP by the phosphorylation of ADP at
the ATP synthase complex. To prevent energy dissipation and ensure that OXPHOS is efficient
mitochondrial inner membrane permeability should be tightly controlled and maintained at low levels.
Stress conditions associated with dysregulation of calcium and ROS homeostasis can lead to an increase
in mitochondrial inner membrane permeability – a phenomenon known as Mitochondrial Permeability
Transition (mPT). mPT causes dissipation of the membrane potential and loss of mitochondrial ATP-
generating capacity leading to cell dysfunction and death. mPT is critically involved in a broad spectrum
of diseases ranging from heart attack to neurodegeneration. Prevention of mPT is highly protective
against cell death and tissue damage suggesting high therapeutics potential. However, molecular
mechanisms of mPT are not well understood, and this gap in knowledge prevents mPT from being a drug
target. Over the past five years, we demonstrated that mPT is a multifaceted phenomenon and depending
on the disease type and stress severity, it can occur through different pathways. The central goal of our
research program is to identify the link between specific molecular mechanisms of mPT and specific
stress conditions. We have already established several original animal and cell disease-relevant models
causing different types of mPT. In our approach, a variety of methods that measure the mPT and tissue
damage at the organismal, cellular and mitochondrial levels are coupled with a number of our original
electrophysiological (patch-clamp) assays that allow direct measurement of mPT at the level of
mitochondrial membranes and give us a unique opportunity to dissect and characterize its multiple
identities and regulation. The results of our study will provide a detailed understanding of one of the most
critical events in cell death cascades and will bring an essential framework for the development of
therapeutically approaches that will selectively target mPT.

## Key facts

- **NIH application ID:** 11100094
- **Project number:** 3R35GM139615-04S2
- **Recipient organization:** NEW YORK UNIVERSITY
- **Principal Investigator:** Evgeny Pavlov
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $125,829
- **Award type:** 3
- **Project period:** 2021-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11100094

## Citation

> US National Institutes of Health, RePORTER application 11100094, Molecular mechanisms of the mitochondrial permeability transition (3R35GM139615-04S2). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11100094. Licensed CC0.

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