# Molecular Regulation of Mitochondrial Permeability Transition and its Role in Regulated Necrosis

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2022 · $400,000

## Abstract

Project Summary/Abstract
Regulated necrotic death of cardiomyocytes is the direct cause of mortality during a myocardial
infarction. One crucial step that is required for regulated necrosis to occur is the opening of the
mitochondrial permeability transition pore (MPTP). Opening of the MPTP, leads to loss of ATP
production, mitochondrial dysfunction, and eventual necrotic cell death. Identification of the
components of the MPTP has plagued the scientific community for over 30 years. The
identification of the inner mitochondrial membrane pore-forming components and regulators of
the MPTP is vital for the mechanistic understanding of regulated necrosis. The adenine nucleotide
translocator (ANT) family was previously thought to be the pore-forming component of the MPTP
within the inner mitochondrial membrane, but this was genetically disproven when mitochondria
lacking ANT1 and ANT2 still underwent mitochondrial permeability transition. However, these
mitochondria are significantly desensitized to MPTP opening. Recently, we generated mice
lacking all three isoforms of the ANT family in liver and showed that the MPTP in mitochondria
isolated from ANT null livers are even more desensitized, but the pore eventually opens in the
presence of very high Ca2+. Surprisingly, when we treated the ANT null mitochondria with
cyclosporine A (CsA), a cyclophilin D (CypD) inhibitor, the MPTP was inhibited. Treatment of CsA
normally desensitizes the MPTP, but with enough Ca2+ CsA can be overcome and the MPTP still
engages. We now have the ability to definitively determine the full therapeutic potential of
complete MPTP inhibition during I/R injury by generating mice lacking the predominant isoforms
of ANT and CypD in the heart. In addition to the ANT family and CypD, the MPTP is also regulated
from from the outer mitochondrial membrane by Bax and Bak. The relationship between the
ANTs, CypD, and Bax/Bak in regards to MPTP regulation is undefined. In this proposal, we aim
to elucidate how they function in concert with one another to lead to MPTP opening. Our
preliminary data suggest the existence of multiple inner membrane pore-forming components of
the MPTP including the ANT family and some other unidentified pore. We will utilize ANT null
mitochondria to explore this hypothesis in further detail and aim to identify the novel pore-forming
component by using targeted and unbiased approaches. Together this proposal will provide
crucial mechanistic insight in the composition and regulation of the MPTP that will reveal potential
strategies to inhibit MPTP opening to prolong cardiomyocyte survival in the face of an ischemic
event.

## Key facts

- **NIH application ID:** 10428355
- **Project number:** 5R01HL150031-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Jason Michael Karch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $400,000
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428355

## Citation

> US National Institutes of Health, RePORTER application 10428355, Molecular Regulation of Mitochondrial Permeability Transition and its Role in Regulated Necrosis (5R01HL150031-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10428355. Licensed CC0.

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