# Essential Role for SPG7 in Mitochondrial Permeability Transition Pore Assembly and Function

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2020 · $305,295

## Abstract

One of the major organ injuries associated with myocardial infarction and stroke is ischemia/reperfusion injury.
I/R injury manifests from the stress-induced opening of the mitochondrial permeability transition pore (PTP), a
lethal form of mitochondrial malfunction leading to necrosis. The resultant myocardial or neuronal necrosis is
linked to dysfunction in mitochondrial Ca2+ handling and oxidative stress. Although the concept of PTP opening
has been examined for several decades, the molecular components of the PTP have been unknown until now
with the exception of a positive regulator cyclophilin D (CypD). Under physiological conditions, the PTP may
function through transient pore opening to release accumulated toxic mitochondrial metabolites. In pathological
states, particularly those involving hypoxia, Ca2+ and ROS accumulate prompting the PTP to open, resulting in
mitochondrial swelling. Because pore opening disrupts the flow of electrons and protons across the mitochondrial
membranes necessary for energy production, PTP activity results in a catastrophic drop in cellular energy levels.
Using a RNA interference (RNAi)-based screen to identify genes that modulate Ca2+ and ROS-induced opening
of the PTP, we identified a necessary and conserved role for spastic paraplegia 7 (SPG7) as a component of
CypD-dependent PTP opening in multiple cell types. Our recently published discovery of this long-sought
molecule, SPG7, places us in a unique position to define SPG7-induced necrotic initiation mechanisms. This
proposal aims to delineate the mechanisms by which SPG7 constitutes PTP assembly and opening at the
mitochondrial level and characterize the relationship between mitochondrial Ca2+ and ROS homeostasis with
PTP induction under physiological and pathophysiological conditions such as hypoxia/reoxygenation (H/R)
damage. Since SPG7 is essential for the PTP complex formation in multiple cell types, this proposal will utilize
in vivo genetically targeted conditional knockout (SPG7cKO), and knock-in mutant mice (SPG7*ID2 KI)
using CRISPR/Cas9 mediated gene targeting for the study of mitochondrial Ca2+/ROS-dependent PTP
signaling networks involved in mitochondrial dysfunction. These models will allow us to translate our in
vitro H/R results to an in vivo murine model of I/R injury. We hypothesize that necrosis will be attenuated in SPG7
knockout and knock-in dysfunctional PTP point mutant SPG7 (SPG7*ID2) models. Accomplishment of these goals
with our newly developed mouse models will authentically demonstrate the role of SPG7 in CypD-dependent
PTP assembly and opening. Our proposed studies will characterize the role of SPG7 in mitochondria-dependent
necrotic cell death and provide new therapeutic targets for the treatment of conditions associated with I/R
damage.

## Key facts

- **NIH application ID:** 10051597
- **Project number:** 1R01GM135760-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** MADESH MUNISWAMY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $305,295
- **Award type:** 1
- **Project period:** 2020-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10051597

## Citation

> US National Institutes of Health, RePORTER application 10051597, Essential Role for SPG7 in Mitochondrial Permeability Transition Pore Assembly and Function (1R01GM135760-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10051597. Licensed CC0.

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