# 4-hydroxy-2-nonenal in mitochondrial damage and mediating heart failure

> **NIH NIH P20** · LOUISIANA STATE UNIV HSC SHREVEPORT · 2022 · $215,448

## Abstract

Accumulated evidence indicates that oxidative stress in mitochondria plays an important role in cardiac injury but how mitochondrial redox mechanisms are involved in cardiac dysfunction remains unclear. A highly toxic aldehyde formed by reactive oxygen species (ROS) is 4-hydroxy-2-nonenal (HNE) through lipid peroxidation following myocardial ischemia/reperfusion (I/R) injury. HNE mediates necrosis, apoptosis, and autophagy within the area rendered ischemic over the first 6 to 24 hours. Several lines of evidence suggest that apoptosis-inducing factor mitochondrion-associated protein (AIFm2), a p53 target gene, a redoxresponsive protein that resides in mitochondria and plays a central role in the caspase-independent cell death pathway. We have demonstrated that HNE adduction of AIFm2 shifts the function of AIFm2 from an NADH oxidoreductase to a pro-apoptotic protein. However, the molecular mechanisms involved in AIFm2 translocation that mediates cardiac injury remain unknown. In this application, we present the first evidence that MnSOD downregulation following cardiac I/R injury activates the translocation of AIFm2 from the mitochondria to the nucleus. Our preliminary data using Tandem mass spectrometric analysis (MS/MS) of the native and oxidatively modified AIFm2 suggest that His174 and Cys 187 are the potential targets for HNE-mediated translocation. Therefore, we hypothesize decreased MnSOD levels lead to HNE-AIFm2 adduction in the mitochondria, and the mitochondrial stress signal is transduced through the translocation of AIFm2 from mitochondria to the nucleus and contribute to the pathogenesis of heart failure following I/R injury.To address this hypothesis, we propose the following aims. Specific Aim #1: To determine if cardiac SOD2 regulates mitochondrial dynamics and function. Specific Aim # 2: Determine the binding motif that mediates the translocation of AIFm2 from mitochondria following oxidative stress. The goal of this proposal is the generation of preliminary data, publication of at least one high impact peer-reviewed manuscript and to submit my R01 by the end of Jan 31st, 2022.

## Key facts

- **NIH application ID:** 10489455
- **Project number:** 5P20GM121307-05
- **Recipient organization:** LOUISIANA STATE UNIV HSC SHREVEPORT
- **Principal Investigator:** Sumitra Miriyala
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $215,448
- **Award type:** 5
- **Project period:** 2018-02-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10489455

## Citation

> US National Institutes of Health, RePORTER application 10489455, 4-hydroxy-2-nonenal in mitochondrial damage and mediating heart failure (5P20GM121307-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10489455. Licensed CC0.

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