# Mitochondrial regulation of the NLRP3 inflammasome in myocardial ischemia-reperfusion injury and heart transplantation

> **NIH NIH R21** · CEDARS-SINAI MEDICAL CENTER · 2021 · $250,500

## Abstract

Project Summary
Heart transplantation (HTx) is the only definitive treatment for end-stage heart failure if other
medical or surgical treatments and interventions have failed. Despite advances in the
management of HTx patients there remains a critical need to optimize long-term outcomes post-
HTx. The cumulative risk of death in African-American HTx recipients is particularly high. While
racial disparity in outcomes among African-American HTx recipients is well documented, the
basis for this difference in is not understood. Mitochondrial DNA (mtDNA) haplogroups reflect
an individual's ancestral geographic origin and have been correlated with the disparity in
cardiovascular risk observed between Caucasians (haplogroup H) and African-Americans
(haplogroup L). An individual's mtDNA haplogroup is known to differentially impact oxidative
phosphorylation and consequently mitochondrial efficiency, ATP turnover, and the production of
reactive oxygen species and other metabolites. We propose a highly innovate concept that racial
differences in mitochondrial function influence the activation of proinflammatory innate immune
pathways and subsequent graft failure after HTx. Activation of the NLRP3 inflammasome
culminates in the processing and secretion of the proinflammatory cytokine IL-1beta. The NLRP3
inflammasome plays a critical role in driving the pathology associated with ischemia/reperfusion
(I/R) injury and targeting this pathway has proven beneficial in both animal models of cardiac I/R
injury and in patients with acute myocardial infarction. Minimizing I/R injury is also critical for
improving graft survival following HTx. Mitochondria serve as a platform upon which the NLRP3
inflammasome assembles and mitochondrial damage-associated molecular patterns (mito-
DAMPs) mediate the priming and activation of the NLRP3 inflammasome. Using the
mitochondrial-nuclear exchange (MNX) mouse models, in which isolated embryonic pro-nuclei
from one mouse strain are implanted into an enucleated embryo of a different strain, we will
assess the importance of functionally distinct mitochondria on the systemic response to ischemic
injury. In humans we will interrogate racial disparity in HTx outcomes by examining the impact
of mtDNA haplogroups on the response to ischemic injury. Our findings will allow us to identify
novel bio-signatures predictive of graft failure allowing for early intervention to limit the NLRP3
inflammasome-dependent pathologic inflammatory response.

## Key facts

- **NIH application ID:** 10133482
- **Project number:** 1R21AI156919-01
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Fayyaz S. Sutterwala
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $250,500
- **Award type:** 1
- **Project period:** 2020-11-20 → 2022-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133482

## Citation

> US National Institutes of Health, RePORTER application 10133482, Mitochondrial regulation of the NLRP3 inflammasome in myocardial ischemia-reperfusion injury and heart transplantation (1R21AI156919-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10133482. Licensed CC0.

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