# The physiologic and genomic relevance of mitoregulin in ischemic heart failure

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $386,250

## Abstract

PROJECT SUMMARY / ABSTRACT
 Myocardial infarction (MI) is a primary cause of morbidity and mortality worldwide. Although reperfusion therapy
improves post-MI survival, the rapid restoration of oxygenated blood flow to the heart elicits oxidative stress that
further damages tissue, known as ischemia-reperfusion (IR) injury, exacerbating one’s risk for developing heart failure
(HF). Central to IR injury are mitochondria, which play key roles in cardiomyocyte Ca2+ buffering and production of
energy and reactive oxygen species (ROS). Upon IR, mitochondrial Ca2+ overload and ROS trigger mitochondrial
permeability transition (mPT) pore opening, which promotes cell death. While many studies highlight the critical role
of mPT in IR injury and cardioprotection, many molecular pathways leading to altered mitochondrial Ca2+ and ROS
(key upstream regulators of mPT) remain poorly defined. In recent work, we discovered that a heart- and muscle-
enriched long, “non-coding” RNA actually does encode for a highly-conserved single-pass transmembrane micro-
protein that localizes to the inner mitochondrial membrane; we named this protein “Mitoregulin” (Mtln). In gain- and
loss-of-function studies, we found that Mtln “supercharges” mitochondria by increasing their 1) respiratory super-
complex levels, 2) respiratory efficiencies, and 3) Ca2+ retention capacities, while reducing ROS. In this grant, we
propose Aims to address two central hypotheses: 1) that Mtln protects against cardiac IR injury by delaying Ca2+- and
ROS-triggered mPT, and 2) that human genetic variation linked to Mtln expression associate with HF patient
outcomes. Our overarching goal is to translationally link Mtln with cardiac IR injury and HF outcomes to justify a need
for future studies to continue defining Mtln’s precise modes of action. In Aim 1, we will define the physiologic and
molecular functions of Mtln in cardiomyocytes by evaluating the acute effects of modulating Mtln expression on
mitochondrial respiration, Ca2+ and ROS, as well as supercomplex levels in cultured rodent cardiomyocytes. We will
also define Mtln domains and protein interactions necessary for its function. In Aim 2, we will elucidate a role for Mtln
in cell and rodent models of IR injury and HF through gain- and loss-of-function studies to evaluate the impact of Mtln
modulation on cardiomyocyte death induced by simulated IR, as well as on responses to cardiac IR injury and ensuing
HF in mice. In Aim 3, we will work to establish links among genetic variants, cardiac Mtln expression, and HF patient
outcomes, focusing on the biological and genetic relevance of a 36-bp 3’UTR deletion variant (Mtln-3’UTRdel) that is
present in 12% of the general population and is known to be linked to decreased Mtln mRNA levels in heart tissues.
We will identify RNA-binding proteins that control Mtln expression and assess the impact of the 3’UTRdel variant on
this regulation and on Mtln protein levels in human hearts. We will also test availab...

## Key facts

- **NIH application ID:** 10051220
- **Project number:** 1R01HL150557-01A1
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** RYAN L BOUDREAU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $386,250
- **Award type:** 1
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10051220

## Citation

> US National Institutes of Health, RePORTER application 10051220, The physiologic and genomic relevance of mitoregulin in ischemic heart failure (1R01HL150557-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10051220. Licensed CC0.

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