# Microprotein Regulation of Mitochondrial Function

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $397,500

## Abstract

Project Summary
Heart failure is a complex clinical syndrome that is driven by impaired myocardial contractile
performance. Several metabolic alterations contribute to heart failure, including mitochondrial
dysfunction and changes in cardiac substrate utilization, resulting in energy deficiency and
reduced cardiomyocyte contractility. Current therapies for heart failure treat the symptoms rather
than the mechanisms underlying the etiology of the disease and are unable to reverse the
molecular changes that occur in diseased cardiomyocytes. Developing novel approaches to
enhance mitochondrial function and modulate cardiac metabolism in heart failure is a promising
approach towards correcting myocardial energetics to restore heart function. Despite the central
role that mitochondria play in cardiac health and disease, we are still lacking critical insight into
how many fundamental mitochondrial processes are regulated at the molecular level. Recent
computational and experimental data suggest that the mammalian genome contains thousands
of previously overlooked small proteins called microproteins, and hundreds of these have been
linked to the mitochondria where they are thought to play important roles as regulatory molecules.
Examples of mitochondrial microproteins (MitoMPs) have been shown to regulate essential
mitochondrial processes including cellular respiration, substrate utilization, metabolism and stress
signaling. MitoMPs typically manifest their functions by binding to and regulating larger protein
partners or multiprotein complexes within membrane domains. In line with this, we recently
discovered 2 novel MitoMPs named MOXI (micropeptide regulator of b-oxidation) and
mitolamban, which each interact with discrete metabolic regulatory complexes to perform distinct
functions. MOXI plays a critical role in regulating long chain fatty acid oxidation, likely through a
direct interaction with the mitochondrial trifunctional protein (MTP), while mitolamban interacts
with complex III of the electron transport chain and contributes to complex assembly and function.
Here we propose a comprehensive research plan to dissect the molecular mechanisms of action
of MOXI (Aim 1) and mitolamban (Aim 2) in the heart using gain- and loss-of-function mouse
models. Additionally, we aim to evaluate their potential as therapeutic targets using experimental
models of heart failure and ischemic heart disease. Furthermore, towards the goal of gaining a
more complete understanding of mitochondrial biology in the heart, we propose the functional
analysis of 3 newly identified MitoMPs (Aim 3). We hypothesize that these microproteins play
unique roles in regulating distinct aspects of mitochondrial function and metabolism and that their
functional characterization could give rise to novel targets for heart failure therapeutics.

## Key facts

- **NIH application ID:** 10335446
- **Project number:** 1R01HL160569-01
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Catherine A Makarewich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $397,500
- **Award type:** 1
- **Project period:** 2021-12-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10335446

## Citation

> US National Institutes of Health, RePORTER application 10335446, Microprotein Regulation of Mitochondrial Function (1R01HL160569-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10335446. Licensed CC0.

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