# A novel mechanism of mitochondrial protein turnover in Complex I deficient mitochondrial cardiomyopathy

> **NIH NIH F30** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2022 · $37,225

## Abstract

PROJECT SUMMARY
Mitochondria are an important source of reactive oxygen species (ROS). Once thought of inherently bad as it
can cause oxidative damage, physiological ROS production is an important signaling molecule. Complex I of
the mitochondria is an important source of ROS production and dysfunctional Complex I has been implicated in
both mitochondrial disease and in adult-onset metabolic, neurodegenerative, cancer, and cardiac diseases. In
fact, Complex I dysfunction is the most common inborn error of metabolism manifests, often resulting in
pediatric mitochondrial cardiomyopathies. Our lab has been studying a mouse model of mitochondrial
cardiomyopathies to discover mechanisms preserving bioenergetic homeostasis during Complex I impairment.
In studying the mitochondrial calcium uniporter (MCU), an important regulator of ATP synthesis, during
Complex I dysfunction, we identified a novel form of ROS-dependent protein regulation. We found that under
normal circumstances, MCU transiently interacts with Complex I, and physiological ROS production in
Complex I leads to MCU turnover. However, during Complex I dysfunction, the Complex I-MCU interaction is
abolished, MCU lifespan increases, and this increased lifespan helps preserve mitochondrial bioenergetic
homeostasis. We term this mechanism Complex I-induced protein turnover (CLIPT), and hypothesize that
CLIPT is a more widespread phenomenon applicable to other mitochondrial proteins.
The objective of this proposal is to determine if CLIPT is a mechanism that enables mitochondrial proteins to
compensate for disruptions to cardiac mitochondrial homeostasis. In a preliminary screen, we show that a
range of mitochondrial proteins may be similarly subject to CLIPT but for this proposal, I will focus on two
proteins of interest: Peroxiredoxin3 (PRDX3) and Hydroxy steroid 17-beta dehydrogenase (HSD17B10).
PRDX3 and HSD17B10 are interesting candidates in the setting of ROS-induced protein turnover as they play
a role in an antioxidant system and in fatty acid metabolism, respectively. In Aim 1, I will demonstrate how
PRDX3 and HSD17B10 is also regulated through CLIPT and in Aim 2, define the clinical relevance to
upregulation of PRDX3 and HSD17B10 in the context of Complex I dysfunction. Our results may offer new
targets for therapies for cardiac mitochondrial disease.

## Key facts

- **NIH application ID:** 10537993
- **Project number:** 1F30HL165806-01
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Sandra Hyunjoo CVRTI
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $37,225
- **Award type:** 1
- **Project period:** 2022-09-30 → 2027-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10537993

## Citation

> US National Institutes of Health, RePORTER application 10537993, A novel mechanism of mitochondrial protein turnover in Complex I deficient mitochondrial cardiomyopathy (1F30HL165806-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10537993. Licensed CC0.

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