# Mechanistic etiology of developmental diseases caused by biallelic mutations in the mitochondrial Lon protease (111)

> **NIH NIH R21** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2024 · $431,750

## Abstract

Summary
Mitochondrial Lon is an ATP-powered protease that plays a pivotal role in regulating mitochondrial proteostasis,
metabolism and cell stress responses. Biallelic mutations in the LONP1 gene cause a broad spectrum of rare
developmental diseases presenting during early development, which include CODAS syndrome- characterized
by cerebral, ocular, dental, auricular and skeletal anomalies, profound neurological dysfunction and depletion of
mitochondrial DNA (mtDNA). This project aims at filling a fundamental knowledge gap pertaining to the
mechanistic impact of Lon binding to mtDNA and its role in regulating mtDNA integrity and expression. We will
employ isogenic patient-derived induced pluripotent cell (iPSCs) with homozygous mutations in the LONP1 gene
causing CODAS syndrome c.2161C>G, (p.Arg721Gly), or severe neurologic dysfunction c.2282 C>T,
(p.Pro761Leu). Using iPSC-derived cell types expressing Lon-WT, Lon-R721G and Lon-P761L we will: (1)
characterize differences in mitochondrial protein turnover, energetics and cell stress responses; (2) determine
mtDNA-binding by wild-type and mutant Lon proteins using chromatin immunoprecipitation with sequencing
(ChIP-seq); and (3) analyze the biogenesis of mtRNA transcripts using single-molecule fluorescence in situ
hybridization (smFISH). The innovative approach of smFISH will allow us to determine differences in mtRNA
synthesis, half-lives (i.e., degradation rates) and spatial localization within mitochondria. This project will provide
new mechanistic insights into the importance of Lon in regulating mtDNA maintenance, transcription and
translation, which has broader implications for its critical roles during normal physiology and common diseases
such as cancer, neurodegeneration and cardiac dysfunction.

## Key facts

- **NIH application ID:** 10989256
- **Project number:** 1R21HD114113-01A1
- **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES
- **Principal Investigator:** CAROLYN K SUZUKI
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $431,750
- **Award type:** 1
- **Project period:** 2024-09-11 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10989256

## Citation

> US National Institutes of Health, RePORTER application 10989256, Mechanistic etiology of developmental diseases caused by biallelic mutations in the mitochondrial Lon protease (111) (1R21HD114113-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10989256. Licensed CC0.

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