# Chemical Approaches to Rescue Human Mitochondrial Disease Mutations

> **NIH NIH F30** · HARVARD MEDICAL SCHOOL · 2020 · $51,320

## Abstract

Abstract
Mutations in the mitochondrial encoded DNA or in the nuclear encoded mitochondrial genes can lead to loss of
function phenotypes in mitochondrial proteins. Mitochondrial diseases (MD) are a heterogeneous group of
disorders with several different mutations leading to a variety of organ phenotypes. In general, mitochondrial
diseases are characterized by diminished function of organs with high energetic demands, such as the heart,
skeletal muscle, and brain. Additionally, patients with MDs often present with dental disease that requires
unique management. Many anesthetic drugs suppress mitochondrial function, which presents a challenge in
the treatment of MD patients. Patients with MD can develop progressive respiratory failure and lactic
acidosis, which are exacerbated with anesthesia. In addition to dental treatment concerns, manifestations of
poor bone heath; such as osteopenia and osteoporosis, have been observed in MD patients.
The proposed study aims to discover novel genetic targets that can be pharmaceutically targeted in order to
restore function and survival to cells carrying a mitochondrial mutation. A high-throughput small molecule
screen on a trans-mitochondrial hybrid (cybrid) model of mitochondrial encephalomyopathy, lactic-acidosis,
and stroke-like episodes (MELAS) syndrome was performed to discover compounds that lead to an increase in
cell survival in conditions of nutrient deprivation. Doxycycline was identified amongst the top hits.
Interestingly, doxycycline was also identified in a high-throughput small molecule screen on Rieske (complex
III) mutant fibroblasts and ND1 (complex I) mutant cybrids using the same cell survival assay as the MELAS
screen. Across the three independent small molecule survival screens, only two families of compounds were
identified as positive hits: antibiotics targeting the mitochondrial ribosome and mTOR inhibitors. mTOR
inhibiton has been previously studied in mitochondrial disease, therefore, this project will focus on the
efficacy of doxycycline as a therapy in mitochondrial disease. Based off the common screen hits across cell
lines, I hypothesize that doxycycline is able promote survival in mitochondrial disease independent of genetic
mutation. Further, I believe this is occurring through decreases in mitochondrial protein synthesis, modulation
of stress response factors, and inhibition of the cell death pathway.
The proposed experiments will first aim to identify the mechanism by which doxycycline promotes cell survival
in cells with mitochondrial mutations. Ndufs4 knockout mice, a well-established mitochondrial mutant mouse
with strong neuronal deterioration and short lifespan, will be treated with doxycycline to evaluate the efficacy of
doxycycline in vivo. The proposed work will lay the groundwork for a novel therapeutic strategy to benefit MD
patients.

## Key facts

- **NIH application ID:** 9790902
- **Project number:** 5F30DE028206-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Elizabeth Aguilar Perry
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $51,320
- **Award type:** 5
- **Project period:** 2018-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9790902

## Citation

> US National Institutes of Health, RePORTER application 9790902, Chemical Approaches to Rescue Human Mitochondrial Disease Mutations (5F30DE028206-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9790902. Licensed CC0.

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