# Preventing and Reversing Mitochondrial Leigh Syndrome with Hypoxia

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $481,230

## Abstract

ABSTRACT
Leigh syndrome is the most common pediatric manifestation of mitochondrial disease and is characterized by
bilaterally symmetric, necrotic lesions in the deep gray matter of the brain. More than 80 different genes –
either in the nuclear DNA or mitochondrial DNA – can underlie Leigh syndrome, yet we do not have approved
medicines for this lethal disease. We recently discovered that low oxygen – hypoxia – can buffer diverse forms
of mitochondrial dysfunction in human cells, worm models, and mice. In fact, breathing hypoxia is able to fully
prevent brain disease in the Ndufs4 KO mouse model of Leigh syndrome, and when hypoxic breathing is
initiated in mice with advanced, end-stage disease, we are able to reverse neurodegeneration. We do not
know the full mechanism by which breathing hypoxia is able reverse disease, whether we can identify small
molecule drugs that can target these mechanisms to reverse disease, and whether hypoxia therapy this
generalize to other mouse models of mitochondrial brain disease. In this application, we will apply cutting edge
single cell genomics, proteomics, mtDNA editing, and mouse physiology studies to address these three
challenges. We anticipate that this project could have important implications for understanding the basic
biology of neurodegeneration and neuroregeneration, with important future implications for the treatment and
management of patients with mitochondrial disease.

## Key facts

- **NIH application ID:** 10745965
- **Project number:** 5R01NS124679-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Vamsi Krishna Mootha
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $481,230
- **Award type:** 5
- **Project period:** 2022-01-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10745965

## Citation

> US National Institutes of Health, RePORTER application 10745965, Preventing and Reversing Mitochondrial Leigh Syndrome with Hypoxia (5R01NS124679-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10745965. Licensed CC0.

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