# Harnessing mitochondria transfer pathways to ameliorate Leigh Syndrome-like disease

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $596,783

## Abstract

PROJECT SUMMARY
Leigh Syndrome (LS) is an inherited mitochondrial disease that presents with prominent neurologic symptoms
and death in childhood. There are currently no effective therapies for this devastating disease, highlighting an
urgent need to identify novel biological pathways that can be targeted therapeutically to treat LS and other
inherited mitochondrial diseases. Over the past 15 years, an emerging body of research, including recent studies
by us (Brestoff et al., Cell Metabolism, 2021 ), indicates that many cell types export their mitochondria for delivery
to neighboring cells, including neurons, in vivo in a process called interce/lular mitochondria transfer. Our
laboratory also recently reported that administering purified mitochondria to Ndufs4-1- mice with LS completely
restores the cell-intrinsic defects in mitochondrial metabolism of macrophages (Borcherding et al., Cell
Metabolism, 2022). However, it is unknown whether intercellular mitochondria transfer can be harnessed
therapeutically to treat LS. In new preliminary studies, we found that weekly systemic administration of purified
wildtype (WT) mitochondria to Ndufs4-1- mice increased their lifespan and markedly reduced their neurologic
morbidity and neurodegeneration. These data provoke our hypothesis that administering exogenous
mitochondria can rescue the metabolism of recipient cells and may be a previously unknown therapeutic strategy
for LS. Exogenous mitochondria appear to be captured first by macrophages, which are mobile cells that can
later export captured mitochondria to neighboring cells. Based on this finding, we transplanted WT bone marrow
into Ndufs4-1
- hosts and found that this intervention led to delivery of healthy donor cell-derived mitochondria to
host cells, ameliorated LS severity, and extended their lifespan. These data suggest that engrafted immune cells
from bone marrow transplantation can provide a systemically distributed, self-renewing supply of healthy
mitochondria to diseased cells in vivo. Collectively. these data provoke our central hypothesis that providing
sources of healthy mitochondria postnatally may ameliorate LS by rescuing cell-intrinsic metabolic defects. We
will address this hypothesis in two aims. In Aim 1, we will determine how administering exogenous mitochondria
improves the morbidity and mortality of LS. In Aim 2, we will investigate how bone marrow transplantation
improves LS by providing a durable, systemically distributed source of healthy mitochondria. This highly
innovative project will leverage our expertise in intercellular mitochondria transfer and new cutting-edge
technologies to establish the efficacy of and identify the mechanisms of these two novel therapeutic strategies
to treat fatal inherited mitochondrial diseases such as LS.

## Key facts

- **NIH application ID:** 10980991
- **Project number:** 1R01NS134932-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jonathan R Brestoff
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $596,783
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980991

## Citation

> US National Institutes of Health, RePORTER application 10980991, Harnessing mitochondria transfer pathways to ameliorate Leigh Syndrome-like disease (1R01NS134932-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10980991. Licensed CC0.

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