# The role of mTOR in mitochondrial encephalopathy

> **NIH NIH R00** · SEATTLE CHILDREN'S HOSPITAL · 2021 · $249,000

## Abstract

Project Summary/Abstract
Our overarching goal is to define the molecular mechanisms underpinning the pathogenesis of
mitochondrial disease. Our overall objective in the studies proposed here, which represent the next step in
pursuing this goal, is to characterize the pathogenesis of subacute necrotizing encephalopathy and define the
role of mTOR in this disease using the Ndufs4(KO) model.
Genetic mitochondrial diseases include an array of symptoms, may affect one organ or present as a
multisystem disorder, and are remarkably heterogeneous in severity. There are few good models for these
diseases and no effective treatment options for mitochondrial disease of any etiology. A clear understanding of
the pathogenesis of individual mitochondrial diseases is severely needed; the molecular mechanisms
underlying their multiple distinct clinical manifestations are currently unknown.
Subacute necrotizing encephalomyelopathy, or Leigh syndrome (LS), is a fatal pediatric mitochondrial disease.
Characteristic features of LS include region specific necrotizing lesions of the brain. Though these lesions are
the major defining feature of LS, virtually nothing is known of initiating events, what underlies the spatial and
temporal specific aspects of the disease, or why some regions of the CNS are inexplicably spared. Our recent
work has shown that inhibition of the nutrient sensing signaling complex mTOR attenuates LS in a mouse
model, but the mechanisms underlying the benefit are unknown.
The goal of this proposal is to define the pathogenesis of LS and the role of mTOR in this disease. We
hypothesize that the neurological lesions characteristic of LS result from region and cell-type specific effects
of mitochondrial dysfunction, and that mTOR inhibition acts through a discreet downstream neurotoxic
pathway.
Our experiments will take advantage of the Ndufs4(KO) mouse model of LS, a premier model of human
genetic mitochondrial disease which closely resembles human LS. Using this model, we will use characterize
the cellular and molecular pathogenesis of neurological lesions in LS by i) identifying the earliest type of cell
death and ii) the CNS cell types first lost in lesion formation, iii) defining the region, cell, and cell compartment
specificity of phospho-proteome changes during CNS lesion formation, and iv) testing the role of key mTOR
regulated pathways in LS using pharmacological approaches. Ultimately, this work will expose basic molecular
features of LS and mitochondrial disease in general. In addition, the career development and training
components of this proposal will provide key elements for my successful transition to an independent career.

## Key facts

- **NIH application ID:** 10150883
- **Project number:** 5R00GM126147-05
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Simon C Johnson
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2017-09-19 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10150883

## Citation

> US National Institutes of Health, RePORTER application 10150883, The role of mTOR in mitochondrial encephalopathy (5R00GM126147-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10150883. Licensed CC0.

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