# Developmental mechanisms of CNS pathology in mitochondrial disease

> **NIH NIH R01** · SEATTLE CHILDREN'S HOSPITAL · 2021 · $471,250

## Abstract

Project Summary/Abstract
Our long-term goal is to define the molecular and cellular mechanisms involved in the pathogenesis and
complex clinical presentations of mitochondrial dysfunction. Our overall objective in the studies proposed
here, which are a next step in pursuing this goal, is to define the relationship between development and onset
of disease resulting from mitochondrial electron transport chain complex I (ETC CI) dysfunction. We
hypothesize, based on substantial preliminary data, that some of the major neurologic sequelae of mitochondrial
disease are mechanistically driven by the interaction between mitochondrial function and specific events in
postnatal development. In particular, our preliminary data reveal a striking specificity to age of disease onset
and, more telling, that treatment during a specific post-natal period is both necessary and sufficient for lasting
benefits from rapamycin treatment, a well-validated intervention in pre-clinical studies of mitochondrial disease.
Our experiments will take advantage of the Ndufs4(KO) mouse, apremier model of mitochondrial disease closely
resembling human LS. In addition, we have generated a novel nematode model of LS which has a robust
developmental phenotype and is defective in the C. elegans homologue of Ndufs4, lpd-5. We will use these
models to define the role of postnatal neurodevelopment in the onset of neurological features of mitochondrial
disease i) probe the interaction between development and onset of major neurological sequelae of disease ; ii)
define the critical window in development for interventions targeting disease; iii) identifying genetic factors
involved in developmental arrest associated with mitochondrial dysfunction in C. elegans. Ultimately, this work
will advance our understanding of the role of mitochondria in developmental biology and help define the cellular
and molecular pathogenesis of mitochondrial diseases.
Relevance
Genetic mitochondrial diseases involve an array of symptoms, can impact one organ or present as a multisystem
disorder, are remarkably heterogeneous, and currently there are no proven treatments for mitochondrial disease
of any etiology. A clear understanding of the pathogenesis of individual mitochondrial diseases is severely
needed; the molecular, cellular, physiological, and developmental mechanisms underlying the complex clinical
syndromes arising from primary genetic mitochondrial dysfunction have not been undefined.

## Key facts

- **NIH application ID:** 10296147
- **Project number:** 1R01NS119426-01A1
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Simon C Johnson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $471,250
- **Award type:** 1
- **Project period:** 2021-08-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10296147

## Citation

> US National Institutes of Health, RePORTER application 10296147, Developmental mechanisms of CNS pathology in mitochondrial disease (1R01NS119426-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10296147. Licensed CC0.

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