# Cerebellar metabolism in mitochondrial disease

> **NIH NIH F31** · SEATTLE CHILDREN'S HOSPITAL · 2021 · $43,474

## Abstract

Project Summary
Metabolic abnormalities may play a role in neurodegeneration in the setting of mitochondrial complex I (CI)
disease. CI deficiency decreases oxidative metabolism of glucose in the brain at a precise developmental
window. However, neither the developmental changes leading to altered nutrient handling, nor the implications
of decreased glucose flux have been described. This proposal will characterize the impact of CI deficiency (in
the Ndufs4(KO) mouse) on glutamine flux pathways, a compensatory nutrient source, in the brain. Glutamine is
unique from glucose as it supplies CI via pathways theoretically more effective than those of glucose in the
presence of CI disease. However, they may also be pathogenic. The applicant will assess glutamine metabolic
flux using stable isotope tracing assays in wildtype and CI defective Ndufs4(KO) mice. The goals of this proposal
are to determine 1) the impact of CI defects on glutamine metabolic handling in brain tissue, 2) posttranslational
changes to enzymes that facilitate glucose handling during development, and 3) whether mTOR inhibition, which
rescues neurodegeneration in the Ndufs4(KO) mouse, impacts CNS glucose flux. Based on substantial
preliminary data, CI dysfunction is hypothesized to increase glutamine flux, in response to decreased oxidative
glucose flux. mTOR inhibition is predicted to rescue disease at least partly through alleviation of defective
glucose flux, decreasing glutamine flux by extension. The metabolic impact of CI dysfunction will be
characterized by 1) 13C glutamine flux experiments performed in cerebellar tissue from control and Ndufs4(KO)
mice as a function of age and disease onset; 2) proteomic analysis of enzymes involved in glucose metabolism
as a function of developmental age, and 3) similar 13C glucose flux experiments in the setting of mTOR inhibition.
Relevance
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 no validated effective treatment options for
mitochondrial disease of any etiology. This work will help define the cellular and molecular mechanisms of
mitochondrial diseases and dysfunction with the goal of leading to treatment.
Environment and Training Plan
Seattle Children’s Research Institute and the University of Washington provide an ideal environment for doctoral
training, through outstanding faculty mentors, state-of-the-art facilities, and myriad opportunities for career
development. The trainee will master biochemical techniques and mouse genetics. She will attend seminars and
workshops to advance her conceptual knowledge of biochemistry, physiology, and neuroscience. Finally, the
trainee will advance her science communication skills by presenting her work at conferences, and preparing at
least two manuscripts for publication per year.

## Key facts

- **NIH application ID:** 10315050
- **Project number:** 1F31NS120442-01A1
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Rebecca Bornstein
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $43,474
- **Award type:** 1
- **Project period:** 2021-08-06 → 2022-07-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10315050

## Citation

> US National Institutes of Health, RePORTER application 10315050, Cerebellar metabolism in mitochondrial disease (1F31NS120442-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10315050. Licensed CC0.

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