# Mechanisms of mitochondrial disease suppression in Ndufs4 knockout mice

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $481,851

## Abstract

7. Project Summary/Abstract
Deficiencies in complex I of the mitochondrial electron transport chain represent an important class of human
mitochondrial diseases that include Leigh Syndrome, Leber’s hereditary optic nephropathy, neonatal lactic
acidosis, cardiomyopathy, and encephalopathy. Leigh Syndrome is generally regarded as the most common
mitochondrial disease of infancy and is characterized primarily by severe neurological defects. There is
currently no effective treatment. A mouse model has been developed in which the complex I structural subunit
NDUFS4 is knocked-out. Ndufs4-/- mice show a profound neurodegenerative phenotype including retarded
growth rate, lethargy, loss of motor skill, blindness, weight loss, and early death. These symptoms are
recapitulated in human patients with Ndufs4 mutations, as well as other Leigh Syndrome-associated mutations.
We have recently reported that treating Ndufs4-/- mice with the drug rapamycin, a specific inhibitor of the
mammalian target of rapamycin complex 1 (mTORC1), results in two to three-fold increase in survival,
dramatic attenuation of neurologial defecits, and reduced neurodegeneration. In unpublished studies, we have
observed similar effects from the NAD+ precursor nicotinamide mononucleotide (NMN) -glucosidase
inhibitor acarbose. The broader goals this proposal to define the mechanistic basis for suppression of
mitochondrial disease by rapamycin, NMN, and acarbose in the Ndufs4 knockout (KO) mouse. This will be
accomplished broadly by assessing changes in the metabolome and phosphoproteome, and specifically by
determining the effects of these interventions on mitochondrial function, mTOR signaling, NAD homeostasis,
and activity of the NAD-dependent mitochondrial SIRT3 deacetylase. We will test the specific hypothesis that
these intervention act by enhancing SIRT3 activity by creating animals lacking both NDUFS4 and SIRT3 and
determining whether this blocks or attenuates rescue of the disease. These studies promise to enhance our
understanding of mitochondrial function in the context of complex I deficiency and facilitate the development of
interventional strategies to improve the lives of patients with mitochondrial disease.

## Key facts

- **NIH application ID:** 9850646
- **Project number:** 5R01NS098329-04
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** MATT KAEBERLEIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $481,851
- **Award type:** 5
- **Project period:** 2017-02-15 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850646

## Citation

> US National Institutes of Health, RePORTER application 9850646, Mechanisms of mitochondrial disease suppression in Ndufs4 knockout mice (5R01NS098329-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9850646. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*