# Anaplerotic Therapy for Mitochondrial Complex I Deficiency

> **NIH NIH R56** · UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA · 2020 · $372,500

## Abstract

ABSTRACT
Mitochondrial diseases manifesting as encephalopathies occur at a rate of 1 in 5000 live births and are often
fatal in the first few years of life. Mitochondrial diseases are respiratory chain disorders in which the mitochondria
are no longer operating efficiently to produce ATP, usually due to a problem with one or more components of
the oxidative phosphorylation machinery. The clinical course of these encephalopathies, e.g. Leigh Syndrome,
are well-described, the precise biochemical alterations that contribute to neuropathology, beyond the ATP defect,
are less understood.
We have previously described the reaction of the citric acid cycle metabolite fumarate with protein cysteine
residues to generate an irreversible modification, 2-succinocysteine (2SC). We have described increased 2SC
in several models, including the Ndufs4 knockout mouse model of mitochondrial Complex I deficiency.
Preliminary data shown in this proposal links the succination of a component of the α-ketoglutarate
dehydrogenase (α-KGDH) complex to the defective function of this enzyme complex. This results in decreased
succinyl CoA production, and impaired substrate level phosphorylation to produce much needed GTP. We
hypothesize that the α-KG is instead converted to 2-hydroxyglutarate under acidic conditions, i.e. lactic acidosis.
We predict that this influences the epigenetic landscape in the affected neurons. Further, we note that metabolic
acidosis combined with Ndufs4 bioenergetic defect also impacts the activated microglia in the affected regions
of the brain, by suppressing production of an anti-inflammatory metabolite. We hypothesize that this leads to
unresolved inflammation that may further exacerbate neuronal cell death. Our novel data suggests that citric
acid cycle dysfunction plays a key role in mediating the biochemical damage within the regions most affected by
pathology. In this proposal we outline several targeted anaplerotic therapies, and an improved delivery method,
that should ameliorate some of these biochemical defects. Importantly, since these compounds are non-toxic
fuels, they can be combined with existing vitamin/antioxidants to support neuronal health.

## Key facts

- **NIH application ID:** 10118501
- **Project number:** 1R56NS116174-01
- **Recipient organization:** UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
- **Principal Investigator:** Norma Frizzell
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $372,500
- **Award type:** 1
- **Project period:** 2020-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10118501

## Citation

> US National Institutes of Health, RePORTER application 10118501, Anaplerotic Therapy for Mitochondrial Complex I Deficiency (1R56NS116174-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10118501. Licensed CC0.

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