# The consequences of human inborn errors in mitochondrial lipoic acid metabolism

> **NIH NIH F32** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $71,430

## Abstract

PROJECT SUMMARY
Inborn errors of metabolism (IEMs) are genetic diseases that cause illness and death in children; however,
early detection and intervention permit children with some IEMs to develop normally. Lipoic acid deficiencies
are a new class of IEMs that cause metabolic acidosis, seizures and severe neurodevelopmental
abnormalities. Lipoic acid (LA) must be synthesized de novo in mammals and is an essential cofactor for
fundamental enzymes in central carbon metabolism. Our lack of understanding LA metabolism and its
relationship to metabolic programs is the primary obstacle in treating LA deficient patients.
 We have unique access to patient samples and through metabolomics analysis we have discovered a
number of unexpected metabolic abnormalities associated with LA deficiencies; including elevation of 2-
hydroxyglutarate (2-HG), a metabolite with wide reaching impacts on cell signaling and epigenetic regulation.
We intend to characterize the LA metabolic pathway in human cells and identify mechanisms contributing to
the elevation of 2-HG and its pathogenic role in LA deficiencies. We have multiple mouse models of LA
deficiency including a novel knock-in model of a patient mutation that are embryonically lethal and with these
models, we intend to investigate the impact of LA deficiencies on embryonic development. The central
hypothesis of this proposal is that in mammals, impaired activity of mitochondrial enzymes due to LA
deficiencies causes aberrant metabolism including accumulation of 2-HG, which contributes to
abnormal development.
 If successful, this proposal will generate a definitive assessment of the role of distinct enzymes in the
LA pathway on central metabolic fluxes in human cells, thereby providing a detailed view of the metabolic
consequences of each LA-related human IEMs. It will also characterize the effects of dysfunctional LA
metabolism in vivo during embryogenesis. The focus on patient-derived cells and mouse models should
increase the disease relevance of the work covered in the proposal.

## Key facts

- **NIH application ID:** 9996749
- **Project number:** 5F32HD096786-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Ashley D Solmonson
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $71,430
- **Award type:** 5
- **Project period:** 2018-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996749

## Citation

> US National Institutes of Health, RePORTER application 9996749, The consequences of human inborn errors in mitochondrial lipoic acid metabolism (5F32HD096786-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9996749. Licensed CC0.

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