# Administrative Supplement for Mitochondrial metabolism and the Lon-PDH axis

> **NIH NIH R01** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2020 · $75,046

## Abstract

SUMMARY- from the parent grant 1R01GM136905-01
The human LonP1 protease is a master regulator of mitochondrial proteostasis, which is essential for
regulating mitochondrial energy metabolism and mitigating cell stress. We recently identified a novel
pathogenic variant in the LONP1 gene encoding the protease, in two siblings with profound neurologic
impairment, cerebral and cerebellar atrophy- proline at position 761 was replaced by leucine (Lon-
P761L). Primary skin fibroblasts from these siblings, showed substantially reduced activity of pyruvate
dehydrogenase (PDH). We showed that deficiency of PDH was caused by the failure of mutant Lon-
P761L to degrade a subunit of PDH- phosphorylated E1a, which accumulates and inhibits PDH activity.
PDH is the central gatekeeper linking glycolysis to the tricarboxylic acid (TCA) cycle and it is also a key
node for regulating glucose and fatty acid catabolism. Our long term goal is to elucidate the crucial role
of LonP1 in the regulation of energy metabolism, and why homozygous Lon-P761L expression causes
severe neurologic dysfunction and neurodegeneration. Glucose is the brain’s principal source of energy.
Neurons generate ATP almost exclusively by glucose oxidization, thus fully functional PDH activity is
crucial. Astrocytes by contrast, have broader metabolic capacity and supply neurons with lactate,
glutamine and ketone bodies, which are used to form acetyl CoA and TCA cycle intermediates required
for glucose oxidation. We hypothesize that wild type LonP1 regulates the architecture and activities of
the PDH complex, and modulates upstream and downstream effectors, to calibrate mitochondrial
metabolism and energetics. In this project, we will employ patient- and parent- derived fibroblasts, and
also fibroblasts that have been reprogrammed to generate induced pluripotent stem cells (iPSCs).
These iPSCs will be differentiated into neurons and astrocytes. Using the patient- and parent- derived
fibroblasts, Aim 1 will test the hypothesis that LonP1-mediated degradation regulates the architecture
and activity of the PDH complex. Aim 2 will identify the up- and down- stream modulators of the LonP1-
PDH axis, which are altered in cells expressing wild type LonP1 versus Lon-P761L. In Aim 3, we will
investigate the regulation of PDH by LonP1 in iPSCs differentiated into neurons and astrocytes. Our
investigation will establish new molecular mechanisms for the Lon-dependent regulation of PDH. The
knowledge gained will also help to identify potential therapeutic protein targets (e.g. PDK, PDP, LonP1),
pharmacologic and dietary interventions for increasing PDH activity and/or for treating PDH deficiency
associated with LonP1 dysfunction. These outcomes will have a broader impact for understanding how
PDH activity and mitochondrial metabolism can be calibrated in rare and also more common disorders
such as heart disease, cancer and neurodegeneration.

## Key facts

- **NIH application ID:** 10135561
- **Project number:** 3R01GM136905-01S1
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** CAROLYN K SUZUKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $75,046
- **Award type:** 3
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135561

## Citation

> US National Institutes of Health, RePORTER application 10135561, Administrative Supplement for Mitochondrial metabolism and the Lon-PDH axis (3R01GM136905-01S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10135561. Licensed CC0.

---

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