# Lon-PDH axis

> **NIH NIH R01** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2022 · $45,093

## Abstract

SUMMARY
From the parent grant R01 GM136905-01 entitled, “Mitochondrial metabolism and the Lon-PDH axis”.
The human Lon 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 Lon, in two siblings with profound neurologic
impairment, cerebral and cerebellar atrophy, in which proline at position 761 was replaced by leucine
(Lon-P761L). Primary skin fibroblasts from these siblings, showed substantially reduced activity of
pyruvate dehydrogenase (PDH). Our results demonstrated that PDH deficiency was caused by the
failure of Lon-P761L to degrade the phosphorylated E1a subunit of PDH, which accumulates and
inhibits PDH activity. PDH is the central gatekeeper linking glycolysis to the tricarboxylic acid (TCA)
cycle and a key regulatory node for glucose and fatty acid catabolism. Neurons generate ATP almost
exclusively by glucose oxidation, thus fully active PDH is crucial. We hypothesize that wild type Lon
regulates the activity and architecture of the PDH complex and is crucial for calibrating mitochondrial
metabolism and energetics. In this project, we will employ patient- and parent- derived fibroblasts, and
also induced pluripotent stem cells (iPSCs), which have been generated from these fibroblasts. The
patient- and parent- derived iPSCs will be differentiated into neurons and astrocytes. Using these cells,
Aim 1 will test the hypothesis that Lon-mediated degradation regulates the architecture and activity of
the PDH complex. Aim 2 will identify the up- and down- stream modulators of the Lon-PDH axis, which
are altered in cells expressing wild type Lon versus Lon-P761L. In Aim 3, we will investigate the
regulation of PDH by Lon 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, pharmacologic and dietary interventions
for increasing PDH activity and/or for treating PDH deficiency associated with Lon dysfunction. These
outcomes have a broader impact for understanding how PDH activity and mitochondrial metabolism
can be calibrated in both rare and more common disorders such as heart disease, cancer and
neurodegeneration.

## Key facts

- **NIH application ID:** 10652122
- **Project number:** 3R01GM136905-03S1
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** CAROLYN K SUZUKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $45,093
- **Award type:** 3
- **Project period:** 2020-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10652122

## Citation

> US National Institutes of Health, RePORTER application 10652122, Lon-PDH axis (3R01GM136905-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10652122. Licensed CC0.

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