# Mitochondrial metabolism and the Lon-PDH axis

> **NIH NIH R01** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2022 · $86,817

## 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. It is also a key regulatory node for glucose and fatty acid catabolism. Neurons generate ATP
almost exclusively by glucose oxidation, thus fully functional PDH activity 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 (1) patient- and parent- derived
fibroblasts, and (2) induced pluripotent stem cells (iPSCs) reprogrammed from these fibroblasts. The
iPSCs will be differentiated into neurons and astrocytes. Using these cells, Aim 1 will test the hypothesis
that Lon-mediated degradation regulates the activity and architecture 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; and Aim 3 will investigate the regulation and dysregulation of PDH by
wild type and mutant Lon in iPSC-derived 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, Lon), 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:** 10620384
- **Project number:** 3R01GM136905-03S2
- **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:** $86,817
- **Award type:** 3
- **Project period:** 2020-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10620384

## Citation

> US National Institutes of Health, RePORTER application 10620384, Mitochondrial metabolism and the Lon-PDH axis (3R01GM136905-03S2). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10620384. Licensed CC0.

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