# Regulation of Peroxisomal Metabolism by Lysine Acylation

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $436,051

## Abstract

Long-chain fatty acid oxidation disorders (LC-FAODs) are a heterogenous group of disorders characterized by
the inability to break down long-chain fatty acids in the mitochondria for energy. Peroxisomal fatty acid
oxidation (FAO) is a parallel pathway to mitochondrial FAO that could be leveraged to alleviate fatty acid
accumulation in patients with LC-FAODs. However, there is currently no pharmacological means of stimulating
peroxisomal FAO in humans. The ability to develop new peroxisome-stimulating therapies is limited by
knowledge gaps regarding the factors that regulate activity of peroxisomal FAO enzymes. Here, it is proposed
that sirtuin-5 (Sirt5) and lysine succinylation—a post-translational modification reversed by Sirt5—represent a
new mechanism for manipulating peroxisomal function. When mice are fed a class of fatty acids called
dicarboxylic acids (DCAs), lysine succinylation accumulates on peroxisomal proteins. Further preliminary data
suggest that lysine succinylation increases peroxisomal function. The capacity of Sirt5 to reverse these effects
remains unclear. The central hypothesis of this grant is that feeding DCAs can improve disease pathology in
mouse models of mitochondrial LC-FAOD by driving protein succinylation and peroxisomal activation. This is
supported by preliminary data in which seven days of DCA feeding improved muscle function in an LC-FAOD
mouse model. The central hypothesis will be fully explored in three Specific Aims. 1) Aim 1 will quantify the
effects of DCA feeding and Sirt5 ablation on the peroxisomal acylome. Sirt5 partially localizes to the
peroxisome but its activity there has not been characterized. A quantitative, site-level lysine “acylome” ± DCA
feeding will be compiled for liver, muscle, and heart—the key tissues affected in LC-FAODs—and all Sirt5
target sites identified. 2) Aim 2 is to delineate the effects of DCA feeding ± Sirt5 ablation on the function of
peroxisomal enzymes and pathway fluxes. This will be done using purified recombinant proteins, cultured cells
with manipulated Sirt5 levels in the peroxisome, and Sirt5-deficient mice. Metabolomics, 14C-substrate flux
studies, and enzyme stability/function testing will be used to determine how reversible lysine PTMs affect the
peroxisome. 3) Aim 3 will be to test DCA feeding as a therapeutic strategy in LC-FAOD mouse models. It is
proposed that DCAs will distribute beyond the liver to the peripheral organs, serving as a source of energy via
partial chain shortening and peroxisomal gain-of-function. Mild and severe LC-FAOD mouse models ± long-
term DCA feeding will be evaluated for liver, heart, and muscle functioning as well as the response to fasting
stress. Ablation of Sirt5 in this context may further enhance peroxisomal function. To test this, the LC-FAOD
mouse models will be crossed onto a Sirt5-/- background. Together, completion of these Specific Aims will form
critical new knowledge for manipulating peroxisomal function to treat LC-FAODs. ...

## Key facts

- **NIH application ID:** 10379464
- **Project number:** 5R01DK090242-12
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** ERIC S GOETZMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $436,051
- **Award type:** 5
- **Project period:** 2011-06-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10379464

## Citation

> US National Institutes of Health, RePORTER application 10379464, Regulation of Peroxisomal Metabolism by Lysine Acylation (5R01DK090242-12). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10379464. Licensed CC0.

---

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