# Regulation of mitochondrial metabolism by lysine acylation

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $397,912

## Abstract

PROJECT ABSTRACT
Fatty acid oxidation (FAO) is a critical energy producing pathway in heart, muscle, and liver, among other
organs. Inborn errors in genes of the FAO pathway are associated with dysfunction in these organs and a high
rate of mortality. Additionally, disruptions in FAO are seen in polygenic diseases such as obesity, diabetes, and
cancer. With advances in mass spectrometry profiling of blood metabolites, FAO defects can be readily
diagnosed. However, despite 30 years of intensive study, treatment options for modulating FAO in human
patients remain limited and ineffective. Knowledge gaps regarding the regulation of FAO enzymes and the
functional organization of the FAO pathway within the greater landscape of mitochondrial energy metabolism
have limited the development of new therapies. In the previous funding period of this grant, we established
reversible lysine post-translational modifications (acetylation, succinylation) as regulators of FAO. We showed
that sirtuin enzymes, which deacylate target lysines and restore them to the native state, are important players
in maximizing function of the FAO pathway. In the present proposal we hypothesize that lysine acylation
regulates FAO enzyme activity, localization to the inner mitochondrial membrane, and the assembly of higher-
order metabolic complexes between FAO proteins and the respiratory chain. In Specific Aim 1, we will employ
in vitro methods that we pioneered in the previous funding period to identify sirtuin-targeted lysines on the
membrane-associated FAO enzymes carnitine palmitoyltransferase-2 (CPT2), mitochondrial trifunctional
protein (TFP), and acyl-CoA dehydrogenase-9 (ACAD9). We will perform mutagenesis studies to determine
the functional role of each of the sirtuin-targeted lysine residues. In Specific Aim 2 we will investigate physical
and functional interactions between the three mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5) and the inner
mitochondrial membrane. We hypothesize that the sirtuins police the inner mitochondrial membrane in order to
facilitate assembly and operation of higher-order metabolic complexes such as those formed between FAO
and the electron transport chain. Finally, Specific Aim 3 will evaluate the effects of lysine acylation on these
higher-order complexes using a combination of mouse models and protein complexes assembled in vitro.
Understanding the role of the sirtuins in regulating FAO and metabolic supercomplexes will lay the ground
work for developing new therapies that manipulate mitochondrial function in human patients with inborn errors
of metabolism, as well as those with chronic diseases such as obesity, diabetes, and cancer.

## Key facts

- **NIH application ID:** 9930583
- **Project number:** 5R01DK090242-10
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** ERIC S GOETZMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $397,912
- **Award type:** 5
- **Project period:** 2011-06-15 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9930583

## Citation

> US National Institutes of Health, RePORTER application 9930583, Regulation of mitochondrial metabolism by lysine acylation (5R01DK090242-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9930583. Licensed CC0.

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