# Novel pathophysiological insights into mitochondrial fatty acid oxidation disorders

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $503,244

## Abstract

In this project, the investigators propose to study the pathophysiology of mitochondrial long-chain fatty acid
-oxidation (FAO) disorders. Patients with a FAO disorder can present with fasting-induced hypoglycemia,
cardiomyopathy, heart beat disorders, sudden infant death, myopathy and (exercise-induced) rhabdomyolysis.
Current therapeutic interventions need to be improved, but development of novel therapies is hampered by
limited insight into pathophysiological mechanisms as well as small patient groups and insufficiently developed
animal models. Therefore the overall objective of this proposal is to increase our knowledge of the
pathophysiology of FAO disorders by studying newly identified molecular mechanisms and metabolic pathways
that contribute to the different disease presentations using well-established mouse and cell models. The
investigators hypothesize that perturbations in metabolic signaling pathways and the resulting impaired
protein homeostasis play crucial roles in the pathophysiology of FAO disorders and that peroxisomal
metabolism is an important alternative pathway for fatty acid degradation when mitochondrial FAO is defective.
They will test this hypothesis by addressing two specific aims. In AIM 1, the investigators will study the
molecular mechanisms underlying perturbed protein homeostasis in a well-established mouse model for
mitochondrial FAO disorders. For this they will determine the dynamics of metabolic signaling during fasting in
liver, heart and skeletal muscle and will quantify metabolic fluxes in protein synthesis and degradation. They
will use a specific therapeutic diet to assess whether the depletion of tricarboxylic acid cycle intermediates that
results from impaired protein mobilization can be delayed. In AIM 2, the investigators will study peroxisomal
metabolic pathways that are alternatives for fatty acid degradation when mitochondrial FAO is defective. Using
genome editing technique in a cell line, they will elucidate the molecular players participating in one of these
alternative pathways. They will also assess the physiological importance of these peroxisomal pathways by
studying the biochemical and clinical features of a unique mouse model with a combined defect in
mitochondrial FAO and peroxisomal -oxidation. Combined these two aims will yield not only the much needed
refined mechanisms, but also novel pathophysiological insights in FAO disorders and thus novel potential
targets for treatment of these diseases.

## Key facts

- **NIH application ID:** 9930597
- **Project number:** 5R01DK113172-04
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Sander Michel Houten
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $503,244
- **Award type:** 5
- **Project period:** 2017-07-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9930597

## Citation

> US National Institutes of Health, RePORTER application 9930597, Novel pathophysiological insights into mitochondrial fatty acid oxidation disorders (5R01DK113172-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9930597. Licensed CC0.

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