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.

Public Health Relevance

Mitochondrial fatty acid oxidation disorders are a group of inborn errors of metabolism caused by defective fat degradation. Although these disorders have been included in newborn screening programs, current treatment options are insufficient to prevent all symptoms. Studying these disorders in animal and cell models is important to learn more about disease mechanisms and can help to develop new treatments.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Therapeutic Approaches to Genetic Diseases Study Section (TAG)
Program Officer
Sechi, Salvatore
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
Zip Code