Mitochondrial fatty acid oxidation and fatty acid biosynthesis2020-12-22T11:05:13+01:00

Project Description

Sara Tucci

Technical head of the Laboratory of Clinical Biochemistry and Metabolism

E: sara.tucci@uniklinik-freiburg.de
T: +49 (0)761 270-43700
F: +49 (0)761 270-45270

Medical Center – University of Freiburg
Center for Pediatrics
Department of General Pediatrics, Adolescent Medicine and Neonatology
Mathildenstr. 1
79106 Freiburg
Germany

Mitochondrial fatty acid metabolism plays a pivotal role in maintaining cellular energy homeostasis. Diseases of fatty acid biosynthesis and oxidation are two groups of rare inborn errors of metabolism. Our main research interest is the characterization of disease pathomechanisms and the regulation of energy homeostasis.

Main methods:

  • Mouse model
  • Cell models
  • Metabolomics

TEAM

  • Prof. Dr. Ute Spiekerkötter (collaborating research group leader)
  • PD Dr. Sarah Grünert (collaborating research group leader)
  • Khaled Alatibi (PhD student)
  • Siti Nurjanah (PhD student)
  • Julia Hesse (MD student)
  • Cäcilia Burg (MD student)
  • Stephanie Kempf (MD student)
  • Stephanie Nauck (MD Student)
  • Alina Nagy (voluntary civil service)

RESEARCH THEMES

Mitochondrial fatty acid metabolism

Mitochondria are the designated organelles for energy supply during situation of increased energy demand. Energy production occurs via β-oxidation of fatty acids. Dysfunction of one or more of enzymes involved in this process results in life-threatening events and death as a consequence of severe energy deficiency due to disrupted fatty acid degradation and the accumulation of toxic metabolites. Fatty acid oxidation disorders are a group of rare diseases that are part of newborn screening programs in Germany and in many countries worldwide.

In addition to β-oxidation, mitochondria are able to synthesize fatty acids with a chain length up to 8 carbons via a mitochondrial fatty acid synthase pathway (mtFAS) that is not fully characterized yet in humans. The synthesized C8 fatty acids are then used as substrate for the biosynthesis of lipoic acid which is an essential cofactor for several mitochondrial enzymes involved in energy metabolism. Very recently an increasing number of patients with defects in one of the mtFAS pathway have been reported. In contrast to β-oxidation, defects of mtFAS enzymes affect function of central nervous system.

Our research address the following aims:

  • Characterization of pathomechanisms involved in the development of symptoms in different tissues and organs
  • Effects of therapeutical interventions in the treatment of long-chain fatty acid oxidation disorders and mtFAS deficiencies
  • Interaction of β-oxidation and mtFAS in the regulation of energy homeostasis

CURRENT PROJECTS

Characterization of the sex specific metabolic phenotype in very-long chain acyl-CoA dehydrogenase deficient (VLCAD-/-) mice

Very-long chain acyl-CoA dehydrogenase deficiency is the most common disorder of mitochondrial long-chain fatty acid oxidation with an incidence of 1:50,000-1:100,000 newborns. Catabolic situations contribute to the aggravation of the symptoms and may induce severe metabolic derangement and death. Treatment for VLCAD deficiency includes avoidance of prolonged fasting and a long-chain fat-restricted and fat-modified diet in which long-chain fatty acids (LCFA) are fully or in part replaced by medium-chain triglycerides (MCT). Our data demonstrated a sexually dimorphic response after long-term application of MCT with the development of a severe metabolic syndrome in female VLCAD-/- mice. Our hypothesis is that the concomitant effect of a deficient β-oxidation pathway and the supplementation with dietary MCT may contribute to the disturbed signaling cascade resulting in the development of a sex specific metabolic phenotype. How MCT affects signaling pathway and the regulation of energy metabolism in a sex specific manner, is still unknown. We aim to investigate whether i) sex may be considered an important variable to take into account in the prospective developing phenotype and ii) whether/ how a diet based on MCT affects signaling pathway and whole-body energy metabolism.

Effects of dietary intervention for the treatment of long-chain fatty acid oxidation disorders (lcFAOD)

Our previous studies in VLCAD-/- mice have shown that compensatory / adaptation mechanisms are up-regulated in tissues and organs to meet the required energy need during higher energy demand but also at rest. Taking advantage of VLCAD-/- mice, and fibroblasts from patients with different lcFAOD we plan to characterize the effects of different dietary interventions (i.e. triheptanoin, protein rich diet) in the regulation of cellular metabolism and on alternative energy producing pathways and how anaplerotic processes can be stimulated to compensate for a defective β-oxidation.

Fat-modified diets, lipidomics of lcFAOD and signaling disturbances

Long-term MCT- and triheptanoin-based diets deeply change membrane fatty acid profiles of tissues from VLCAD-/- mice. In murine fibroblasts we have shown that treatment with octanoate markedly disturbs also the composition of complex lipids. Because MCT and triheptanoin are applied in the treatment of lcFAOD we are addressing the question whether medium chain fatty acids (C7 and C8) redesign the lipidome of fibroblasts from patients with different lcFAOD and how membrane lipid modification affect cell signaling.

Mitochondrial β-oxidation and mtFAS in the regulation of energy metabolism

The malonyl-CoA synthetase (ACSF3) catalyzes the first step of the mitochondrial fatty acid biosynthesis (mFASII) which provides octanoate necessary for the biosynthesis of lipoic acid, an essential cofactor for several mitochondrial enzymes involved in energy metabolism.

Our studies on ACSF3-deficient fibrobrasts have shown a severe impairment of mitochondrial energy metabolism and reduced metabolic flexibility accompanied by the up-regulation of β-oxidation. On the other hand, the metabolic switch and morphologic transdifferentiation of white skeletal muscle of VLCAD-/- mice was associated with a marked up-regulation of mtFAS. How exactly β-oxidation and mtFAS interact and how they regulate each other will be investigated in ACSF3 deficient cells and in cells from patients with different lcFAOD.

Effects of medium-chain triglycerides (cooperation projects with PD Dr. Sarah Grünert)

Medium-chain triglycerides (MCT) are commonly used in the dietary treatment of lcFAODs. However, long-term effects of MCT have scarcely been investigated. Two studies are currently ongoing. In one project performed in cooperation with the Medical Physics Department Freiburg we evaluate the effects of MCT on the body fat distribution and composition applying magnet resonance imaging (MRI) and spectroscopy (MRS).

In another study, we investigate the effects of MCT supplementation on the composition of fatty acids in plasma and erythrocyte membranes of patients with FAODs and healthy controls.

COLLABORATIONS, CO-OPERATIONS AND NETWORKS

SELECTED RECENT PUBLICATIONS

For a complete publication list for Sara Tucci, please use the following links:

PubMed: https://pubmed.ncbi.nlm.nih.gov/?term=sara+tucci&sort=date

ORCID: https://orcid.org/0000-0003-3851-4843

FUNDING

DFG

Ultragenyx

Vitaflo Pharma

Fritz-Thyssen-Stiftung

Müller-Fahnenberg-Stiftung

Eva-Uth-Stiftung

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