Journal Article

Mitochondrial fatty acid synthesis coordinates oxidative metabolism in mammalian mitochondria

Fogarty, Sarah, Ouyang, Yeyun, Lettlova, Sandra, Cox, James E, Solmonson, Ashley, Funai, Katsuhiko, Naylor, Bradley C, Gygi, Steven P, Rutter, Jared, Paulo, Joao A, Bensard, Claire L, Jeong, Mi-Young, Morgan, Jeffrey T, Rusin, Scott F, Maschek, J Alan, Winge, Dennis R, Nowinski, Sara M, DeBerardinis, Ralph J, Berg, Jordan A

2020

Overview

Cells harbor two systems for fatty acid synthesis, one in the cytoplasm (catalyzed by fatty acid synthase, FASN) and one in the mitochondria (mtFAS). In contrast to FASN, mtFAS is poorly characterized, especially in higher eukaryotes, with the major product(s), metabolic roles, and cellular function(s) being essentially unknown. Here we show that hypomorphic mtFAS mutant mouse skeletal myoblast cell lines display a severe loss of electron transport chain (ETC) complexes and exhibit compensatory metabolic activities including reductive carboxylation. This effect on ETC complexes appears to be independent of protein lipoylation, the best characterized function of mtFAS, as mutants lacking lipoylation have an intact ETC. Finally, mtFAS impairment blocks the differentiation of skeletal myoblasts in vitro. Together, these data suggest that ETC activity in mammals is profoundly controlled by mtFAS function, thereby connecting anabolic fatty acid synthesis with the oxidation of carbon fuels. In human, plant and other eukaryotic cells, fats are an important source of energy and also play many other roles including waterproofing, thermal insulation and energy storage. Eukaryotic cells have two systems that make the building blocks of fats (known as fatty acids) and one of these systems, called the mtFAS pathway, operates in small compartments known as mitochondria. This pathway only has one known product, a small fat molecule called lipoic acid, which mitochondria attach to several enzymes to allow them to work properly. The main role of mitochondria is to break down fats and other molecules to release chemical energy that powers many processes in cells. They achieve this using large groups of proteins known as ETC complexes. To build these complexes, families of proteins known as ETC assembly factors carefully coordinate the assembly of many proteins and small molecules into specific structures. However, it remains unclear precisely how this process works. Here, Nowinski et al. used a gene editing technique to mutate the genes encoding three enzymes in the mtFAS pathway in mammalian cells. The experiments found that the mutant cells had fewer ETC complexes and seemed to be less able to break down fats and other molecules than ‘normal’ cells. Furthermore, a family of ETC assembly factors were less stable in the mutant cells. These findings suggest that the mtFAS pathway controls how mitochondria assemble ETC complexes. Further experiments indicated that lipoic acid is not involved in the assembly of ETC complexes and that the mtFAS pathway produces another, as yet unidentified, product that regulates this process, instead. MEPAN syndrome is a rare neurological disorder that leads to progressive loss of control of movement, slurred speech and impaired vision in children. Patients with this syndrome have genetic mutations affecting components of the mtFAS pathway, therefore, a better understanding of how the pathway works may help researchers develop new treatments in the future. More broadly, these findings will have important ramifications for many other situations in which the activity of ETC complexes in mitochondria is modified.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications, Ltd,eLife Sciences Publications Ltd
• Subject: Animals / Biochemistry and Chemical Biology / Biological products / Cell Differentiation / Cell Line / Cells (Biology) / Electron transport / electron transport chain / Electron Transport Chain Complex Proteins - genetics / Electron Transport Chain Complex Proteins - metabolism / Energy (Physics) / Enzymes / Fatty acid synthesis / Fatty acids / Fatty Acids - biosynthesis / Gene mutation / HEK293 Cells / Humans / Lipoylation - genetics / metabolism / Mice / mitochondria / Mitochondria - metabolism / myoblast / Myoblasts - physiology / Oxidation-Reduction / Physiological aspects / TCA cycle