Acylation of the mitochondrial acyl carrier protein coordinates mitochondrial metabolism with nutrient status
Sara M. Nowinski1, Jonathan G. Van Vranken1, Katie J. Clowers4, Mi-Young Jeong1,2, Yeyun Oyang1, Jordan Berg1, Jeremy Gygi4, Steven P. Gygi4, Dennis R. Winge1,2, and Jared Rutter1,3 1Department of Biochemistry; 2Department of Medicine; and 3Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, USA; 4Department of Cell Biology, Harvard University School of Medicine, Boston, MA 02115, USA
Mitochondrial acetyl-CoA is the primary substrate that drives not only the TCA cycle and oxidative phosphorylation, but also mitochondrial fatty acid synthesis (FASII). The FASII pathway previously had only one described function: the production of lipoic acid, an important cofactor for several TCA cycle enzymes. However, we show that FASII plays an additional, crucial role in the support of ETC biogenesis via acylation of the mitochondrial acyl carrier protein (ACP). ACP physically interacts with a family of ETC complex assembly factors, the LYR proteins, which preferentially bind the acylated form of ACP through an evolutionarily conserved Leu-Tyr-Arg (LYR) motif. This binding is required to support the function(s) of the LYR proteins in the assembly of Complex II (Sdh6/Sdhaf1, Sdh7/Sdhaf3), Complex III (Mzm1/Lyrm7), and Complex V (Fmc1), as well as the iron-sulfur cluster biogenesis machinery (Isd11/Lyrm4). When ACP is deacylated - either via knockout of FASII enzymes, or as a result of low mitochondrial acetyl-CoA levels - ETC complexes fail to assemble, and the cells are respiratory deficient. This effect is rescued by targeting a fatty acyl-CoA synthetase to mitochondria, which drives re-acylation of ACP. As such, monitoring ACP acylation via interaction with the LYR proteins provides the cell with a mechanism to coordinate ETC biogenesis with acetyl-CoA levels, ensuring that mitochondrial metabolism remains balanced with substrate availability. Here we show, for the first time, the conservation of this mitochondrial regulatory mechanism in mammalian cells. These results highlight the importance of this pathway in higher eukaryotes and raise new considerations in the treatment of human patients with FASII deficiencies.
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