Altering the Mitochondrial Fatty Acid Synthesis (mtFASII) Pathway Modulates Cellular Metabolic States and Bioactive Lipid Profiles as Revealed by Metabolomic Profiling

Abstract

Despite the presence of a cytosolic fatty acid synthesis pathway, mitochondria have retained their own means of creating fatty acids via the mitochondrial fatty acid synthesis (mtFASII) pathway. The reason for its conservation has not yet been elucidated. Therefore, to better understand the role of mtFASII in the cell, we used thin layer chromatography to characterize the contribution of the mtFASII pathway to the fatty acid composition of selected mitochondrial lipids. Next, we performed metabolomic analysis on HeLa cells in which the mtFASII pathway was either hypofunctional (through knockdown of mitochondrial acyl carrier protein, ACP) or hyperfunctional (through overexpression of mitochondrial enoyl-CoA reductase, MECR). Our results indicate that the mtFASII pathway contributes little to the fatty acid composition of mitochondrial lipid species examined. Additionally, loss of mtFASII function results in changes in biochemical pathways suggesting alterations in glucose utilization and redox state. Interestingly, levels of bioactive lipids, including lysophospholipids and sphingolipids, directly correlate with mtFASII function, indicating that mtFASII may be involved in the regulation of bioactive lipid levels. Regulation of bioactive lipid levels by mtFASII implicates the pathway as a mediator of intracellular signaling.

Identifying off-target effects of etomoxir reveals that carnitine palmitoyltransferase I is essential for cancer cell proliferation independent of β-oxidation

“…Complex lipids synthesized in the endoplasmic reticulum can be transported to the mitochondria and deacylated to make long-chain fatty acids [ 51 , 52 ], or long-chain fatty acids can be generated in the mitochondrial matrix by type II mitochondrial fatty acid synthesis, a pathway that resembles fatty acid synthesis in bacteria [ 53 ]. Although the fates of long-chain fatty acids generated by these processes remain poorly understood, disrupting mitochondrial fatty acid synthesis slows cell growth, influences mitochondrial phospholipid composition, and alters mitochondrial morphology [ 54 – 58 ], phenotypes which are highly consistent with those that we observed here with CPT1A knockdown. One possible explanation for these findings is that long-chain fatty acids generated in mitochondria are involved in phospholipid side-chain remodeling [ 54 ].…”

Mitochondrial fatty acid biosynthesis and muscle fiber plasticity in very long‐chain acyl‐CoA dehydrogenase‐deficient mice

“…Overall, our here presented findings displayed that the upregulation of both pathways occurs in parallel to the changes in muscle fiber type. It has recently been shown that MECR, one protein of the mFASII pathway, regulates gene expression via PPARa and PPARc signaling and modulates the abundance of bioactive lipids [48,49]. Therefore, a role of this pathway in metabolic regulation cannot be excluded.…”

Fatty Acid Biosynthesis: Chain‐Length Regulation and Control

“…[51b, 57] Whereas the shortchain C 8 fatty acids are the precursors of lipoic acids ynthesis, [58] the fate of long fatty acidsp roduced in mitochondriai s only poorly understood. [59] Recently,i tw as shown that mitochondrial ACPs carrying long acyl chains are accessory subunits of the ETC complex I. [8,60] In plants, fattya cids are predominantly synthesized in the plastids.P lants harbor type II FASs ystemsc onsisting of separated enzymes.…”