Short- and medium-chain fatty acids in energy metabolism: the cellular perspective

Abstract

Short- and medium-chain fatty acids (SCFAs and MCFAs), independently of their cellular signaling functions, are important substrates of the energy metabolism and anabolic processes in mammals. SCFAs are mostly generated by colonic bacteria and are predominantly metabolized by enterocytes and liver, whereas MCFAs arise mostly from dietary triglycerides, among them milk and dairy products. A common feature of SCFAs and MCFAs is their carnitine-independent uptake and intramitochondrial activation to acyl-CoA thioesters. Contrary to long-chain fatty acids, the cellular metabolism of SCFAs and MCFAs depends to a lesser extent on fatty acid-binding proteins. SCFAs and MCFAs modulate tissue metabolism of carbohydrates and lipids, as manifested by a mostly inhibitory effect on glycolysis and stimulation of lipogenesis or gluconeogenesis. SCFAs and MCFAs exert no or only weak protonophoric and lytic activities in mitochondria and do not significantly impair the electron transport in the respiratory chain. SCFAs and MCFAs modulate mitochondrial energy production by two mechanisms: they provide reducing equivalents to the respiratory chain and partly decrease efficacy of oxidative ATP synthesis.

Keywords: long-chain fatty acids; mitochondria; short-chain fatty acids.

Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.

Figures

Fig. 1.

Uncoupling by LCFAs and pseudo-uncoupling by SCFAs and MCFAs of energized mitochondria. A: Real protonophoric uncoupling by LCFAs. Undissociated LCFAs undergo spontaneous flip-flop movements across the inner mitochondrial membrane. In the alkaline environment at the inner (matrix) side of the membrane, they undergo dissociation to proton (H+) and the fatty acid anion (RCOO−), which is subsequently transported by the adenine nucleotide transporter (ANT) and other mitochondrial anion carriers back to the external side of the membrane. Here, the LCFA anion becomes reprotonated and can undergo another flip-flop transfer. B: Pseudo-uncoupling by SCFAs and MCFAs. SCFAs and MCFAs are activated to their CoA thioesters in the mitochondrial matrix compartment. This process utilizes ATP and releases AMP and pyrophosphate (PPi). AMP can subsequently react with ATP yielding two molecules of ADP that are rephosphorylated at the expense of the mitochondrial transmembrane potential (ΔΨm), thus producing an uncoupling-like effect. In addition, both acyl-AMP and acyl-CoA are subject to slow hydrolysis, thus increasing AMP production and futile energy utilization.

Fig. 2.

Electron transfer from fatty acids to complex IV during β-oxidation and possible sites of superoxide generation. Shown is a simplified scheme summarizing the sites of superoxide generation supported by the mitochondrial degradation of fatty acid thioesters. Electrons are donated from the first enzyme of the β-oxidation pathway, acyl-CoA dehydrogenase (Acyl-CoA-DH), and are transmitted via the ETF to electron-transferring ubiquinone oxidoreductase (ETF-QOR). ETF-QOR reduces ubiquinone (Q) to ubiquinole (QH2). Finally, ubiquinole becomes oxidized to ubiquinone and subsequently electrons move to complex III. The 3-hydroxyacyl-CoA dehydrogenase (HO-CoA-DH), the third enzyme of the β-oxidation pathway, which oxidizes HO-acyl-CoA to keto-acyl-CoA, donates electrons directly to complex I. Sites of superoxide generation are indicated in red.