Abstract
Acyl-CoA thioesterase (Acot)2 localizes to the mitochondrial matrix and hydrolyses long-chain fatty acyl-CoA into free FA and CoASH. Acot2 is expressed in highly oxi-dative tissues and is poised to modulate mitochondrial FA oxidation (FAO), yet its biological role is unknown. Using a model of adenoviral Acot2 overexpression in mouse liver (Ad-Acot2), we show that Acot2 increases the utilization of FA substrate during the daytime in ad libitum-fed mice, but the nighttime switch to carbohydrate oxidation is similar to control mice. In further support of elevated FAO in Acot2 liver, daytime serum ketones were higher in Ad-Acot2 mice, and overnight fasting led to minimal hepatic steatosis as compared with control mice. In liver mitochondria from Ad-Acot2 mice, phosphorylating O₂ consumption was higher with lipid substrate, but not with nonlipid substrate. This increase depended on whether FA could be activated on the outer mitochondrial membrane, suggesting that the FA released by Acot2 could be effluxed from mitochondria then taken back up again for oxidation. This circuit would prevent the build-up of inhibitory long-chain fatty acyl-CoA esters. Altogether, our findings indicate that Acot2 can enhance FAO, possibly by mitigating the accumulation of FAO intermediates within the mitochondrial matrix.
Highlights
Acyl-CoA thioesterase (Acot)2 localizes to the mitochondrial matrix and hydrolyses long-chain fatty acyl-CoA into free FA and CoASH
Thioesterase activity in Ad-Ctrl liver mitochondria could derive from the activity of Acot13 [Them2, likely associated with the outer mitochondrial membrane [11]] and Acot15 [Them5, localized to the matrix [9]], the Km for PCoA is closer to that measured for purified Acot15 [9]
There was no difference between Ad-Ctrl and Ad-Acot2 mitochondria in the total abundance of phospholipids (Fig.4B). These analyses suggest that the higher FA utilization during the daytime in ad libitum-fed Ad-Acot2 mice is unrelated to changes in mitochondrial content or CL metabolism
Summary
Acyl-CoA thioesterase (Acot) localizes to the mitochondrial matrix and hydrolyses long-chain fatty acyl-CoA into free FA and CoASH. In liver mitochondria from AdAcot mice, phosphorylating O2 consumption was higher with lipid substrate, but not with nonlipid substrate This increase depended on whether FA could be activated on the outer mitochondrial membrane, suggesting that the FA released by Acot could be effluxed from mitochondria taken back up again for oxidation. This circuit would prevent the build-up of inhibitory long-chain fatty acyl-CoA esters. Acyl-CoA thioesterases (Acots) in mitochondria, by virtue of their major substrates (long-chain fatty acyl-CoAs) and hydrolase activity which generates FA anion and free CoASH, have the potential to modulate the levels of FAO substrates and intermediates, and to modulate FAO.
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