Abstract

Acyl-CoA thioesterases (Acots) hydrolyze fatty acyl-CoA esters. Acots in the mitochondrial matrix are poised to mitigate β-oxidation overload and maintain CoA availability. Several Acots associate with mitochondria, but whether they all localize to the matrix, are redundant, or have different roles is unresolved. Here, we compared the suborganellar localization, activity, expression, and regulation among mitochondrial Acots (Acot2, -7, -9, and -13) in mitochondria from multiple mouse tissues and from a model of Acot2 depletion. Acot7, -9, and -13 localized to the matrix, joining Acot2 that was previously shown to localize there. Mitochondria from heart, skeletal muscle, brown adipose tissue, and kidney robustly expressed Acot2, -9, and -13; Acot9 levels were substantially higher in brown adipose tissue and kidney mitochondria, as was activity for C4:0-CoA, a unique Acot9 substrate. In all tissues, Acot2 accounted for about half of the thioesterase activity for C14:0-CoA and C16:0-CoA. In contrast, liver mitochondria from fed and fasted mice expressed little Acot activity, which was confined to long-chain CoAs and due mainly to Acot7 and Acot13 activities. Matrix Acots occupied different functional niches, based on substrate specificity (Acot9 versus Acot2 and -13) and strong CoA inhibition (Acot7, -9, and -13, but not Acot2). Interpreted in the context of β-oxidation, CoA inhibition would prevent Acot-mediated suppression of β-oxidation, while providing a release valve when CoA is limiting. In contrast, CoA-insensitive Acot2 could provide a constitutive siphon for long-chain fatty acyl-CoAs. These results reveal how the family of matrix Acots can mitigate β-oxidation overload and prevent CoA limitation.

Highlights

  • Acyl-CoA thioesterases (Acots) hydrolyze fatty acyl-CoA esters

  • Subcompartmental localization of Acot2 and Acot15 to the mitochondrial matrix was demonstrated by immunogold EM [11, 12], whereas localization of Acot7, -9, and -13 within mitochondria has not been determined

  • Using two different proteases and mitochondria from three different tissues, we provide evidence that Acot13 localizes to the mitochondrial matrix, even though the prediction of an N-terminal mitochondrial targeting sequence (MTS) or an internal targeting sequence is low (ϳ30%)

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Summary

Introduction

Acyl-CoA thioesterases (Acots) hydrolyze fatty acyl-CoA esters. Acots in the mitochondrial matrix are poised to mitigate ␤-oxidation overload and maintain CoA availability. We compared the suborganellar localization, activity, expression, and regulation among mitochondrial Acots (Acot2, -7, -9, and -13) in mitochondria from multiple mouse tissues and from a model of Acot depletion. Type I and II Acots have a signature substrate specificity that includes saturated and unsaturated fatty acyl-CoAs of different chain lengths and, in fewer cases, other CoA esters [3,4,5]. Mice with whole-body Acot deletion had improved glucose homeostasis on a high-fat diet [9] and improved hepatic insulin sensitivity in the setting of steatosis [10] These observations suggest that Acot loss protects fatty liver from insulin resistance, it should be noted that Acot has dual mitochondria-cytosol localization and that the subcompartmentalization of Acot within mitochondria has not yet been determined.

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