Multiple mitochondrial thioesterases have distinct tissue and substrate specificity, and CoA regulation, suggesting unique functional roles
Multiple mitochondrial thioesterases have distinct tissue and substrate specificity, and CoA regulation, suggesting unique functional roles
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DOI：
10.1074/jbc.ra119.010901
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发表时间：
2019-12-13
影响因子：
4.8
通讯作者：
Seifert, Erin L.
中科院分区：
文献类型：
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作者：
Bekeova, Carmen;Anderson-Pullinger, Lauren;Seifert, Erin L.
酰基辅酶A硫代酯酶(ACOTS)能水解酯。线粒体基质中的辅酶A可减轻β-氧化过载并维持辅酶A的可获得性。有几个AcoT与线粒体相关，但它们是否都定位于基质，是多余的，还是具有不同的作用尚不清楚。在这里，我们比较了线粒体AcoT(Acot2、7、9和13)在多个小鼠组织和Acot2耗尽模型中的细胞器下定位、活性、表达和调控。Acot7、9和13定位到基质上，加入了之前被证明定位在那里的Acot2。来自心脏、骨骼肌、棕色脂肪组织和肾脏的线粒体强烈表达Acot2、9和13；在棕色脂肪组织和肾脏线粒体中，Acot9的水平显著高于C4：0-CoA，这是一种独特的Acot9底物。在所有组织中，Acot2约占C14：0-CoA和C16：0-CoA硫酯酶活性的一半。相比之下，喂食和禁食小鼠的肝脏线粒体表达的Acot活性很低，这仅限于长链COA，主要是由于Acot7和Acot13的活性。根据底物专一性(Acot9与Acot2和13)和较强的CoA抑制作用(Acot7、9和13，但不包括Acot2)，基质AcoT占据了不同的功能生态位。在β-氧化的背景下解释，CoA抑制将阻止Acot介导的抑制β-氧化，同时在CoA受限时提供一个释放阀。相反，CoA不敏感的Acot2可以为长链脂肪酰基COAS提供一个结构性虹吸。这些结果揭示了基质Acots家族如何减轻β-氧化过载和防止CoA限制。
Acyl-CoA thioesterases (Acots) hydrolyze fatty acyl-CoA esters. Acots in the mitochondrial matrix are poised to mitigate beta-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 vs. Acot2 and 13) and strong CoA inhibition (Acot7, 9, and 13, but not Acot2). Interpreted in the context of beta-oxidation, CoA inhibition would prevent Acotmediated suppression of beta-oxidation, while providing a release valve when CoA is limiting. In contrast, CoA-insensitive Acot2 could provide a constitutive syphon for long- chain fatty acyl-CoAs. These results reveal how the family of matrix Acots can mitigate beta-oxidation overload and prevent CoA limitation.