Sidorova-Darmos Elena, Fallah Merrick S, Logan Richard, Lin Cheng Yu, Eubanks James H
Division of Experimental and Translational Neuroscience, Krembil Research Institute, University Health Network, Toronto, Canada.
Department of Physiology, University of Toronto, Toronto, Canada.
Front Physiol. 2022 Sep 6;13:948387. doi: 10.3389/fphys.2022.948387. eCollection 2022.
Post-translational modification of mitochondrial proteins represents one mechanism by which the functional activity of mitochondria can be regulated. In the brain, these modifications can influence the functional properties of different neural circuitries. Given that the sirtuin family member Sirt3 represents the primary protein deacetylase enzyme in mitochondria, we tested whether brain mitochondrial proteome acetylation would increase in male or female mice lacking Sirt3. Our results confirm that whole brain mitochondrial proteome acetylation levels are indeed elevated in both sexes of Sirt3-KO mice relative to controls. Consistently, we found the mitochondria of mouse embryonic fibroblast (MEF) cells derived from Sirt3-KO mice were smaller in size, and fewer in number than in wild-type MEFs, and that mitochondrial free calcium levels were elevated within the mitochondria of these cells. As protein acetylation can influence mitochondrial function, and changes in mitochondrial function have been linked to alterations in neural circuit function regulating motor activity and anxiety-like behavior, we tested whether Sirt3-deficient mice would display sensitized responsiveness to the stimulant amphetamine. Both male and female Sirt-KO mice displayed hyper-locomotion and attenuated anxiety-like behavior in response to a dose of amphetamine that was insufficient to promote any behavioural responses in wild-type mice. Collectively, these results confirm that Sirt3 regulates mitochondrial proteome acetylation levels in brain tissue, and that the absence of Sirt3 increases the sensitivity of neural systems to amphetamine-induced behavioural responses.
线粒体蛋白的翻译后修饰是一种可调节线粒体功能活性的机制。在大脑中，这些修饰能够影响不同神经回路的功能特性。鉴于沉默调节蛋白家族成员Sirt3是线粒体中的主要蛋白质脱乙酰酶，我们测试了缺乏Sirt3的雄性或雌性小鼠的脑线粒体蛋白质组乙酰化水平是否会升高。我们的结果证实，相对于对照组，Sirt3基因敲除（KO）小鼠两性的全脑线粒体蛋白质组乙酰化水平确实升高。一致地，我们发现源自Sirt3-KO小鼠的小鼠胚胎成纤维细胞（MEF）的线粒体尺寸更小，数量比野生型MEF少，并且这些细胞线粒体内的线粒体游离钙水平升高。由于蛋白质乙酰化可影响线粒体功能，并且线粒体功能的变化与调节运动活动和焦虑样行为的神经回路功能改变有关，我们测试了Sirt3缺陷小鼠对兴奋剂苯丙胺是否会表现出敏化反应。雄性和雌性Sirt-KO小鼠在给予一剂不足以在野生型小鼠中引发任何行为反应的苯丙胺后，均表现出运动亢进和焦虑样行为减弱。总体而言，这些结果证实Sirt3调节脑组织中线粒体蛋白质组的乙酰化水平，并且Sirt3的缺失增加了神经系统对苯丙胺诱导的行为反应的敏感性。
