Mimicking nature's ability to orchestrate molecular self-assembly in living cells is important yet challenging. Molecular self-assembly has found wide applications in cellular activity control, drug delivery, biomarker imaging, etc. Nonetheless, exam-ples of suborganelle-confined supramolecular self-assembly are quite rare and research in this area remains challenging. Herein, we have presented a new strategy to program supramolecular self-assembly specifically in mitochondria by leverag-ing on a unique enzyme SIRT5. SIRT5 is a mitochondria-localized enzyme belonging to a family of NAD+-dependent histone deacetylases. Accumulating studies suggest that SIRT5 is involved in regulating diverse biological processes, such as reactive oxygen defense, fatty acid metabolism and apoptosis. In this study, we designed a novel class of succinylated peptide precur-sors that can be transformed into self-assembling building blocks through SIRT5 catalysis, leading to the formation of supra-molecular nanofibers in vitro and in living cells. The increased hydrophobicity arising from self-assembly remarkably en-hanced the fluorescence of nitrobenzoxadiazole (NBD) in the nanofibers. With this approach, we have enabled activity-based imaging of SIRT5 in living cells for the first time. Moreover, SIRT5-mediated peptide self-assembly was found to depolarize mitochondria membrane potential and promote ROS formation. Co-incubation of the peptide with three different chemo-therapeutic agents significantly boosted the anticancer activities of these drugs. Our work has thus illustrated a new way of mitochondria-confined peptide self-assembly for SIRT5 imaging and potential anticancer treatment.

中文翻译：

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脱琥珀酰化触发肽自组装：SIRT5 活性和线粒体活性调节的活细胞成像

模仿大自然在活细胞中协调分子自组装的能力很重要，但也具有挑战性。分子自组装在细胞活性控制、药物递送、生物标志物成像等方面有着广泛的应用。然而，亚细胞器限制的超分子自组装的例子非常罕见，该领域的研究仍然具有挑战性。在此，我们提出了一种新策略，通过利用一种独特的酶 SIRT5，专门在线粒体中编程超分子自组装。SIRT5 是一种定位于线粒体的酶，属于 NAD+ 依赖性组蛋白脱乙酰酶家族。越来越多的研究表明，SIRT5 参与调节多种生物过程，如活性氧防御、脂肪酸代谢和细胞凋亡。在这项研究中，我们设计了一类新型琥珀酰化肽前体，可通过 SIRT5 催化转化为自组装构件，从而在体外和活细胞中形成超分子纳米纤维。自组装引起的疏水性增加显着增强了纳米纤维中硝基苯并恶二唑（NBD）的荧光。通过这种方法，我们首次在活细胞中实现了基于活性的 SIRT5 成像。此外，发现 SIRT5 介导的肽自组装使线粒体膜电位去极化并促进 ROS 形成。该肽与三种不同的化疗药物共同孵育显着增强了这些药物的抗癌活性。