Research Center for Clinical Pharmacy & Key Laboratory for Drug Evaluation and Clinical Research of Zhejiang Province, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Department of Biochemistry & Molecular Medical Center, Zhejiang University School of Medicine, Hangzhou, China.
Autophagy. 2021 Mar;17(3):818-819. doi: 10.1080/15548627.2020.1860542. Epub 2020 Dec 20.
Mitochondrial dysfunction is associated with the occurrence of a variety of neurodegenerative diseases, especially Alzheimer disease (AD). As a mitochondrial quality control process, mitophagy is greatly inhibited in AD; increasing evidence shows that the induction of mitophagy is an effective therapeutic intervention strategy. However, the lack of more safe, effective, and clear mechanisms for mitophagy inducers has limited the clinical application. In recent studies, we have identified a small molecule compound, UMI-77, that can safely and effectively induce mitophagy. UMI-77 is an established BH3-mimetic for MCL1 and was developed to induce apoptosis in cancer cells. We found that UMI-77 can bind MCL1 and enhance its function as a mitophagy receptor protein, thus enhancing its interaction with LC3A to induce mitophagy. UMI-77 effectively improves the cognitive decline seen in an AD mouse model. Our findings shed light on the novel mechanisms of mitophagy, reveal that MCL1 is a mitophagy receptor that can be targeted to induce mitophagy, and identify MCL1 as a drug target for therapeutic intervention in AD.
线粒体功能障碍与多种神经退行性疾病的发生有关，尤其是阿尔茨海默病（AD）。作为一种线粒体质量控制过程，自噬在 AD 中受到极大抑制；越来越多的证据表明，诱导自噬是一种有效的治疗干预策略。然而，缺乏更安全、有效和明确的自噬诱导剂机制限制了其临床应用。在最近的研究中，我们已经确定了一种小分子化合物 UMI-77，它可以安全有效地诱导自噬。UMI-77 是 MCL1 的一种已建立的 BH3 模拟物，用于诱导癌细胞凋亡。我们发现 UMI-77 可以与 MCL1 结合并增强其作为自噬受体蛋白的功能，从而增强其与 LC3A 的相互作用以诱导自噬。UMI-77 可有效改善 AD 小鼠模型中的认知能力下降。我们的研究结果揭示了自噬的新机制，表明 MCL1 是一种可以作为靶点诱导自噬的自噬受体，并确定 MCL1 是 AD 治疗干预的药物靶点。
