Hu Dongxue, Yang Qiaoyun, Xian Hongxu, Wang Minghao, Zheng Hong, Mallilankaraman Karthik Babu, Yu Victor C, Liou Yih-Cherng
Department of Biological Sciences Faculty of Science National University of Singapore Singapore Singapore.
Department of Pharmacology School of Medicine University of California San Diego La Jolla California USA.
MedComm (2020). 2025 May 10;6(5):e70214. doi: 10.1002/mco2.70214. eCollection 2025 May.
Mitochondrial homeostasis is essential for cell survival and function, necessitating quality control mechanisms to ensure a healthy mitochondrial network. Death-associated protein 3 (DAP3) serves as a subunit of the mitochondrial ribosome, playing a pivotal role in the translation of mitochondrial-encoded proteins. Apart from its involvement in protein synthesis, DAP3 has been implicated in the process of cell death and mitochondrial dynamics. In this study, we demonstrate that DAP3 mediates cell death via intrinsic apoptosis by triggering excessive mitochondrial fragmentation, loss of mitochondrial membrane potential (Δm), ATP decline, and oxidative stress. Notably, DAP3 induces mitochondrial fragmentation through the Mitochondrial Rho GTPase 1 (Miro1), independently of the canonical fusion/fission machinery. Mechanistically, DAP3 promotes mitochondrial calcium accumulation through the MCU complex, leading to decreased cytosolic Ca levels. This reduction in cytosolic Ca is sensed by Miro1, which subsequently drives mitochondrial fragmentation. Depletion of Miro1 or MCU alleviates mitochondrial fragmentation, oxidative stress, and cell death. Collectively, our findings reveal a novel function of the mitoribosomal protein DAP3 in regulating calcium signalling and maintaining mitochondrial homeostasis.
线粒体稳态对于细胞存活和功能至关重要，因此需要质量控制机制来确保线粒体网络的健康。死亡相关蛋白3（DAP3）作为线粒体核糖体的一个亚基，在线粒体编码蛋白的翻译中起关键作用。除了参与蛋白质合成外，DAP3还与细胞死亡和线粒体动力学过程有关。在本研究中，我们证明DAP3通过触发过度的线粒体碎片化、线粒体膜电位（Δm）丧失、ATP下降和氧化应激，经由内源性凋亡介导细胞死亡。值得注意的是，DAP3通过线粒体Rho GTP酶1（Miro1）诱导线粒体碎片化，独立于经典的融合/分裂机制。机制上，DAP3通过MCU复合体促进线粒体钙积累，导致胞质Ca水平降低。Miro1感知到这种胞质Ca的减少，随后驱动线粒体碎片化。敲低Miro1或MCU可减轻线粒体碎片化、氧化应激和细胞死亡。总的来说，我们的研究结果揭示了线粒体核糖体蛋白DAP3在调节钙信号和维持线粒体稳态方面的新功能。
