Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea.
Center for Wave Energy Materials, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea.
Nat Commun. 2021 Jan 4;12(1):26. doi: 10.1038/s41467-020-20210-3.
Mitochondrial oxidation-induced cell death, a physiological process triggered by various cancer therapeutics to induce oxidative stress on tumours, has been challenging to investigate owing to the difficulties in generating mitochondria-specific oxidative stress and monitoring mitochondrial responses simultaneously. Accordingly, to the best of our knowledge, the relationship between mitochondrial protein oxidation via oxidative stress and the subsequent cell death-related biological phenomena has not been defined. Here, we developed a multifunctional iridium(III) photosensitiser, Ir-OA, capable of inducing substantial mitochondrial oxidative stress and monitoring the corresponding change in viscosity, polarity, and morphology. Photoactivation of Ir-OA triggers chemical modifications in mitochondrial protein-crosslinking and oxidation (i.e., oxidative phosphorylation complexes and channel and translocase proteins), leading to microenvironment changes, such as increased microviscosity and depolarisation. These changes are strongly related to cell death by inducing mitochondrial swelling with excessive fission and fusion. We suggest a potential mechanism from mitochondrial oxidative stress to cell death based on proteomic analyses and phenomenological observations.
线粒体氧化诱导的细胞死亡是一种生理过程，多种癌症疗法通过诱导肿瘤氧化应激来触发这种过程，但由于难以产生线粒体特异性氧化应激和同时监测线粒体反应，因此一直难以研究。因此，据我们所知，氧化应激导致的线粒体蛋白氧化与随后的细胞死亡相关生物学现象之间的关系尚未确定。在这里，我们开发了一种多功能铱（III）光增敏剂 Ir-OA，它能够诱导大量的线粒体氧化应激，并监测相应的粘度、极性和形态变化。Ir-OA 的光激活引发线粒体蛋白交联和氧化的化学修饰（即氧化磷酸化复合物以及通道和转位酶蛋白），导致微环境变化，例如增加微粘度和去极化。这些变化与通过过度分裂和融合导致线粒体肿胀的细胞死亡密切相关。我们基于蛋白质组学分析和现象学观察提出了一种从线粒体氧化应激到细胞死亡的潜在机制。
