College of Life Sciences, Taikang center for life and medical sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, 430072, Hubei, China.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
Nat Commun. 2023 Jul 11;14(1):4105. doi: 10.1038/s41467-023-39811-9.
Mitochondria are the key organelles for sensing oxygen, which is consumed by oxidative phosphorylation to generate ATP. Lysosomes contain hydrolytic enzymes that degrade misfolded proteins and damaged organelles to maintain cellular homeostasis. Mitochondria physically and functionally interact with lysosomes to regulate cellular metabolism. However, the mode and biological functions of mitochondria-lysosome communication remain largely unknown. Here, we show that hypoxia remodels normal tubular mitochondria into megamitochondria by inducing broad inter-mitochondria contacts and subsequent fusion. Importantly, under hypoxia, mitochondria-lysosome contacts are promoted, and certain lysosomes are engulfed by megamitochondria, in a process we term megamitochondria engulfing lysosome (MMEL). Both megamitochondria and mature lysosomes are required for MMEL. Moreover, the STX17-SNAP29-VAMP7 complex contributes to mitochondria-lysosome contacts and MMEL under hypoxia. Intriguingly, MMEL mediates a mode of mitochondrial degradation, which we termed mitochondrial self-digestion (MSD). Moreover, MSD increases mitochondrial ROS production. Our results reveal a mode of crosstalk between mitochondria and lysosomes and uncover an additional pathway for mitochondrial degradation.
线粒体是感知氧气的关键细胞器，氧气通过氧化磷酸化被消耗以产生 ATP。溶酶体含有水解酶，可降解错误折叠的蛋白质和受损的细胞器，以维持细胞内环境稳定。线粒体与溶酶体在物理和功能上相互作用，以调节细胞代谢。然而，线粒体-溶酶体通讯的模式和生物学功能在很大程度上仍然未知。在这里，我们表明，缺氧通过诱导广泛的线粒体间接触和随后的融合，将正常的管状线粒体重塑为巨线粒体。重要的是，在缺氧条件下，促进了线粒体-溶酶体接触，并且某些溶酶体被巨线粒体吞噬，这一过程我们称之为巨线粒体吞噬溶酶体（MMEL）。巨线粒体和成熟的溶酶体都是 MMEL 所必需的。此外，STX17-SNAP29-VAMP7 复合物在缺氧条件下有助于线粒体-溶酶体接触和 MMEL。有趣的是，MMEL 介导了一种线粒体降解的模式，我们称之为线粒体自噬（MSD）。此外，MSD 增加了线粒体 ROS 的产生。我们的结果揭示了线粒体和溶酶体之间的一种串扰模式，并揭示了线粒体降解的另一种途径。
