Hypoxia-reprogramed megamitochondrion contacts and engulfs lysosome to mediate mitochondrial self-digestion

Tianshu Hao, Jianglong Yu, Zhida Wu, Jie Jiang, Longlong Gong, Bingjun Wang, Hanze Guo, Huabin Zhao, Bin Lu, Simone Engelender, He He () and Zhiyin Song ()
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Tianshu Hao: Renmin Hospital of Wuhan University, Wuhan University
Jianglong Yu: Renmin Hospital of Wuhan University, Wuhan University
Zhida Wu: Renmin Hospital of Wuhan University, Wuhan University
Jie Jiang: Renmin Hospital of Wuhan University, Wuhan University
Longlong Gong: Renmin Hospital of Wuhan University, Wuhan University
Bingjun Wang: Renmin Hospital of Wuhan University, Wuhan University
Hanze Guo: Renmin Hospital of Wuhan University, Wuhan University
Huabin Zhao: Renmin Hospital of Wuhan University, Wuhan University
Bin Lu: University of South China
Simone Engelender: Rappaport Faculty of Medicine, Technion-Israel Institute of Technology
He He: Renmin Hospital of Wuhan University, Wuhan University
Zhiyin Song: Renmin Hospital of Wuhan University, Wuhan University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-39811-9

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