Abstract 1900: Hypoxia induces accumulation of lysosomal proteins within mitochondria.

Abstract

Mitochondrial quality control (MQC) plays a critical role in maintaining a healthy status of mitochondria, preventing aging, cancer, and a variety of degenerative diseases. However, the mechanism largely remains unclear. Recently, we discovered a novel MQC mechanism regulated by Mieap, a p53-inducible protein, in which Mieap induces intramitochondrial lysosome-like organella that plays a critical role in the elimination of oxidized mitochondrial proteins (designated MALM for Mieap-induced accumulation of lysosome-like organelles within mitochondria) in response to mitochondrial damage (1-4). Here, we report a physiological role of the MALM function. Hypoxia dramatically induced accumulation of lysosomal proteins within mitochondria without the destruction of mitochondrial structure in both human normal mammary epithelial cells (HMEC4s) and mouse embryonic fibroblasts cells (MEFs). In response to the hypoxic stress, the MALM was inducible in ATG5-KO, ATG7-KO, and PINK1-KO MEFs, but not in p53-KO and Mieap-KO MEFs, suggesting that the phenomenon is completely different from canonical autophagy. In the MALM-deficient cells, hypoxia caused an increase of mitochondrial reactive oxygen species (ROS) generation and accumulation of oxidized proteins within the mitochondria. Surprisingly, the MALM-deficient cells in the hypoxic condition revealed enhanced activities of cell migration and invasion. This phenotype was totally cancelled by a ROS scavenger reagent, Ebselen. These results suggest that the MALM is a universal and fundamental function in the cell (at least from mouse to human), which plays a critical role in MQC under hypoxia. Alteration of the MALM function in cancer cells could facilitate cancer invasion and metastasis via mitochondrial ROS generated by unhealthy mitochondria. 1. Miyamoto Y et al. PLoS ONE 6: e16054, 2011 2. Kitamura N et al. PLoS ONE 6: e16060, 2011 3. Nakamura Y et al. PLoS ONE 7: e30767, 2012 4. Miyamoto T et al. Sci Rep 2: 379, 2012 Citation Format: Yasuyuki Nakamura, Masaki Yoshida, Noriaki Kitamura, Hiroki Kamino, Ryuya Murai, Yuri Saito, Hitoya Sano, Hirofumi Arakawa. Hypoxia induces accumulation of lysosomal proteins within mitochondria. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1900. doi:10.1158/1538-7445.AM2013-1900