Abstract
Abstract Background: Mitochondria-eating protein (Mieap), a p53-inducible protein is known to have tumor suppressive functions by repairing or degrading unhealthy mitochondria. When Mieap degrades mitochondria, Mieap-induced vacuoles (MIVs) are formed to eat mitochondria, which subsequently induce iron-dependent cell death. Previously, we elucidated that the MIVs contain lysosomal proteins and degraded mitochondria, suggesting the MIVs represent non-canonical mitophagy. However, the process of MIV formation is still unclear. Methods: The process of MIV formation was visualized by high spatial and temporal resolution confocal live cell imaging with the EGFP-tagged Mieap protein (EGFP-Mieap) that was ectopically expressed in A549 cells. To interpret the imaging data, we performed the Mieap-interactome analysis, and consulted the list of proteins immunoprecipitated by anti-Mieap antibody. Further, we investigated the mechanism for MIV formation using various deletion-mutant forms of EGFP-Mieap. Results: The enforced expression of EGFP-Mieap generated characteristic endosomes whose membrane contained Mieap. The unique endosomes showed directed movement toward clusters of mitochondria, where MIVs were generated, and enlarged by eating mitochondria and fusing to each other. When we reviewed the list of Mieap-interacting proteins considering the directed movement, alpha tubulins were found to be included. The endosomes consisting of C-terminus deficient Mieap showed nondirected movement and accumulated at the edge of the cells. Conclusions: Besides lysosomes and mitochondria, MIVs are derived from the Mieap-related endosomes via the endocytosis/pinocytosis. Possibly, the interaction between the C-terminus region of Mieap and alpha tubulins is critical for the endosome delivery to the mitochondria in MIV formation. Citation Format: Naoki Ikari, Yasuyuki Nakamura, Hirofumi Arakawa. Involvement of unique endosomes in the Mieap-induced vacuoles formation during Mieap-mediated cancer cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 814.
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