Abstract 2465: p53-dependent and independent functions of Mieap

Abstract

Abstract Mieap, a p53-inducible protein, plays a pivotal role in mitochondrial quality control (MQC) by repairing or eliminating unhealthy mitochondria1-4. To investigate physiological significance of the Mieap-regulated MQC, we generated and analyzed the Mieap-KO mice. (1) p53-dependent: Hypoxia induced Mieap expression and accumulation of lysosomal proteins within mitochondria in WT MEFs, but not Mieap-/- and p53-/- MEFs. Mieap-/- and p53-/- MEFs exhibited accumulation of oxidized mitochondrial proteins and increased ROS generation by unhealthy mitochondria under hypoxia, which enhanced cell migration and invasion. (2) p53-dependent: Mieap+/- / ApcMIN/+ mice displayed a shortening of the lifetime, compared to the ApcMIN/+ mice (average life-span: Mieap+/- / ApcMIN/+ mice vs ApcMIN/+ mice = 19.1 weeks vs 24.4 weeks), suggesting that Mieap deficiency may affect intestinal tumorigenesis. (3) p53-independent: Mieap was highly expressed in the midpiece, where the sperm mitochondria are localized, of the sperm in WT mice. This Mieap expression was independent on p53. Mieap-/- mice are fertile in vivo. However, in vitro fertilization of Mieap-/- sperm was severely impaired because of a failure of sperm motility. The oxidized proteins were dramatically accumulated in the midpiece of Mieap-/- sperm. These results, taken together, suggest that Mieap plays a crucial role in protection of the cell against oxidative stresses probably through its MQC function. This may also largely contribute to p53 tumor suppression. 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, Hiroki Kamino, Yuri Saito, Hitoya Sano, Hirofumi Arakawa. p53-dependent and independent functions of Mieap. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2465. doi:10.1158/1538-7445.AM2014-2465