Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria. BNIP3 and NIX are critical mediators for the Mieap-regulated mitochondrial quality control. Mieap suppresses murine intestinal tumor via its mitochondrial quality control function. To explore the role of the Mieap-regulated mitochondria quality control function in colorectal cancer patients, we examined the statuses of p53, Mieap, BNIP3 and NIX in 57 primary colorectal cancer tissues. Promoter methylation of the Mieap and BNIP3 genes was found in 9% and 47% of colorectal cancer cases, respectively, whereas p53 mutation was found in more than 50% of colorectal cancer tissues lacking methylation of the Mieap and BNIP3 promoters, implying that the p53/Mieap/BNIP3-regulated mitochondria quality control pathway is inactivated in more than 70% of colorectal cancer patients. In LS174T colorectal cancer cells, hypoxia activated the Mieap-regulated mitochondria quality control function. Knockdown of p53, Mieap or BNIP3 in LS174T cells severely impaired the hypoxia-activated function, leading to the accumulation of unhealthy mitochondria and increase of mitochondrial reactive oxygen species generation. The mitochondrial reactive oxygen species generated by unhealthy mitochondria in the p53/Mieap/BNIP3-deficient cells remarkably enhanced cancer cell migration and invasion under hypoxic condition. These results suggest that the Mieap-regulated mitochondria quality control has a critical role in colorectal cancer suppression in the in vivo hypoxic tumor microenvironment.
Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria via Mieap-induced accumulation of lysosome-like organelles within mitochondria (MALM) or Mieap-induced vacuole (MIV), respectively (1-4). BNIP3 and NIX are essential mediators of MALM. MIV generation is closely related to the endocytic pathway. However, the mechanism of MALM and MIV function and of their selection and regulation remains unclear. UVRAG was identified as a Mieap-interacting protein. UVRAG plays a role in canonical autophagy through the endocytic pathway. Interestingly, Mieap α, but not Mieap β, specifically interacts with UVRAG. Knockdown of UVRAG severely inhibited MIV generation induced by Mieap α. On the other hand, endogenous Mieap β, but not Mieap α, accumulated at and within mitochondria during the MALM process. These results, taken together, suggest that Mieap α has a specific role in MIV generation through an interaction with UVRAG by regulating the endocytic pathway. In addition, UVRAG and Mieap are inactivated in human cancers including colorectal cancer patients, suggesting that the MIV regulated by the interaction of Mieap and UVRAG may play a role in tumor suppression. In this paper, we discuss several possible mechanisms for the selection of MALM or MIV and the role of Mieap/UVRAG in tumorigenesis on the basis of our recent data. 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, Noriaki Kitamura, Hitoya Sano, Hirofumi Arakawa. Specific role of Mieap α in Mieap-induced vacuole generation through an interaction with UVRAG. [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 318. doi:10.1158/1538-7445.AM2014-318
Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria via MALM (Mieap-induced Accumulation of Lysosome-like organelles within Mitochondria) or MIV (Mieap-Induced Vacuole), respectively (1, 2). Two mitochondrial outer membrane proteins, BNIP3 and NIX are essential mediators of MALM (3). Previously, we reported that the Mieap-regulated mitochondrial quality control (MQC) pathway was inactivated in almost 80% of colorectal cancer patients. To evaluate the role of the Mieap-regulated MQC in pancreatic and breast cancer, we analyzed the status of p53, Mieap, BNIP3 and NIX in 50 cases of primary pancreatic cancer and 63 cases of primary breast cancer by examining p53 mutation and Mieap/BNIP3/NIX promoter methylation. As the result, the Mieap-regulated MQC pathway was inactivated in 71% of pancreatic and 27% of breast cancer patients. Interestingly, the BNIP3 promoter methylation was frequently detected in colorectal and pancreatic cancer patients (49% and 58%, respectively) whereas it was not detected in breast cancer patients at all (0%). Instead, the Mieap promoter methylation was highly detected in breast cancer patients (12.7%) compared to colorectal and pancreatic cancer patients (8.8% and 2.0%, respectively). These results suggest that the Mieap-regulated MQC pathway plays a critical role in tumorigenesis of pancreatic and breast cancer, and that there may be some different mechanisms between colorectal/pancreatic and breast cancers for inactivation of the Mieap-regulated MQC pathway. Inactivation of Mieap-regulated MQC pathway leads to the accumulation of unhealthy mitochondria generating high level of mitochondrial reactive oxygen species. We are now investigating whether the p53/Mieap/BNIP3 MQC pathway affects cell growth, cell motility or tumorigenicity using several pancreatic and breast cancer cell lines that are subcutaneously implanted into nude mice. In this paper, we discuss the potential role of the Mieap-regulated MQC in pancreatic and breast 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 Citation Format: Hiroki Kamino, Yasuyuki Nakamura, Hitoya Sano, Ryuya Murai, Yuri Saito, Manabu Futamura, Kazuhiro Yoshida, Nobuyoshi Hiraoka, Yae Kanai, Ryoji Kushima, Toyomasa Katagiri, Hirofumi Arakawa. Frequent inactivation of the Mieap-regulated mitochondrial quality control in pancreatic and breast cancer. [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 320. doi:10.1158/1538-7445.AM2014-320
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
Recently, we discovered a novel mechanism for mitochondrial quality control (MQC), in which Mieap, a p53-inducible protein, controls MQC by repairing or eliminating unhealthy mitochondria in a process known as MALM (Mieap-induced Accumulation of Lysosome-like organelles within Mitochondria) or MIV (Mieap-Induced Vacuole), respectively (1, 2). We also reported that two mitochondrial outer membrane proteins, BNIP3 and NIX, are essential mediators of the MALM (2, 3). To examine the role of Mieap-regulated MQC pathway in tumorigenesis, we analyzed the status of p53, Mieap, BNIP3, and NIX in 57 cases of primary colorectal cancer. Of the 57 patients, Mieap and BNIP3 promoter methylation was observed in 5 (8.8%) and 26 (45.6%) patients, respectively. A p53 mutation was detected in 4 (18%) of the 22 patients with either Mieap or BNIP3 promoter methylation whereas it was found in 9 (52%) of the 17 patients with neither Mieap nor BNIP3 promoter methylation, implying that the p53/Mieap/BNIP3 pathway in the Mieap-regulated MQC is inactivated in at least 80% of colorectal cancer cases. Hypoxia induced MALM in the colorectal cancer cell line LS174T (wild-type p53, Mieap-positive, BNIP3-positive). In vitro knockdown of p53, Mieap, or BNIP3 in the LS174T cells severely inhibited hypoxia-induced MALM, leading to the accumulation of unhealthy mitochondria and increased mitochondrial reactive oxygen species (mtROS) generation. Furthermore, the mtROS dramatically enhanced cancer migration and invasion under hypoxic conditions. These results suggest that the Mieap-regulated MQC function plays a critical role in tumor suppression in colorectal cancer. 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 Citation Format: Hiroki Kamino, Yasuyuki Nakamura, Noriaki Kitamura, Manabu Futamura, Masaki Yoshida, Ryuya Murai, Yuri Saito, Hitoya Sano, Yae Kanai, Yoshihiro Moriya, Hirofumi Arakawa. Frequent inactivation of the Mieap-regulated mitochondrial quality control in colorectal cancer. [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 1687. doi:10.1158/1538-7445.AM2013-1687
The accumulation of unhealthy mitochondria results in mitochondrial dysfunction, which has been implicated in aging, cancer, and a variety of degenerative diseases. However, the mechanism by which mitochondrial quality is regulated remains unclear. Here, we show that Mieap, a novel p53-inducible protein, plays a critical role in mitochondrial quality control. Mieap expression is directly regulated by p53 and is frequently lost in human cancer as result of DNA methylation. Mieap dramatically induces the accumulation of lysosomal proteins within mitochondria and mitochondrial acidic condition without destroying the mitochondrial structure (designated MALM, for Mieap-induced accumulation of lysosome-like organelles within mitochondria) in response to mitochondrial damage. MALM is involved in the degradation of oxidized mitochondrial proteins, leading to increased ATP synthesis and decreased reactive oxygen species generation. However, when MALM is inhibited, Mieap induces vacuole-like structures (designated as MIV for Mieap-induced vacuole), which engulf and degrade the unhealthy mitochondria by accumulating lysosomes. The inactivation of p53 severely impairs both MALM and MIV generation. These results suggest that Mieap plays a pivotal role in mitochondrial quality control by repairing or eliminating unhealthy mitochondria via MALM or MIV generation, respectively. Cancer cells might accumulate unhealthy mitochondria due to p53 mutations and/or Mieap methylation, representing a potential cause of the Warburg effect. Citation Format: Yasuyuki Nakamura, Hiroki Kamino, Hitoya Sano, Hirofumi Arakawa. Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy 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 LB-131. doi:10.1158/1538-7445.AM2013-LB-131
Recently, we discovered a novel mechanism for mitochondrial quality control (MQC), in which Mieap, a p53-inducible protein, controls MQC by repairing or eliminating unhealthy mitochondria via MALM (Mieap-induced Accumulation of Lysosome-like organelles within Mitochondria) or MIV (Mieap-Induced Vacuole) generation, respectively (1, 2). We also reported that two mitochondrial outer membrane proteins, BNIP3 and NIX, are essential mediators of the MALM (2, 3). To examine the role of Mieap-regulated MQC pathway in tumorigenesis, we analyzed the status of p53, Mieap, BNIP3, and NIX in 50 cases of primary gastric cancer. Of the 50 patients, Mieap and BNIP3 promoter methylation was observed in 2 (4%) and 29 (58%) patients, respectively. A p53 mutation was detected in 2 (10%) of the 20 patients with either Mieap or BNIP3 promoter methylation whereas it was found in 3 (15.8%) of the 19 patients with neither Mieap nor BNIP3 promoter methylation, implying that the p53/Mieap/BNIP3 MQC pathway is inactivated in at least 70% of gastric cancer cases. In a colorectal cancer cell line, hypoxia induced MALM. Knockdown of p53, Mieap, or BNIP3 in the cell line severely inhibited hypoxia-induced MALM, leading to the accumulation of unhealthy mitochondria and increased mitochondrial reactive oxygen species (mtROS) generation. Furthermore, the mtROS dramatically enhanced cancer migration and invasion in hypoxic conditions. These results suggest that the p53/Mieap/BNIP3 MQC pathway plays a tumor-suppressive role in gastric cancer. 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 Citation Format: Hitoya Sano, Hiroki Kamino, Yasuyuki Nakamura, Masaki Yoshida, Ryuya Murai, Yuri Saito, Manabu Futamura, Kazuhiro Yoshida, Hirofumi Arakawa. Frequent inactivation of the p53/Mieap/BNIP3 mitochondrial quality control pathway in gastric cancer. [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 LB-132. doi:10.1158/1538-7445.AM2013-LB-132
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