Abstract
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.
Highlights
Mieap, a p53-inducible protein, was recently identified as an important regulator of a novel mitochondrial quality control system.[1,2,3,4] We previously reported that Mieap regulates mitochondrial quality via two mechanisms.[1,2] One of the mechanisms, designated MALM (Mieap-induced Accumulation of Lysosomal proteins within Mitochondria), involves the repair of unhealthy mitochondria.[1]
We reported that Bcl-2/adenovirus E1B kDa interacting protein 3 (BNIP3) and NIX interact with Mieap in response to various artificial cellular stresses and mediate induction of the MALM, suggesting that BNIP3 and NIX have a critical role in the Mieap-regulated mitochondrial quality control pathway.[2,3]
As Mieap expression is inactivated in more than 60% of cancer cell lines owing to the promoter methylation,[1] we speculated that methylation of the BNIP3 and/or NIX promoters could be involved in the inactivation of the Mieap-regulated mitochondrial quality control pathway
Summary
A p53-inducible protein, was recently identified as an important regulator of a novel mitochondrial quality control system.[1,2,3,4] We previously reported that Mieap regulates mitochondrial quality via two mechanisms.[1,2] One of the mechanisms, designated MALM (Mieap-induced Accumulation of Lysosomal proteins within Mitochondria), involves the repair of unhealthy mitochondria.[1] In this mechanism, Mieap induces the accumulation of lysosomal proteins within the unhealthy mitochondria that produce high level of reactive oxygen species (ROS) to eliminate oxidized mitochondrial proteins.[1] This process leads to a reduction of ROS generation and a restoration of mitochondrial adenosine triphosphate synthesis activity,[1] thereby mediating the repair process of unhealthy mitochondria. The MIV (Mieap-induced vacuole) mechanism occurs,[2] when MALM is blocked. In the MIV mechanism, Mieap induces a vacuole-like structure known as MIV in the cytoplasm.[2] The MIV engulfs the severely damaged mitochondria and accumulates lysosomes, leading to the degradation of unhealthy mitochondria.[2]
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