Discovery of Mieap-regulated mitochondrial quality control as a new function of tumor suppressor p53

Abstract

The tumor suppressor p53 gene is frequently mutated in human cancers, and the p53 protein suppresses cancer. However, the mechanism behind the p53-mediated tumor suppression is still unclear. Recently, Mieap (the mitochondria-eating protein) was identified as a p53-inducible protein. Mieap induces the accumulation of lysosomal proteins within mitochondria (MALM: Mieap-induced accumulation of lysosome-like organelles within mitochondria) in response to mitochondrial damage, and eliminates the oxidized mitochondrial proteins to repair unhealthy mitochondria. Furthermore, Mieap also induces vacuole-like structures (MIV: Mieap-induced vacuole) to eat and degrade unhealthy mitochondria. Therefore, Mieap controls mitochondrial quality by repairing or eliminating unhealthy mitochondria via MALM or MIV, respectively. This mechanism is not mediated by canonical autophagy. Mieap-deficient Apc^Min/+ mice exhibit strikingly high rates of intestinal tumor development as wells as advanced-grade adenomas and adenocarcinomas. The p53/Mieap/BNIP3 mitochondrial quality control pathway is frequently inactivated in human colorectal cancers. Defects in the Mieap-regulated mitochondrial quality control lead to accumulation of unhealthy mitochondria in cancer cells. Cancer-specific unhealthy mitochondria could contribute to cancer development and aggressiveness via mitochondrial reactive oxygen species and altered metabolism. Mieap-regulated mitochondrial quality control is a newly discovered function of p53 and plays a critical role in tumor suppression.

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