Abstract
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, induces intramitochondrial lysosome-like organella that 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 was not related to canonical autophagy. MALM is involved in the degradation of oxidized mitochondrial proteins, leading to increased ATP synthesis and decreased reactive oxygen species generation. These results suggest that Mieap induces intramitochondrial lysosome-like organella that plays a critical role in mitochondrial quality control by eliminating oxidized mitochondrial proteins. Cancer cells might accumulate unhealthy mitochondria due to p53 mutations and/or Mieap methylation, representing a potential cause of the Warburg effect.
Highlights
In aerobic eukaryotic cells, the energy source is the mitochondria, which produce ATP by oxidative phosphorylation [1]
Several yeast studies have suggested that mitochondrial autophagy is mediated by macroautophagy [11,35], and studies on mammalian cells have supported this finding [29,36]
It has been suggested that some type of mitophagy can be mediated by the selective macroautophagy of mitochondria
Summary
The energy source is the mitochondria, which produce ATP by oxidative phosphorylation [1]. These cytoplasmic organelles are essential for growth, division, and energy metabolism in aerobic eukaryotic cells. Each cell contains hundreds of mitochondria, and without these organelles, even cancer cells are unable to grow and survive in vivo [2]. Mitochondria play a pivotal role in apoptosis [3]. The functional and physical interplay of the Bcl-2 family of proteins, including Bax and Bak, in the mitochondria promotes the opening of the outer membrane pore, leading to the release of cytochrome c, caspase activation, and apoptosis. Deficits in mitochondrial function have been implicated in various human degenerative diseases, aging, and cancer [5,6]
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