Lon is a mitochondrial matrix protease that assists protein folding, degrades oxidized/damaged proteins. Lon overexpression promotes cell apoptotic resistance to stresses, and transformation. However, little literature undertakes detailed investigations on how Lon regulates apoptosis. Accumulating evidences indicate that the stress signals also induce transportation of p53 to mitochondria, leading to induction of apoptosis in a transcription-independent manner. Here, we found that overexpression of Lon increases p53 expression and knockdown of Lon reverses the effects in oral cancer cell lines. We observed that Lon interactes with p53 in mitochondrial and traps p53 to restrain the apoptosis induced by oxidative stress, suggesting that Lon overexpression inhibits apoptosis through interaction with and sequestering p53 in mitochondria. Indeed, the mRNA expression of p53 target genes is significantly reduced when overexpressed Lon traps p53 in mitochondria. In addition, the ATPase mutant of Lon decreases the interaction with p53 and fails to inhibit apoptosis. These findings suggest that targeting mitochondrial Lon will increase the efficacy of p53-induced apoptosis in cancer therapy.
