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Department of Biological SciencesHostile microenvironmental conditions within tumor masses, such as nutrient deprivation, oxygen limitation, high metabolic demand, and oxidative stress are provoking an adaptive mechanism. Interestingly, the emerging evidence strongly suggest that mitochondria, a hub subcellular organelle in regulating metabolism and apoptosis, endows malignant cells with greater tumorigenic, metastatic, and drug-resistant capacity. However, an exact role of mitochondrial stress response and interplay between these responses in coordination for mitochondrial functions in cancer progression remain largely unexplored. Here, we identified LONP1 and ClpP, mitochondrial proteases, retain mitochondrial protein homeostasis by degrading misfolded/unfolded proteins and sustains tumor survival. We found that LonP1 and ClpP are highly upregulated in most of human cancer and correlated with poor survival rate of cancer patients. LONP1 and ClpP were specifically overexpressed in prostate cancer cell lines in comparison to a normal cell. Downregulation of LONP1 and ClpP decrease tumor growth and induce the cancer cell death. Furthermore, we identified target substrate proteins of these proteases which related to tumor development and metabolic reprogramming by conducting APEX. Therefore, we assumed activities of LONP1 and ClpP are critical for the mitochondrial stress response to adapt diverse tumor microenvironment stress. Thus, targeting LONP1 and ClpP might be a promising way for cancer treatment.clos