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Mitochondria play a primary role in cellular bioenergetics Protein homeostasis within mitochondria matrix is essential for the tumor viability.As a ATP-dependent protease located in mitochondrial matrix,Lon contributes to the degradation of abnormal proteins.Although the majority of Lon is located in mitochondrial matrix,it is also found in mitochondrial nucleoids.Lon is a stress protein and can be induced by lots of stresses such as hypoxia.The Lon up-regulation may be critical for cancer cell survival by preventing abnormal mitochondrial proteins accumulation and aggregation in response to oxidative,hypoxic,and ER stress.Our recent studies demonstrated that Lon expression was increased in cervical cancer tissues and Lon may serve as a potential therapeutic target in cervical cancer.we knocked down Lon and found drastically reduction of cancer cell proliferation and cell growth.The mtDNA encoded subunit Ⅱ of COX and the nuclear-encoded Subunit Ⅳ and Ⅴ of COX were rapidly reduced under ER stress.During hypoxia,HIF-1 activates the LON gene transcription to up-regulate Lon expression.Increased Lon degrades COX4-1 to facilitate the switch from COX4-1 to more efficient COX4-2 to challenge the low oxygen by enhancing mitochondrial respiration.Thus,Lon mediated protein degradation can relieve the heavy load of abnormal mitochondrial proteins accumulation.Moreover,down-regulation of Lon decreased mitochondrial ROS production and blocks JNK activation.we proposed that the down-regulation of Lon leads to the impairment of mitochondrial respiratory chain complexes and inhibits the mitochondrial ROS production to inhibit cancer cell proliferation.Surprisingly,Lonp1deletion causes embryonic lethality which indicated that Lon may play crucial role in embryonic development.Together,we suggest that Lon could serve as a potential diagnostic biomarker and therapeutic target for cancer treatment.