Lon protease 1 (LONP1) is an ATP-dependent protease located in the mitochondrial matrix and plays a crucial role in regulating mitochondrial proteostasis, metabolism, and cellular stress responses et al. Aberrant LONP1 expression has been found in the progression of various tumors
however, the role and molecular mechanisms of LONP1 in prostate cancer (PCa) remain poorly understood. Here we show that overexpression of LONP1 is closely related to adverse clinic pathological features and poor prognosis in PCa patients. Mechanistically, the findings reveal that LONP1 is implicated in modulating the metabolic switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, thereby promoting tumor proliferation, invasion, and metastasis both in vitro and in vivo. Meanwhile, we prove that LONP1 as a protease directly targets mitochondrial pyruvate carrier 1 (MPC1), a key metabolic protein in the process of glycolysis, and enhances its degradation, which in turn suppresses tricarboxylic acid (TCA) cycle and ultimately promotes the progression of PCa. Furthermore, using PCa in cancer-prone mice homozygous for a prostate-targeted conditional Pten knockout and Lonp1 knockin, we integrate transcriptomic and proteomic analyses of prostate tumors, upon which reveals that Lonp1 overexpression results in a significant downregulation of NADH: ubiquinone oxidoreductase activity, consequently impeding the electron transfer process and mitochondrial ATP synthesis, associated with metastasis of PCa. Collectively, our results highlight that metabolic reprogramming induced by LONP1 in PCa is closely coupled with disease progression, suggesting that targeting the LONP1-mediated cascade in the mitochondrial may provide therapeutic potential for PCa disease.