Lon protease, an ATP-dependent mitochondrial protease, is important in mitochondrial protein maintenance. Lon protease is a multifunctional enzyme, and its functions include the degradation of damaged proteins and naturally short-lived proteins, ATPase and chaperone-like activities, as well as DNA binding. Lon protease plays a major role in the protein quality control system in mammalian cell mitochondria. It is present in the mitochondrial matrix and degrades oxidized and misfolded proteins, thereby protecting the cell from various extracellular stresses, including oxidative stress. The intellectual disability-associated and thalidomide-binding protein cereblon (CRBN) contains a large, highly conserved Lon domain. The Lon ATP-dependent protease plays an important role in regulating many biological processes in bacteria.