Mitochondriai transcription factor A (TFAM), a member of high-mobility group (HMG) protein family encoded by the nuclear genome and transported into the mitochondrial matrix, which is essential for the replication, transcription and maintenance ofmitochondrial DNA (mtDNA).We recently reported that Lon protease degrades TFAM in cells with severe mtDNA deficits and the degradation of TFAM is blocked by several anti-cancer drugs.TFAM knockout in mice causes mtDNA depletion and abolishes oxidative phosphorylation, which leads to embryonic lethality.The heart-specific knockout mice exhibit the phenotype of heart failure and premature aging.