Title:
Importance of mitochondrial genome in cellular functions: Energy, ROS, Aging and TFAM,

Dongchon Kang, MD, Ph.D
Department of Clinical Chemistry and Laboratory Medicine,
Kyushu University Graduate School of Medical Sciences,

Abstract:
Mitochondria have their own genome (mitochondrial DNA, mtDNA). This genome is essential for the mitochondrial respiratory chain which accounts for over 80% of ATP production. Thus, mitochondrial genome plays a critical role in energy metabolism and so is involved in the development of many lifestyle-related diseases. Mitochondria produce huge amount of reactive oxygen species inevitably along with the aerobic ATP production. The mitochondrial genome is, therefore, highly susceptible for oxidative damage. TFAM is a main protein component of a huge mtDNA-protein complex called “nucleoid”. TFAM plays an architectural role like nuclear histones. However, its precise mechanisms are not fully elucidated yet. To further know the role of TFAM in the maintenance of mtDNA and mitochondrial functions, we present two TFAM overexpression models: inducible TFAM expression in HeLa cells and transgenic mice overexpressing human TFAM. We examined (1) how TFAM affects mitochondrial transcription/replication states in the former and (2) whether TFAM protects the heart in the latter. The overexpression of TFAM could make an overpackaging of mtDNA, changed a D-loop state, and moudlated both transcription and replication in HeLa cells. In the transgenic mice, the TFAM overexpression attenuated the decrease in mtDNA copy number and mitochondrial complex enzyme activities in the failing hearts. This preservation in mtDNA copy number by TFAM attenuated cardiac dysfunction and structural alterations such as hypertrophy, apoptosis, and interstitial fibrosis in association with oxidative stress. In addition, the TFAM over-expression delays neurological dysfunctions caused by aging. Interestingly, the exogenously added TFAM protein enters into cells, accumulates in mitochondria, and shows similar effects observed in the overexpression model.