Mitochondrial Regulation of Cell Cycle and Proliferation

Eukaryotic mitochondria resulted from symbiotic incorporation of α-proteobacteria into ancient archaea species. During evolution, mitochondria lost most of the prokaryotic bacterial genes and only conserved a small fraction including those encoding 13 proteins of the respiratory chain. In this process, many functions were transferred to the host cells, but mitochondria gained a central role in the regulation of cell proliferation and apoptosis, and in the modulation of metabolism; accordingly, defective organelles contribute to cell transformation and cancer, diabetes, and neurodegenerative diseases. Most cell and transcriptional effects of mitochondria depend on the modulation of respiratory rate and on the production of hydrogen peroxide released into the cytosol. The mitochondrial oxidative rate has to remain depressed for cell proliferation; even in the presence of O2, energy is preferentially obtained from increased glycolysis (Warburg effect). In response to stress signals, traffic of pro- and antiapoptotic mitochondrial proteins in the intermembrane space (B-cell lymphoma-extra large, Bcl-2-associated death promoter, Bcl-2 associated X-protein and cytochrome c) is modulated by the redox condition determined by mitochondrial O2 utilization and mitochondrial nitric oxide metabolism. In this article, we highlight the traffic of the different canonical signaling pathways to mitochondria and the contributions of organelles to redox regulation of kinases. Finally, we analyze the dynamics of the mitochondrial population in cell cycle and apoptosis. Antioxid. Redox Signal. 16, 1150–1180. I. Introduction II. Introduction to Mitochondrial Biology A. The physiology of mitochondria and redox biology B. NO and mitochondrial redox metabolism C. H2O2 and antagonistic antioxidant enzymes D. The intermembrane space and the redox status III. Mitochondrial Metabolism and Cell Proliferation A. The Warburg effect: The mitochondrial control of proliferation B. Mitochondria and redox control in normal and tumor cells C. Stem cells, mitochondrial ROS metabolism, and differentiation D. ROS and mitochondrial malignancy: The example of p53 E. The glycolytic effects for mitochondrial oxidative rate F. Mitochondrial signaling in hypoxia G. Mechanistic target of rapamycin (serine/threonine kinase)/Akt pathways H. Hexokinase I. The regulation of glycolysis and proliferation by the ubiquitination system IV. ROS: From Proliferation to Cell Death V. Kinases, Mitochondria, and Cell Cycle A. The MAPK cascade B. Akt/protein kinase B C. Protein kinase C D. Protein kinase A VI. Mitochondrial Biogenesis A. Transcriptional control of mitochondrial biogenesis B. Mitochondrial biogenesis, NO, and ROS VII. Mitochondrial Dynamics A. Mitochondrial fusion B. Mitochondrial fusion machinery and apoptosis C. Mitochondrial fission D. Mitochondrial fission machinery and apoptosis E. Mitochondrial dynamics, NO, and ROS VIII. Mitochondrial Biogenesis, Mitochondrial Dynamics, and Cell Cycle IX. Concluding Remarks