Masahiro Higuchi, Ph.D.  

Assistant Professor

Ph.D., University of Tokyo, Tokyo, Japan

Roles of mitochondria and mitochondrial DNA in apoptosis and cancer progression

Mitochondria are now considered a key organelle regulating apoptosis.
We showed that depletion of mitochondrial DNA (mtDNA) reduced apoptosis induced by specific mediators. Several characteristics associated with metastatic competence, such as invasion and overexpression of the tumor-specific regulator cathepsin L and transforming growth factor- can also be induced by depletion of mtDNA. Thus, mutation or loss of mtDNA could contribute to cancer development by inhibiting apoptosis or inducing metastatic competence. Certain cancers have a high frequency of large deletions in the mtDNA in addition to point mutants. Cells with a high proportion of large deletion mutant mtDNA lack some or most mtDNA-encoded proteins and therefore might show characteristics similar to those of cells with depleted mtDNA. Our studies are designed to investigate the mechanisms and the roles of accumulation of mutant mtDNA as a potential cause of cancer progression.

Selected Publications

Higuchi, M., Aggarwal, B. B. and Yeh, E. T. H.: Activation of CPP32-like protease in TNF-induced apoptosis is dependent on mitochondrial function. J. Clin. Invest. 99, 1751-1758 (1997)

Higuchi, M. Rita J. P. and Yeh E. T. H. : Inhibition of mitochondrial respiratory chain complex I by TNF results in cytochrome c release, membrane permeability transition, and apoptosis. Oncogene 17. 2515-2524 (1998)

Higuchi, M., Honda T., Rita, J. P. and Yeh E. T. H. Regulation of Reactive Oxygen Species-Induced Apoptosis and Necrosis by Caspase 3-like Proteases. Oncogene 17. 2753-2760 (1998)

Haridas V., Higuchi, M., Mujoo, K., Jayatilake G., Bailey, D., Blake M. E. and Gutterman J.U. Avicins: Novel triterpenoid saponins from Acacia vivtoriaeinduce apoptosis by mitochondrial perturbation. Proc. Natl. Acad. Sci. USA 98 5821-5826 (2001)

Nishimura G., Proske R. J., Doyama H, and Higuchi, M. Regulation of Apoptosis by Respiration : Cytochrome c Release by Respiratory Substrates. FEBS letter 505 398-404 (2001)

Higuchi, M., Manna, S.K., Sasaki R. and Aggarwal, B. B. Regulation of the Activation of Nuclear Transcriptional Factor by Mitochondrial Respiratory Function. Evidence for the Reactive Oxygen Species (ROS)-Dependent and Independent Pathways. Antioxidants and Redox Signaling 4 945-955 (2002)

Higuchi, M., Kudo T., Evans T., Sasaki R., Wada T., Shirakawa T., Sawyer JR., and Gotoh, A. Mitochondrial DNA Determines Androgen Sensitivity in Prostate Cancer Cell Lines. Oncogene 25 1437-1445 (2006)

Higuchi, M. Regulation of mitochondrial DNA content and cancer. Mitochondrion in press (2006)

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Department of Biochemistry and Molecular Biology
University of Arkansas for Medical Sciences
4301 W. Markham St., Slot 516
Little Rock, AR 72205