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Journal of Lipid Research, Vol. 49, 2545-2556, December 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Cardiolipin and electron transport chain abnormalities in mouse brain tumor mitochondria: lipidomic evidence supporting the Warburg theory of cancer^*

Michael A. Kiebish^*, Xianlin Han, Hua Cheng, Jeffrey H. Chuang^* and Thomas N. Seyfried^1,*

^* Department of Biology, Boston College, Chestnut Hill, MA
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO

^* This work was supported by the National Institutes of Health, Grant NS-055195, the National Cancer Institute, Grant CA-102135), and the National Institute on Aging, Grant AG-23168.

Published, JLR Papers in Press, August 13, 2008.

¹ To whom correspondence should be addressed. e-mail: Thomas.Seyfried{at}bc.edu

Otto Warburg first proposed that cancer originated from irreversible injury to mitochondrial respiration, but the structural basis for this injury has remained elusive. Cardiolipin (CL) is a complex phospholipid found almost exclusively in the inner mitochondrial membrane and is intimately involved in maintaining mitochondrial functionality and membrane integrity. Abnormalities in CL can impair mitochondrial function and bioenergetics. We used shotgun lipidomics to analyze CL content and composition in highly purified brain mitochondria from the C57BL/6J (B6) and VM/Dk (VM) inbred strains and from subcutaneously grown brain tumors derived from these strains to include an astrocytoma and ependymoblastoma (B6 tumors), a stem cell tumor, and two microgliomas (VM tumors). Major abnormalities in CL content or composition were found in all tumors. The compositional abnormalities involved an abundance of immature molecular species and deficiencies of mature molecular species, suggesting major defects in CL synthesis and remodeling. The tumor CL abnormalities were also associated with significant reductions in both individual and linked electron transport chain activities. A mathematical model was developed to facilitate data interpretation. The implications of our findings to the Warburg cancer theory are discussed.

Supplementary key words metabolism • tumorigenesis • carcinogenesis • bioenergetics

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