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, Thomas N. Seyfried

Research output: Contribution to journalArticlepeer-review

181 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2545-2556
Number of pages12
JournalJournal of lipid research
Volume49
Issue number12
DOIs
StatePublished - 2008

Keywords

  • Bioenergetics
  • Carcinogenesis
  • Metabolism
  • Tumorigenesis

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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