Mitochondrial Genome Acquisition Restores Respiratory Function and Tumorigenic Potential of Cancer Cells without Mitochondrial DNA

• DOI: 10.1016/j.cmet.2014.12.003
• Publication Date: 2015-01-06T16:47:39Z
• Authors: An S. Tan; James W. Baty; Lan-Feng Dong; Ayenachew Bezawor...; Berwini Endaya; Jacob Goodwin; Martina Bajzikova; Jaromira Kovarova; Martin Peterka; Bing Yan; Elham Alizadeh Pe...; Margarita Sobol; Anatolyj Filimonenko; Shani Stuart; Magdalena Vondrusova; Katarina Kluckova; Karishma Sachaphi...; Jakub Rohlena; Pavel Hozak; Jaroslav Truksa; David Eccles; Larisa M. Haupt; Lyn R. Griffiths; Jiri Neuzil; Michael V. Berridge
• Keywords: 0301 basic medicine; 570; Lung Neoplasms; Physiology; Melanoma, Experimental; 610; Citrate (si)-Synthase; Mice, SCID; DNA, Mitochondrial; Mice; 03 medical and health sciences; Mice, Inbred NOD; Cell Line, Tumor; Medical biochemistry and metabolomics; Animals; Transplantation, Homologous; RNA, Messenger; Cancer genetics; Molecular Biology; Cell Proliferation; Mice, Inbred BALB C; NADH Dehydrogenase; Cell Biology; Mitochondria; Mice, Inbred C57BL; Electron Transport Chain Complex Proteins; Biochemistry and cell biology; Energy Metabolism; Reactive Oxygen Species

We report that tumor cells without mitochondrial DNA (mtDNA) show delayed tumor growth, and that tumor formation is associated with acquisition of mtDNA from host cells. This leads to partial recovery of mitochondrial function in cells derived from primary tumors grown from cells without mtDNA and a shorter lag in tumor growth. Cell lines from circulating tumor cells showed further recovery of mitochondrial respiration and an intermediate lag to tumor growth, while cells from lung metastases exhibited full restoration of respiratory function and no lag in tumor growth. Stepwise assembly of mitochondrial respiratory (super)complexes was correlated with acquisition of respiratory function. Our findings indicate horizontal transfer of mtDNA from host cells in the tumor microenvironment to tumor cells with compromised respiratory function to re-establish respiration and tumor-initiating efficacy. These results suggest pathophysiological processes for overcoming mtDNA damage and support the notion of high plasticity of malignant cells.