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

• Published in: Cell metabolism Vol. 21; no. 1; pp. 81 - 94
• Main Authors: Tan, An S., Baty, James W., Dong, Lan-Feng, Bezawork-Geleta, Ayenachew, Endaya, Berwini, Goodwin, Jacob, Bajzikova, Martina, Kovarova, Jaromira, Peterka, Martin, Yan, Bing, Pesdar, Elham Alizadeh, Sobol, Margarita, Filimonenko, Anatolyj, Stuart, Shani, Vondrusova, Magdalena, Kluckova, Katarina, Sachaphibulkij, Karishma, Rohlena, Jakub, Hozak, Pavel, Truksa, Jaroslav, Eccles, David, Haupt, Larisa M., Griffiths, Lyn R., Neuzil, Jiri, Berridge, Michael V.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.01.2015
• Subjects: Animals; Cell Line, Tumor; Cell Proliferation; Citrate (si)-Synthase - metabolism; DNA, Mitochondrial - metabolism; Electron Transport Chain Complex Proteins - metabolism; Energy Metabolism; Lung Neoplasms - pathology; Lung Neoplasms - secondary; Melanoma, Experimental - pathology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Mitochondria - genetics; Mitochondria - metabolism; Mitochondria - ultrastructure; NADH Dehydrogenase - genetics; NADH Dehydrogenase - metabolism; Reactive Oxygen Species - metabolism; RNA, Messenger - metabolism; Transplantation, Homologous
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2014.12.003

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. [Display omitted] •Tumor cells lacking mtDNA form tumors only after acquiring host mtDNA•Tumor microenvironment instructs stepwise recovery of respiration•Recovery of mitochondrial function aligns with efficient tumor formation•Functional respirasome and complex II assembly occur in metastatic cells Mitochondrial genome acquisition from cells in the tumor microenvironment restores tumorigenicity and respiration in cells lacking mtDNA. Cell lines derived from primary and circulating tumor cells and lung metastases that grew from these cells showed stepwise recovery of tumorigenicity and respiration that was associated with respirasome and complex II assembly.