Mitochondrial transplantation regulates antitumour activity, chemoresistance and mitochondrial dynamics in breast cancer

BACKGROUND: The transfer of whole mitochondria that occurs during cell contact has been found to support cancer progression. However, the regulatory role of mitochondria alone is difficult to elucidate due to the complex microenvironment. Currently, mitochondrial transplantation is an available approach for restoring mitochondrial function in mitochondrial diseases but remains unclear in breast cancer. Herein, effects of mitochondrial transplantation via different approaches in breast cancer were investigated. METHODS: Whole mitochondria (approximately 10.5 μg/ml) were transported into MCF-7 breast cancer cells via passive uptake or Pep-1-mediated delivery. Fresh mitochondria isolated from homeoplasmic 143B osteosarcoma cybrids containing mitochondrial DNA (mtDNA) derived from health individuals (Mito) or mtDNA with the A8344G mutation (Mito(8344)) were conjugated with cell-penetrating peptide Pep-1 (P-Mito) or not conjugated prior to cell co-culture. Before isolation, mitochondria were stained with MitoTracker dye as the tracking label. After 3 days of treatment, cell viability, proliferation, oxidative stress, drug sensitivity to Doxorubicin/Paclitaxel and mitochondrial function were assessed. RESULTS: Compared with P-Mito, a small portion of Mito adhered to the cell membrane, and this was accompanied by a slightly lower fluorescent signal by foreign mitochondria in MCF-7 cells. Both transplantations induced cell apoptosis by increasing the nuclear translocation of apoptosis-inducing factor; inhibited cell growth and decreased oxidative stress in MCF-7 cells; and increased the cellular susceptibility of both the MCF-7 and MDA-MB-231 cell lines to Doxorubicin and Paclitaxel. Mitochondrial transplantation also consistently decreased Drp-1, which resulted in an enhancement of the tubular mitochondrial network, but a distinct machinery through the increase of parkin and mitochondrial fusion proteins was observed in the Mito and P-Mito groups, respectively. Furthermore, although there were no differences in energy metabolism after transplantation of normal mitochondria, metabolism was switched to the energetic and glycolytic phenotypes when the mitochondria were replaced with dysfunctional mitochondria, namely, Mito(8344) and P-Mito(8344), due to dramatically induced glycolysis and reduced mitochondrial respiration, respectively. Consequently, transplant-induced growth inhibition was abolished, and cell growth in the Mito(8344) group was even higher than that in the control group. CONCLUSION: This study reveals the antitumour potential of mitochondrial transplantation in breast cancer via distinct regulation of mitochondrial function. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13046-019-1028-z) contains supplementary material, which is available to authorized users.