Abstract
BackgroundThe 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.MethodsWhole 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 (Mito8344) 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.ResultsCompared 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, Mito8344 and P-Mito8344, due to dramatically induced glycolysis and reduced mitochondrial respiration, respectively. Consequently, transplant-induced growth inhibition was abolished, and cell growth in the Mito8344 group was even higher than that in the control group.ConclusionThis study reveals the antitumour potential of mitochondrial transplantation in breast cancer via distinct regulation of mitochondrial function.
Highlights
The transfer of whole mitochondria that occurs during cell contact has been found to support cancer progression
Mitochondrial transplantations via passive uptake and Pep-1-mediated delivery After a 48-h co-culture of green fluorescent protein (GFP)-labelled mitochondria (MitoGFP, Fig. 1a-c) or Pep-1-modified Green fluorescent protein-tagged mitochondria (MitoGFP) (P-MitoGFP, Fig. 1d-f) with MCF-7 breast cancer cells whose mitochondria were pre-stained with MitoTracker Red, the foreign mitochondria were clearly internalized in both treatment groups and translocated into the host-cell mitochondria, as indicated by the yellow signals shown in Fig. 1a and d
Treatment of breast cancer using mitochondrial transplantation is not an innovative concept, but this study takes the lead in conducting a comprehensive analysis of mitochondrial function, including mitochondrial dynamics, oxidative stress and metabolism, and comparing the effects of different transplant routes on treatment outcomes
Summary
The transfer of whole mitochondria that occurs during cell contact has been found to support cancer progression. Effects of mitochondrial transplantation via different approaches in breast cancer were investigated. Mitochondrial dyna mics are diverse in different cell types, and their function is determined by a delicate shift in the balance of morphological fusion and fission in cells to adapt to physiological stress. The role of mitochondrial dynamics in cancer development and progression is still complex and elusive because cancer cells are distinct from normal cells in terms of their ability to survive and proliferate despite their exposure to microenvironmental apoptotic stimuli, such as hypoxia, oxidative stress, nutrient deprivation and inflammation [1]. The role of mitochondrial dynamics needs to be investigated during mitochondrial transfer (mitotransfer), which occurs frequently in cancer cell interactions with their surrounding environment [5]
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