Abstract
Mitochondrial integrity is critical for the regulation of cellular energy and apoptosis. Metformin is an energy disruptor targeting complex I of the respiratory chain. We demonstrate that metformin induces endoplasmic reticulum (ER) stress, calcium release from the ER and subsequent uptake of calcium into the mitochondria, thus leading to mitochondrial swelling. Metformin triggers the disorganization of the cristae and inner mitochondrial membrane in several cancer cells and tumors. Mechanistically, these alterations were found to be due to calcium entry into the mitochondria, because the swelling induced by metformin was reversed by the inhibition of mitochondrial calcium uniporter (MCU). We also demonstrated that metformin inhibits the opening of mPTP and induces mitochondrial biogenesis. Altogether, the inhibition of mPTP and the increase in mitochondrial biogenesis may account for the poor pro-apoptotic effect of metformin in cancer cells.
Highlights
Mitochondrial integrity is critical for the regulation of cellular energy and apoptosis
To further characterize and validate the endoplasmic reticulum (ER) stress response induced by metformin, we studied the expression of key players of the unfolded protein response (UPR) by western blotting
We observed a burst of fluorescence corresponding to the release of calcium into the cytoplasm (Fig. 1C, Movie S1) even in calcium-free medium that excluded the entry of extracellular calcium
Summary
To better characterize the molecular targets of metformin in cancer cells, we performed microarray analysis in the prostate cancer cell line LNCaP, which was treated with metformin for 24 h. We found that metformin increased the levels of IP3R1, IP3R2 IP3R3 and MCU mRNA as well as VDAC1 protein (Figs 1D, 2D and 4B) These results demonstrate that there is a direct relationship between the release of calcium and mitochondrial swelling. We suggest that this discrepancy may be due to the massive influx of calcium into the mitochondria, probably through VDAC1 and MCU, which causes influx of water and osmotic swelling independently of mPTP This hypothesis was supported by the electron microscopy data showing a clearer density of the matrix (Figs 2A and 3C and Figure 2-supplement 1 and 2) and by the increase in VDAC1 and MCU expression observed in the metformin-treated cells. The inhibition of mPTP opening and increase in mitochondrial biogenesis are consistent with the anti-apoptotic and pro-survival response that should be considered in the future for the potential use of metformin in cancer therapy
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