Metformin treatment impairs the adenine nucleotide translocator activity and energy metabolism in human clear cell renal carcinoma cells.

Although metformin (MET), the well-known antidiabetic drug, exhibits clear antineoplastic effects and is reported to target mitochondria, several issues are still open in this regard, thus limiting its utilization as an anticancer drug alone or in combination with other molecules. Here a functional investigation was carried out to reveal how MET impacted on mitochondrial functions and cell energy metabolism in human cultured clear cell renal carcinoma cells (ccRCCs), in which the anticancer effect of MET is already known. The in vitro effect of increasing MET concentrations on cell viability, necrosis and apoptosis of ccRCCs was checked and compared to normal immortalized HK2 cells. At the same time, the effect of MET on mitochondrial functions, ATP synthesis via oxidative phosphorylation, cellular ATP level, L-lactate (L-LAC) production and export, glucose consumption and key mitochondrial and cytosolic enzyme activities was also investigated in cancer cells. MET affected ccRCC viability and impaired mitochondrial respiration, membrane potential generation and ATP production by targeting complex I (CI), III and IV of the respiratory chain at a concentration near to the IC