Super-Resolution Quantification of T2DM-Induced Mitochondrial Morphology Changes and Their Implications in Pharmacodynamics of Metformin and Sorafenib

Abstract

Mitochondria, as the powerhouse of cells, are involved in various processes of cellular homeostasis, especially energy metabolism. The morphology of mitochondria is a critical indicator for their functions, referring to mitochondrial fusion and fission. Here, we performed structured illumination microscopy (SIM) to measure the mitochondrial morphology in living cells. Benefitting from its nano-scale resolution, this SIM-based strategy can quantify the fusion and fission of mitochondria with high sensitivity. Furthermore, as type 2 diabetes mellitus (T2DM) is caused by a disorder of energy substrate utilization, this strategy has the potential to study T2DM by analyzing the mitochondrial morphology of insulin-resistant (IR) cells. With SIM, we found that mitochondrial fission was increased in IR MRC-5, LO2, FHs 74 Int, and HepG2 cells but not in IR Huh7 cells with high-invasiveness ability. Furthermore, we found that metformin could inhibit mitochondrial fission in IR cells, and sorafenib could promote mitochondrial fusion in HepG2 cancer cells, especially in those IR cells. To conclude, mitochondrial fission is involved in T2DM, and cancer cells with high-invasiveness ability may be equipped with stronger resistance to energy metabolism disorder. In addition, the pharmacodynamics of metformin and sorafenib in cancer may be related to the inhibition of mitochondrial fission, especially for patients with T2DM.

Metformin sensitizes hepatocellular carcinoma to sorafenib by facilitating NHE1 degradation

“…Previous studies have shown that metformin enhances the antitumor effect of sorafenib by inhibiting the ferroptosis induced via the p62-Keap1-Nrf2 pathway [15] as well as the ATF4/STAT3 pathway [27]. In addition, metformin can also improve the e cacy of sorafenib by inhibiting mitochondrial ssion [17]. Another study found that the combination of sorafenib and metformin improves the recurrence and metastasis after liver resection in orthotopic mouse model [18].…”

“…Previous studies have demonstrated that the combination of metformin and sorafenib showed a synergistic effect in hepatocellular carcinoma cells in terms of induction of ferroptosis through the p62-Keap1-Nrf2 pathway [15], induction of autophagy, and inhibition of cell proliferation through the mTOR pathway [16]. Yang et.al [17] have suggested that metformin promotes the drug effect of sorafenib by inhibiting mitochondrial ssion. Other studies have also indicated that metformin may enhance the effect of sorafenib in inhibiting HCC recurrence and metastasis after liver resection by regulating the expression of HIF-2α and TIP30 [18].…”