Figure 2.

Relationships between mitochondrial uncoupler-induced phenotypes in cancer cells. Mitochondrial uncouplers induce mitochondrial membrane depolarisation, decrease ATP levels, increase ROS, and decrease anti-oxidant defence by reducing levels of GSH. These phenotypes are linked to changes in signalling pathways including Wnt/β-catenin, AMPK, mTOR, and HIF1α, many of which inhibit cancer cell proliferation and viability (apoptosis). Other phenotypes include arrest in the G_o/G₁ phase of the cell cycle, altered expression of cell cycle-regulated proteins including cyclin-dependent kinases (CDK), and upregulation of CDK inhibitors such as p21 and p27. Mitochondrial uncouplers also increase opening the mitochondrial permeability transition pore (mPTP), mitochondrial swelling, and rupture of mitochondrial membranes, which leads to calcium and cytochrome c release and subsequent apoptosis (or necrosis) when given in higher doses and longer durations (denoted by ∗). Phenotypes elevated by uncouplers are shown in green boxes, phenotypes decreased by uncouplers are shown in red boxes, and those in the blue boxes show differences in phenotypes (increased or decreased) that are closely related.