Mitochondrial dysfunction and nuclear-mitochondrial shuttling of TERT are involved in cell proliferation arrest induced by G-quadruplex ligands

• DODC is more efficient in cell growth inhibition than TMPyP4.
• Both DODC and TMPyP4 cause nuclear-mitochondrial shuttling of TERT.
• Perturbation of mitochondrial function may account for the toxicity of DODC.

G-quadruplex ligands DODC and TMPyP4 have different binding modes to quadruplex structure and cause cell proliferation arrest. Here we showed that DODC was more efficient in cell growth inhibition than TMPyP4. Both G-quadruplex ligands induced nuclear-cytoplasmic shuttling and accumulation of TERT in mitochondria. This effect was not fully dependent on cellular oxidative stress. DODC induced robust cell apoptosis by perturbing mitochondrial function intensively. Overexpression of TERT could not counteract the effects of DODC on mitochondrial respiratory function. Taken together, our results suggest that interference of mitochondrial function by DODC is one of main targets for its anti-tumor ability.