A G-quadruplex-binding platinum complex induces cancer mitochondrial dysfunction in vitro and in vivo independently of ROS induction

G-quadruplex DNA (G4) is a non-canonical structure forming in guanine-rich regions, which play a vital role in cancer biology and are now being acknowledged in both nuclear and mitochondrial (mt) genome. However, the impact of G4-based targeted therapy on both nuclear and mt genome, affecting mt function and its underlying mechanisms remain largely unexplored. Here, we first demonstrated that the G4-binding platinum(II) complex, Pt-ttpy, shows a highest accumulation in the mitochondria of A2780 cancer cells as compared with two other platinum(II) complexes with no/weak G4-binding properties, Pt-tpy and cisplatin. Pt-ttpy significantly induces deletion, copy number reduction and transcription inhibition of mt DNA, and it hinders the translation of mt proteins. Functional study shows that Pt-ttpy induces a potent mt dysfunction indicated by a high reduction of mt membrane potential, oxygen consumption rate and ATP synthesis, as well as toxic mt morphology switching, but without reactive oxygen species (ROS) induction. Mechanistic study by RNA-seq, Chip-seq and CUT-RUN shows Pt-ttpy impairs most nuclear-encoded mt ribosome genes’ transcription initiation through dampening the recruiting of TAF1 and NELFB to their promoter, which are highly enriched in G4 forming sequences. In vivo studies on a A2780 tumor xenograft mouse model suggest Pt-ttpy’s efficient anti-tumor effects, causing substantial disruption in mt genome function, while exhibiting less side effects compared to cisplatin. Overall, this study presents the first evidence that a G4-binding platinum(II) complex can harm cancer cell mitochondria potently without inducing ROS activity, potentially reducing side effects that shows promise in developing safer and effective platinum-based G4-binding molecules in cancer therapy.