Volume 42 Issue 8, August 2021

Schematic diagram of the role of FOXO3a in TMZ-induced BNIP3-mediated mitophagy. TMZ treatment induced the excessive generation of mitochondrial superoxide. The overproduction of mitochondrial superoxide not only resulted in mitochondrial depolarization and AIF translocation from mitochondria into nuclei but also led to intracellular accumulation of ROS and ROS-dependent DNA DSBs. Within nuclei, AIF could be recruited to γH2AX that are generated when DNA DSBs occur and could act as a nuclease to degrade DNA (chromatinolysis). Thus, mitochondrial superoxide contributes to TMZ-triggered glioma cell death. On the other hand, the expression of the transcription factor FOXO3a was upregulated by ROS and promoted the expression of BNIP3 and ATG5. BNIP3 was distributed to damaged mitochondria, and ATG5 initiated the formation of phagophores. Then, the mitochondria primed by BNIP3 were engulfed by phagophores to form mitophagosomes, and mitophagosomes fused with lysosomes to form mitolysosomes. Within mitolysosomes, mitochondria are eventually degraded by enzymes released from the lysosomes. Thus, autophagic removal of mitochondria with increased superoxide levels inhibited TMZ-induced glioma cell death via suppression of mitochondria-related oxidative stress. Taken together, these data show that FOXO3a protects glioma cells against temozolomide-induced DNA double-strand breaks via promotion of BNIP3-mediated mitophagy.