Candidate Name: Garrett Driscoll
Program: Biology​​​​​​​
Committee Chair: Dr. Shan Yan​​​​​​​
Committee Members: Dr. Christine Richardson, Dr. Kausik Chakbrabarti, Dr. Junya Tomida, Dr. In Hong Yang
Abstract:

Cisplatin-associated acute kidney injury (C-AKI) is a significant challenge in cancer treatment, closely tied to mitochondrial problems. Since mitochondria have a limited ability to repair their DNA, damage caused by cisplatin to mitochondrial DNA (mtDNA) can be especially harmful to kidney tubular cells. In our study with human kidney proximal tubule cells (HK2), we discovered that apurinic/apyrimidinic endonuclease 2 (APE2) plays a crucial role in responding to this type of damage. We observed that cisplatin increases APE2 levels and fosters a connection between APE2 and DNA-dependent protein kinase catalytic subunit (DNA-PKcs), as shown by proximity ligation assay. Moreover, we found that DNA-PKcs signaling is linked to the activation of mitochondrial fission proteins, such as FIS1 and DRP1, which aligns with the observed mitochondrial fragmentation following mtDNA damage. Interestingly, cisplatin exposure also causes damaged mtDNA to be released into the cytosol, activating the cGAS-STING pathway. Importantly, reducing APE2 levels through knockdown experiments decreased mtDNA release, indicating that APE2 is involved in signaling mitochondrial stress caused by cisplatin. In summary, our research highlights APE2 as a key player connecting cisplatin-induced mtDNA damage with mitochondrial fission and immune responses in kidney cells, offering new insights into the mechanisms behind these processes C-AKI.