Cisplatin-Mediated Upregulation of APE2 Binding to MYH9 Provokes Mitochondrial Fragmentation and Acute Kidney Injury

Abstract

Cisplatin chemotherapy is standard care for many cancers but is toxic to the kidneys. How this toxicity occurs is uncertain. In this study, we identified apurinic/apyrimidinic endonuclease 2 (APE2) as a critical molecule upregulated in the proximal tubule cells (PTC) following cisplatin-induced nuclear DNA and mitochondrial DNA damage in cisplatin-treated C57B6J mice. The APE2 transgenic mouse phenotype recapitulated the pathophysiological features of C-AKI (acute kidney injury, AKI) in the absence of cisplatin treatment. APE2 pulldown-MS analysis revealed that APE2 binds myosin heavy-Chain 9 (MYH9) protein in mitochondria after cisplatin treatment. Human MYH9-related disorder is caused by mutations in MYH9 that eventually lead to nephritis, macrothrombocytopenia, and deafness, a constellation of symptoms similar to the toxicity profile of cisplatin. Moreover, cisplatin-induced C-AKI was attenuated in APE2-knockout mice. Taken together, these findings suggest that cisplatin promotes AKI development by upregulating APE2, which leads to subsequent MYH9 dysfunction in PTC mitochondria due to an unrelated role of APE2 in DNA damage repair. This postulated mechanism and the availability of an engineered transgenic mouse model based on the mechanism of C-AKI provides an opportunity to identify novel targets for prophylactic treatment of this serious disease. Significance: These results reveal and highlight an unexpected role of APE2 via its interaction with MYH9 and suggest that APE2 has the potential to prevent acute kidney injury in patients with cisplatin-treated cancer.

Cisplatin Mouse Models: Treatment, Toxicity and Translatability

“…Cisplatin mouse models have been used to investigate pharmacokinetics and tissue distribution of cisplatin [15][16][17], the repair capacity of cisplatin-DNA adducts [18], the molecular mechanisms of cisplatin toxicity [19][20][21][22][23] and to test a new generation of platinumbased chemotherapy drugs or adjunctive therapies [24][25][26][27][28][29][30][31][32][33][34][35], or other potential agents or strategies to prevent or treat cisplatin toxicities [36][37][38][39][40][41].…”

“…The proteins that participate in the NER mechanism are imported into the mitochondria in response to oxidative stress [172]. Thus, it is possible, that the NER mechanism is indeed involved in mitochondrial dysfunction (not only in DRG neurons but also in other tissues with high amounts of mitochondria like proximal tubular cells [19] and the brain [41]). However, the contribution of NER in mitochondrial dysfunction remains to be determined.…”

Mesenchymal stem cell-derived extracellular vesicles prevent the development of osteoarthritis via the circHIPK3/miR-124-3p/MYH9 axis

“…Further predictive functional analysis revealed that MYH9 might be the target of miR-124-3p. MYH9, a class of MYH9 gene encoding “gastric” framework-related protein, is a hexamer composed of two 220 kDa heavy chains, two 17 kDa essential light chains, and two 20 kDa regulatory light chains, widely expressed in cells and tissues [ 78 – 80 ]. MYH9 has been confirmed to have vital regulatory effects in papillary thyroid cancer [ 81 ], osteosarcoma [ 82 ], gastric cancer [ 83 ], melanoma [ 84 ] and other diseases.…”

miR-125b Disrupts Mitochondrial Dynamics via Targeting Mitofusin 1 in Cisplatin-Induced Acute Kidney Injury

“…The causes of AKI mainly include ischemia-reperfusion, sepsis, and various exogenous nephrotoxins [8]. During the development of AKI, mitochondrial fission in tubular cells is elevated, and characterized by mitochondrial fragmentation, which promotes cell apoptosis and renal injury [9]. Recently, more and more studies focus on improving mitochondrial function to prevent PTC injury and restore renal function during AKI.…”