Background: ATP13A2 have been reported as a causative gene of PARK9. ATP13A2 is a lysosomal localized ATPase and is thought to be the membrane transport of cations such as polyamines, proton, and metal ions. In addition, it has been reported that iron accumulation is observed in the brains of PARK9 patients, suggesting that ATP13A2 contributes to intracellular iron homeostasis. However, the effects of ATP13A2 for iron homeostasis is unclear. In our previous study, we reported iron increase in cell organelles by knockdown of ATP13A2. In this study, we attempt to reveal the mechanism of intracellular iron increase.
Method: We generated PARK9 model cells by ATP13A2 knockdown in SH-SY5Y, and analyzed expression of iron-related genes, and function of cell organelles. Heme synthesize is examined by heme assay kit.
Result: In PARK9 model cell, expression of iron-related genes such as Transferrin Receptor (TfR) was increased, suggesting the disruption of iron homeostasis. To examine iron homeostasis, we focus on the capacity of heme synthesize. Heme is known to play a role in regulating intracellular iron concentration. The ability to heme synthesizes was decreased in PARK9 model cells. Since heme is synthesized in mitochondria, it is assumed that mitochondrial disorders are involved in the reduction of heme synthesis. Therefore, it is possible that mitochondrial dysfunction may be a factor in the abnormal intracellular iron homeostasis in PARK9 model cells. In addition, we found dysfunction of mitophagy, suggesting that accumulation of damaged mitochondria.