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<p>Elevated iron in the SNpc may play a key role in Parkinson’s disease (PD) neurodegeneration, yet the underlying mechanism accounting for this iron accumulation is unclear. Although iron is an essential element, excessive amounts produce toxicity. Here, we focused on the role of iron and ATP13A2, the causative gene of PARK9 neurodegeneration with brain iron accumulation, using a cellular model. ATP13A2 deficiency resulted in impaired lysosomal function and iron accumulation in cell organelles. Further, we found dysfunction of mitophagy, which is involved in managing mitochondrial quality, as well as mitochondrial damage. Furthermore, we confirmed a decreased heme synthesis capacity, which is important to maintain intracellular iron homeostasis. Overall, our study indicates that lysosome-derived mitochondrial impairment can disrupt intracellular iron homeostasis in a cell model of PD pathology. This could help better understand the mechanisms underlying PD.</p>

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Disruption of intracellular iron homeostasis through mitochondrial dysfunction associated with suppression of ATP 13A2 expression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月10日

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  • Takanori Murakami,
  • Kazuki Ohuchi,
  • Masanori Kiuchi,
  • Hisaka Kurita,
  • Kanta Kawai,
  • Ryo Kakiuchi,
  • Tasuku Hirayama,
  • Hideko Nagasawa,
  • Zhiliang Wu,
  • Yoichi Maekawa,
  • Isao Hozumi,
  • Masatoshi Inden

摘要

Elevated iron in the SNpc may play a key role in Parkinson’s disease (PD) neurodegeneration, yet the underlying mechanism accounting for this iron accumulation is unclear. Although iron is an essential element, excessive amounts produce toxicity. Here, we focused on the role of iron and ATP13A2, the causative gene of PARK9 neurodegeneration with brain iron accumulation, using a cellular model. ATP13A2 deficiency resulted in impaired lysosomal function and iron accumulation in cell organelles. Further, we found dysfunction of mitophagy, which is involved in managing mitochondrial quality, as well as mitochondrial damage. Furthermore, we confirmed a decreased heme synthesis capacity, which is important to maintain intracellular iron homeostasis. Overall, our study indicates that lysosome-derived mitochondrial impairment can disrupt intracellular iron homeostasis in a cell model of PD pathology. This could help better understand the mechanisms underlying PD.