Dysregulated iron metabolism in C. elegans catp-6/ATP13A2 mutant impairs mitochondrial function
Dysregulated iron metabolism in C. elegans catp-6/ATP13A2 mutant impairs mitochondrial function
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DOI：
10.1016/j.nbd.2020.104786
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发表时间：
2020-06-01
影响因子：
6.1
通讯作者：
Chamoli, Manish
中科院分区：
文献类型：
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作者：
Anand, Nikhita;Holcom, Angelina;Chamoli, Manish
人类ATP 13 A2基因的突变与一种早发性帕金森病（PD）相关，称为Kufor Rakeb综合征（KRS）。KRS患者基底神经节铁沉积增加，提示铁毒性诱导的神经变性是与ATP 13 A2突变相关的潜在发病机制。以前，我们证明ATP 13 A2的功能丧失破坏了溶酶体储存过量铁的能力，导致多巴胺能神经元细胞的存活减少。为了了解可能的机制，我们研究了秀丽隐杆线虫突变体catp-6功能缺陷，人类ATP 13 A2基因的直系同源物。在这里，我们发现catp-6突变蠕虫有缺陷的自噬和溶酶体功能，表现出特征性的PD表型，包括运动功能降低和铁代谢失调。此外，这些突变体具有缺陷的线粒体健康，这可以通过铁螯合或线粒体自噬诱导来挽救。
Mutations in the human ATP13A2 gene are associated with an early-onset form of Parkinson's disease (PD) known as Kufor Rakeb Syndrome (KRS). Patients with KRS show increased iron deposition in the basal ganglia, suggesting iron toxicity-induced neurodegeneration as a potential pathogenesis associated with the ATP13A2 mutation. Previously we demonstrated that functional losses of ATP13A2 disrupt the lysosomes ability to store excess iron, leading to reduce survival of dopaminergic neuronal cells. To understand the possible mechanisms involved, we studied a Caenorhabditis elegans mutant defective in catp-6 function, an ortholog of human ATP13A2 gene. Here we show that catp-6 mutant worms have defective autophagy and lysosomal function, demonstrate characteristic PD phenotypes including reduced motor function and dysregulated iron metabolism. Additionally, these mutants have defective mitochondrial health, which is rescuable via iron chelation or mitophagy induction.