Targeting NKAα1 to treat Parkinson's disease through inhibition of mitophagy-dependent ferroptosis

Zhang，Xiaoyan1; Li，Guanghong1; Chen，Hanbin1; Nie，Xiao Wei2; Bian，Jin Song1

2024-06-01

10.1016/j.freeradbiomed.2024.04.002

Free Radical Biology and Medicine   影响因子和分区

0891-5849

1873-4596

Dysfunction of the Na/K-ATPase (NKA) has been documented in various neurodegenerative diseases, yet the specific role of NKAα1 in Parkinson's disease (PD) remains incompletely understood. In this investigation, we utilized NKAα1 haploinsufficiency (NKAα1) mice to probe the influence of NKAα1 on dopaminergic (DA) neurodegeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our findings reveal that NKAα1 mice displayed a heightened loss of DA neurons and more pronounced motor dysfunction compared to the control group when exposed to MPTP. Intriguingly, this phenomenon coincided with the activation of ferroptosis and impaired mitophagy both in vivo and in vitro. To scrutinize the role and underlying mechanism of NKAα1 in PD, we employed DR-Ab, an antibody targeting the DR-region of the NKA α subunit. Our study demonstrates that the administration of DR-Ab effectively reinstated the membrane abundance of NKAα1, thereby mitigating MPTP-induced DA neuron loss and subsequent improvement in behavioral deficit. Mechanistically, DR-Ab heightened the formation of the surface NKAα1/SLC7A11 complex, inhibiting SLC7A11-dependent ferroptosis. Moreover, DR-Ab disrupted the cytosolic interaction between NKAα1 and Parkin, facilitating the translocation of Parkin to mitochondria and enhancing the process of mitophagy. In conclusion, this study establishes NKAα1 as a key regulator of ferroptosis and mitophagy, identifying its DR-region as a promising therapeutic target for PD.

DR-Ab Ferroptosis Mitophagy Na+/K+ ATPase Parkinson's disease

SCI

英语

第一

BIOLOGY & BIOCHEMISTRY

2-s2.0-85190850857

Scopus

1.Department of Pharmacology,Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases,School of Medicine,Southern University of Science and Technology,Shenzhen,Guangdong,518055,China
2.Key Laboratory of Shenzhen Respiratory Disease,Shenzhen Institute of Respiratory Disease,Shenzhen People's Hospital (the First Affiliated Hospital,Southern University of Science and Technology,the Second Clinical Medical College,Jinan University,Shenzhen,Guangdong,518055,China

Zhang，Xiaoyan,Li，Guanghong,Chen，Hanbin,et al. Targeting NKAα1 to treat Parkinson's disease through inhibition of mitophagy-dependent ferroptosis[J]. Free Radical Biology and Medicine,2024,218:190-204.

Zhang，Xiaoyan,Li，Guanghong,Chen，Hanbin,Nie，Xiao Wei,&Bian，Jin Song.(2024).Targeting NKAα1 to treat Parkinson's disease through inhibition of mitophagy-dependent ferroptosis.Free Radical Biology and Medicine,218,190-204.

Zhang，Xiaoyan,et al."Targeting NKAα1 to treat Parkinson's disease through inhibition of mitophagy-dependent ferroptosis".Free Radical Biology and Medicine 218(2024):190-204.