NIX Mediates Mitophagy in Spinal Cord Injury in Rats by Interacting with LC3

Overview

Journal Cell Mol Neurobiol

Publisher Springer

Specialties Cell Biology
Molecular Biology
Neurology

Date 2021 Mar 29

PMID 33779883

Citations 4

Authors

Piming Nie

Honggang Wang

Datang Yu

Hongchen Wu

Bing Ni

Jiming Kong

Zhengfeng Zhang

Affiliations

Soon will be listed here.

Abstract

Excessive mitophagy plays a role in neuronal death in spinal cord injury (SCI), its molecular regulation remains largely unknown. The present study aims to determine the role of NIX, a member of a unique subfamily of death-inducing mitochondrial proteins, in the regulation of mitophagy in SCI. Here we show that NIX is highly upregulated in SCI and hypoxia, and localized to mitochondria. The mitochondria-bound NIX interacts with autophagosome-localized LC3 (Microtubule-associated protein 1 light chain 3) to form a mitochondria-NIX-LC3-autophagosome complex, resulting in excessive mitophagy in SCI. Downregulation of NIX by RNA interference restores the function of mitochondria in spinal cord neurons under hypoxia. Importantly, inhibition of NIX improves recovery of locomotor function in rats after SCI. The present study demonstrates that NIX interacts with LC3 to activate excessive mitophagy in SCI. Inhibition of NIX is therefore likely a neuroprotective strategy.

Citing Articles

Mitophagy-associated programmed neuronal death and neuroinflammation.

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Enhancing mitophagy by ligustilide through BNIP3-LC3 interaction attenuates oxidative stress-induced neuronal apoptosis in spinal cord injury.

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Microglial depletion impairs glial scar formation and aggravates inflammation partly by inhibiting STAT3 phosphorylation in astrocytes after spinal cord injury.

Zhou Z, Xie H, Tian X, Xu H, Li W, Yao S Neural Regen Res. 2022; 18(6):1325-1331.

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References

Shi R, Zhu S, Li V, Gibson S, Xu X, Kong J . BNIP3 interacting with LC3 triggers excessive mitophagy in delayed neuronal death in stroke. CNS Neurosci Ther. 2014; 20(12):1045-55. PMC: 6492992. DOI: 10.1111/cns.12325. View

Zhang J, Ney P . Role of BNIP3 and NIX in cell death, autophagy, and mitophagy. Cell Death Differ. 2009; 16(7):939-46. PMC: 2768230. DOI: 10.1038/cdd.2009.16. View

GROSSMAN S, Wolfe B, Yasuda R, Wrathall J . Alterations in AMPA receptor subunit expression after experimental spinal cord contusion injury. J Neurosci. 1999; 19(14):5711-20. PMC: 6783105. View

Lin C, Chen B, Huang K, Dai Y, Teng H . Inhibition of Autophagy by Estradiol Promotes Locomotor Recovery after Spinal Cord Injury in Rats. Neurosci Bull. 2016; 32(2):137-44. PMC: 5563739. DOI: 10.1007/s12264-016-0017-x. View

Basso D, Beattie M, Bresnahan J . A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma. 1995; 12(1):1-21. DOI: 10.1089/neu.1995.12.1. View

Diwan A, Wansapura J, Syed F, Matkovich S, Lorenz J, Dorn 2nd G . Nix-mediated apoptosis links myocardial fibrosis, cardiac remodeling, and hypertrophy decompensation. Circulation. 2008; 117(3):396-404. PMC: 2538800. DOI: 10.1161/CIRCULATIONAHA.107.727073. View

Chakrabarti L, Eng J, Ivanov N, Garden G, La Spada A . Autophagy activation and enhanced mitophagy characterize the Purkinje cells of pcd mice prior to neuronal death. Mol Brain. 2009; 2:24. PMC: 2729476. DOI: 10.1186/1756-6606-2-24. View

Kubli D, Ycaza J, Gustafsson A . Bnip3 mediates mitochondrial dysfunction and cell death through Bax and Bak. Biochem J. 2007; 405(3):407-15. PMC: 2267317. DOI: 10.1042/BJ20070319. View

Noda N, Ohsumi Y, Inagaki F . Atg8-family interacting motif crucial for selective autophagy. FEBS Lett. 2010; 584(7):1379-85. DOI: 10.1016/j.febslet.2010.01.018. View

10.

Hamacher-Brady A, Brady N . Mitophagy programs: mechanisms and physiological implications of mitochondrial targeting by autophagy. Cell Mol Life Sci. 2015; 73(4):775-95. PMC: 4735260. DOI: 10.1007/s00018-015-2087-8. View

11.

Yuan Y, Zheng Y, Zhang X, Chen Y, Wu X, Wu J . BNIP3L/NIX-mediated mitophagy protects against ischemic brain injury independent of PARK2. Autophagy. 2017; 13(10):1754-1766. PMC: 5640199. DOI: 10.1080/15548627.2017.1357792. View

12.

Mullen R, Buck C, Smith A . NeuN, a neuronal specific nuclear protein in vertebrates. Development. 1992; 116(1):201-11. DOI: 10.1242/dev.116.1.201. View

13.

Kanki T . Nix, a receptor protein for mitophagy in mammals. Autophagy. 2010; 6(3):433-5. DOI: 10.4161/auto.6.3.11420. View

14.

Twig G, Elorza A, Molina A, Mohamed H, Wikstrom J, Walzer G . Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 2008; 27(2):433-46. PMC: 2234339. DOI: 10.1038/sj.emboj.7601963. View

15.

Youle R, Narendra D . Mechanisms of mitophagy. Nat Rev Mol Cell Biol. 2010; 12(1):9-14. PMC: 4780047. DOI: 10.1038/nrm3028. View

16.

Zhao C, Chen Z, Qi J, Duan S, Huang Z, Zhang C . Drp1-dependent mitophagy protects against cisplatin-induced apoptosis of renal tubular epithelial cells by improving mitochondrial function. Oncotarget. 2017; 8(13):20988-21000. PMC: 5400560. DOI: 10.18632/oncotarget.15470. View

17.

Shi R, Weng J, Zhao L, Li X, Gao T, Kong J . Excessive autophagy contributes to neuron death in cerebral ischemia. CNS Neurosci Ther. 2012; 18(3):250-60. PMC: 6493486. DOI: 10.1111/j.1755-5949.2012.00295.x. View

18.

Rogov V, Suzuki H, Marinkovic M, Lang V, Kato R, Kawasaki M . Phosphorylation of the mitochondrial autophagy receptor Nix enhances its interaction with LC3 proteins. Sci Rep. 2017; 7(1):1131. PMC: 5430633. DOI: 10.1038/s41598-017-01258-6. View

19.

Ashrafi G, Schwarz T . The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ. 2012; 20(1):31-42. PMC: 3524633. DOI: 10.1038/cdd.2012.81. View

20.

Byrnes K, Stoica B, Fricke S, Di Giovanni S, Faden A . Cell cycle activation contributes to post-mitotic cell death and secondary damage after spinal cord injury. Brain. 2007; 130(Pt 11):2977-92. DOI: 10.1093/brain/awm179. View