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

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 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. Funding Statement: This study was supported by grants from the National Natural Science Foundation of China (81572210 and 81372106 to Z.Z.), and from the Brain Canada and ALS Canada (to J.K). Declaration of Interests: The authors declare no competing financial interests exist. Ethics Approval Statement: The animal protocol was approved by the animal care and ethics committee of the Third Military Medical University, whose standards meet the Animal Care guidelines of the NIH, USA.