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NL-1 Promotes PINK1-Parkin-Mediated Mitophagy Through MitoNEET Inhibition in Subarachnoid Hemorrhage

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A Correction to this article was published on 29 December 2023

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Abstract

NL-1 is a mitoNEET ligand known for its antileukemic effects and has recently shown neuroprotective effects in an ischemic stroke model. However, its underlying process in subarachnoid hemorrhage (SAH) is still unclear. Thus, we aimed to investigate the possible mechanism of NL-1 after SAH in rats. 112 male adult Sprague–Dawley rats were used for experiments. SAH model was performed with endovascular perforation. Rats were dosed intraperitoneally (i.p.) with NL-1 (3 mg/kg, 10 mg/kg, 30 mg/kg) or a vehicle (10% DMSO aqueous solution) at 1 h after SAH. A novel mitophagy inhibitor liensinine (60 mg/kg) was injected i.p. 24 h before SAH. SAH grades, short-term and long-term neurological scores were measured for neurobehavior. TdTmediated dUTP nick end labeling (TUNEL) staining, dihydroethidium (DHE) staining and western blot measurements were used to detect the outcomes and mechanisms of NL-1 administration. NL-1 treatment significantly improved short-term neurological behavior in Modified Garcia and beam balance sores in comparison with SAH + vehicle group. NL-1 administration also increased mitoNEET which induced phosphatase and tensin-induced kinase 1 (PINK1), Parkin and LC3II related mitophagy compared with SAH + vehicle group. In addition, the expressions of apoptotic protein Cleaved Caspase-3 and oxidative stress related protein Romo1 in NL-1 treatment group were reversed from SAH + vehicle group. Meanwhile, NL-1 treatment notably reduced TUNEL-positive cells, DHE-positive cells compared with SAH + vehicle group. NL-1 treatment notably improved long-term neurological behavior in rotarod and water maze tests compared to SAH + vehicle group. However, the administration of liensinine may inhibit the treatment effect of NL-1, leading to reduced expression of mitophagy markers Pink1, Parkin, LC3I/II, and increased expressions of Romo1 and Cleaved Caspase-3. NL-1 induced PINK1/PARKIN related mitophagy via mitoNEET, which reduced oxidative stress and apoptosis in early brain injury after SAH in rats. NL-1 may serve as a prospective drug for the treatment of SAH.

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Funding

The authors disclosed receipt of the following financial support for the research and authorship of this article: this research was supported by the National Natural Science Foundation of China to Dr. TY Zhang [Grant No. 82001324].

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Authors and Affiliations

  1. Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China

    Tongyu Zhang & Minghai Zhang

  2. Department of Neurosurgery, Chongqing Tongnan District People’s Hospital, Chongqing, China

    Minghai Zhang

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TZ performed the studies and wrote the manuscript. MZ contributed to the design and review. All authors analyzed the results and approved the final version of the manuscript.

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Correspondence to Minghai Zhang.

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11064_2023_4024_MOESM1_ESM.tif

Supplemental Fig. 1 Immunofluorescence results of NL-1 reatment increased functional autophagy of mitochondria after SAH. (A) Representative images of mitochondria marker (Mitotracker) with lysosomal marker (Lysotracker) staining from all groups. (B) Quantitative analysis of mitophagy positive cells (percentage of Mitotracker-positive merged Lysotracker-positive cells) from all groups. n = 3 for each group. Scale bars = 100 µm. Bars represent the mean ± SD. # P < 0.05 vs. Sham + vehicle group; * P < 0.05 vs. SAH + vehicle group. (TIF 3703 KB)

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Zhang, T., Zhang, M. NL-1 Promotes PINK1-Parkin-Mediated Mitophagy Through MitoNEET Inhibition in Subarachnoid Hemorrhage. Neurochem Res 49, 1506–1516 (2024). https://doi.org/10.1007/s11064-023-04024-5

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