硒代蛋氨酸通过PINK1/Parkin介导的线粒体自噬缓解氟诱导的抑郁样行为

doi:10.11843/j.issn.0366-6964.2024.07.039

摘要/Abstract

摘要：

本文旨在探究PINK1/Parkin介导的线粒体自噬在硒代蛋氨酸(selenomethionine, Se-Met)缓解氟致抑郁样行为中的作用。选取40只BALB/c小鼠随机分为5组：空白对照组(C组)、氟组(NaF 150 mg·L^-1，F组)、氟+低硒组(NaF 150 mg·L^-1+1.5 mg·L^-1，F+LSe组)、氟+中硒组(NaF 150 mg·L^-1+3.0 mg·L^-1，F+MSe组)、氟+高硒组(NaF 150 mg·L^-1+6.0 mg·L^-1，F+HSe组)。氟化钠暴露90 d后，通过高架O型迷宫和悬尾试验观察小鼠的行为学表现，运用HE染色观察小鼠大脑皮质的损伤情况，采用生化试剂盒检测氧化应激相关指标的含量，并使用实时荧光定量PCR方法检测线粒体自噬相关基因的表达水平。动物行为学结果显示：与C组相比，F组小鼠在悬尾试验中的“静止”时间显著增加(P＜0.05)，在高架O型迷宫中进入闭合臂的时间有明显升高趋势(P＜0.05)。在补充Se-Met后小鼠“静止”时间显著减少(P＜0.05)，F+LSe和F+MSe小鼠进入闭合臂的时间相比于F组显著减少(P＜0.05)。病理组织切片结果显示：F组小鼠大脑皮质细胞排列紊乱，细胞体积缩小，且椎体细胞数量减少。经Se-Met改善后，F+LSe组的大脑皮质组织核仁清晰，细胞质更加均匀，改善效果更显著。氧化应激相关指标结果显示：与C组相比，F组活性氧(reactive oxygen species, ROS)显著升高(P＜0.05)，谷胱甘肽过氧化物酶(glutathione peroxidase, GSH-PX)含量显著减少(P＜0.05)。与F组相比，F+LSe、F+HSe和F+MSe组ROS含量均显著降低(P＜0.05)，且含量依次表现为F+LSe<F+HSee<F+MSe；F+LSe和F+HSe组GSH-PX含量相比于F组显著升高(P＜0.05)。自噬相关基因的mRNA表达水平结果显示：与C组相比，F组自噬相关基因Parkin、PINK1、LC3、OPTN、NBR1、Drp1、Fis1的mRNA表达水平显著升高(P＜0.05)，OPA1、Mfn1、Mfn2的mRNA表达水平显著降低(P＜0.05)。与F组相比，F+LSe和F+HSe组显著降低Parkin、OPTN、PINK1、P62、NBR1和Fis1的mRNA表达水平(P＜0.05)，F+LSe和F+MSe组显著降低Parkin、LC3、Drp1和P62的mRNA表达水平(P＜0.05)，显著增加OPA1的mRNA表达水平(P＜0.05)，F+LSe组显著增加Mfn2的mRNA表达水平(P＜0.05)。综上所述，1.5 mg·L^-1 Se-Met可通过影响线粒体自噬相关基因的表达，恢复线粒体融合与分裂的动态平衡状态，缓解大脑皮质氧化应激，从而改善大脑皮质组织损伤和抑郁样行为的出现。

关键词: 硒代蛋氨酸, 氟, 线粒体自噬, 大脑皮质

Abstract:

This experiment aims to investigate the role of PINK1/Parkin-mediated mitochondrial autophagy in the alleviation of fluoride-induced depressive-like behavior by selenomethionine (Se-Met). Forty BALB/c mice were selected and randomly divided into five groups: the blank control group (Group C), the fluorine group (NaF 150 mg·L^-1, Group F), the fluorine+low selenium group (NaF 150 mg·L^-1+1.5 mg·L^-1, Group F+LSe), the fluorine+medium selenium group (NaF 150 mg·L^-1+3.0 mg·L^-1, Group F+MSe), the fluorine+high selenium group (NaF 150 mg·L^-1+6.0 mg·L^-1, Group F+HSe). After 90 d of sodium fluoride exposure, the behavioral performance of mice was assessed by means of an elevated O-maze and hanging tail experiments; HE staining was used to evaluate the damage of the mouse cortex; biochemical kits were used to measure the content of oxidative stress-related indices; and real-time fluorescence quantitative PCR was utilized to determine the expression levels of mitochondrial autophagy-related genes. Animal behavioral results showed: the results indicated that mice in group F had a significantly longer "resting" time in the tail suspension test compared to group C (P<0.05) and a tendency to take more time to enter the closed arm of the elevated O-maze (P<0.05). After Se-Met supplementation, the "resting" time of mice was reduced significantly (P<0.05), and the F+LSe and F+MSe mice took significantly less time to enter the closed arm (P<0.05), compared to the F group. The results of the histopathological sections showed: the mice in group F had disorganized cortical cells, reduced cell volume, and fewer vertebral cells. Following Se-Met enhancement, the F+LSe group showed distinct nuclei and more uniform cytoplasm, and the improvement was notably more pronounced. The results of oxidative stress related indicators showed: group F had a significantly higher level of reactive oxygen species (ROS) (P<0.05), and a significantly reduced content of glutathione peroxidase (GSH-PX) (P<0.05), when compared to group C. Groups F+LSe, F+HSe, and F+MSe showed significantly lower levels of ROS (P<0.05). Compared to group F, the ROS content was considerably lower (P<0.05), in groups F+LSe, F+HSe, and F+MSe, with the content decreasing in the order of F+LSe<F+HSe<F+MSe; the GSH-PX content, on the other hand, was significantly higher (P<0.05), in groups F+LSe and F+HSe, compared to group F. Results of mRNA expression levels of autophagy-related genes were shown: group F showed significantly higher mRNA expression levels of autophagy-related genes Parkin, PINK1, LC3, OPTN, NBR1, Drp1, and Fis1 (P<0.05), compared to group C, and significantly lower mRNA expression levels of OPA1, Mfn1, and Mfn2 (P<0.05). Compared to group F, the mRNA expression levels of Parkin, PINK1, P62, NBR1, OPTN, and Fis1 were significantly lower in the F+LSe and F+HSe groups (P<0.05), LC3, Parkin, P62 and Drp1 were significantly decreased in the F+LSe and F+MSe groups (P<0.05), OPA1 was significantly increased (P<0.05), and the F+LSe group showed a significant increase in the mRNA expression level of Mfn2 (P<0.05). In summary, 1.5 mg·L^-1 of Se-Met can alleviate cortical oxidative stress by affecting the expression of mitochondrial autophagy-related genes, restoring the dynamic equilibrium state of mitochondrial fusion and fission, and thus ameliorating cerebral cortex damage and the emergence of depressive-like behaviors.

Key words: selenomethionine, fluoride, mitochondrial autophagy, cerebral cortex

中图分类号:

S856.9

李媛媛, 王天玉, 李梦, 张文慧, 王英卉, 赵天瑞, 李浩洁, 赵阳飞, 王金明. 硒代蛋氨酸通过PINK1/Parkin介导的线粒体自噬缓解氟诱导的抑郁样行为[J]. 畜牧兽医学报, 2024, 55(7): 3213-3224.

Yuanyuan LI, Tianyu WANG, Meng LI, Wenhui ZHANG, Yinghui WANG, Tianrui ZHAO, Haojie LI, Yangfei ZHAO, Jinming WANG. Selenomethionine, through PINK1/Parkin-mediated Mitochondrial Autophagy, Alleviates Fluoride-induced Depressive-like Behavior[J]. Acta Veterinaria et Zootechnica Sinica, 2024, 55(7): 3213-3224.

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基因名称 Gene name	引物序列(5′→3′) Primer sequences	产物大小 Size	登录号 Accession No.
β-actin	F：CCATTGAGCACGGTATTG R：CTGTTGGCTTTGGGATTC	139	AF057040.1
Parkin	F：ACGGTGGTTACACTGGAAGA R：AGACAAGGACACGTCGGTAG	115	AB019558.1
PINK1	F：AGACAAGGACACGTCGGTAG R：TCTCAAGTCCGACAACATCC	146	AB053476.1
P62	F：CTCCGTTCAAGTAGGACAAT	97	U17961.1
	R：GCCCATGCTATGGAAGAA
LC3	F：GTTGACCAGCAGGAAGAA	144	NM_025735.3
	R：CGCTACAAGGGTGAGAAG
NBR1	F：ACGAGGAGCGGAATACTT	143	NM_001252223.1
	R：GCCTATGCCCATCCTACA
OPTN	F：CTGGCTCACAGTCAGTTCTT	98	AY071834.1
	R：ACTGCCCTACACCCACAA
OPA1	F：TTCTTGGTTTCGTTGTGA	156	NM_001403172.1
	R：GGATGCAGCCATTTACTT
Mfn1	F：AAGATGTTGGGCTTGGAG	115	NM_024200.5
	R：TTTGCCTTGATGCTGATG
Mfn2	F：AGCACTTCGCTGATACCC	102	AY123975.1
	R：AGACACCCACAGGAACAC
Drp1	F：TGTCCTCGGATTCAGTCA	124	AB079133.1
	R：AGTGTCCCAAAGGCAGTA
Fis1	F：TTATCAATCAGGCGTTCC	84	BC010783.1
	R：AAAGGCTCTAAAGTATGTGC

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