PGC-1α介导的线粒体生物发生在铝致小鼠学习记忆能力损伤中的作用研究

职业与健康 ›› 2024, Vol. 40 ›› Issue (8): 1013-1019.

PGC-1α介导的线粒体生物发生在铝致小鼠学习记忆能力损伤中的作用研究

贺小玉¹, 向长鑫¹, 王茹¹, 刘洋¹, 殷金珠², 张慧芳¹

1.山西医科大学公共与卫生学院,山西太原 030001;
2.国药同煤总医院,山西大同 037000

收稿日期:2023-09-14 修回日期:2023-10-23 出版日期:2024-04-15 发布日期:2026-03-16
通信作者: 张慧芳,副教授,E-mail：zhf2008y@163.com
作者简介:贺小玉,女,在读硕士研究生,研究方向为职业环境与健康。
基金资助:
山西省自然科学基金（202203021211245）; 山西省神经疾病防治委级重点实验室（2020SY20）

Role of PGC-1α-mediated mitochondrial biogenesis in aluminum-induced learning and memory impairment in mice

HE Xiaoyu¹, XIANG Changxin¹, WANG Ru¹, LIU Yang¹, YIN Jinzhu², ZHANG Huifang¹

1. School of Public Health,Shanxi Medical University,Taiyuan Shanxi,030001, China;
2. National Medicine Tongmei General Hospital,Datong Shanxi,037000, China

Received:2023-09-14 Revised:2023-10-23 Online:2024-04-15 Published:2026-03-16
Contact: ZHANG Huifang,Associate professor,E-mail：zhf2008y@163.com

摘要/Abstract

摘要： 目的探究海马过氧化物酶增殖体激活受体共激活因子-1α（peroxisome proliferator-activated receptor gamma coactivator-1α,PGC-1α）介导的线粒体生物发生在铝致小鼠学习记忆能力损伤中的作用。方法将成年雄性SPF级ICR小鼠随机分为4组：对照组（生理盐水组）、铝剂量组[14、28 和56 μmol/kg Al（mal）₃],染毒3个月。采用新物体识别实验检测小鼠学习及记忆能力的变化情况;采用透射电子显微镜观察海马神经元细胞内线粒体结构的变化;采用比色法检测小鼠海马三磷酸腺苷（adenosine triphosphate,ATP）的含量;采用反转录-聚合酶链反应（reverse transcription-polymerase chain reaction,RT-PCR）检测海马PGC-1α、核呼吸因子 1（nuclear respiratory factor 1,NRF-1）、线粒体转录因子 A（mitochondrial transcription factor A,TFAM）的mRNA含量和线粒体 DNA（mitochondrial DNA,mtDNA）的含量;Western blotting检测海马PGC-1α、TFAM和NRF-1等的蛋白表达。结果新物体识别实验结果显示,随着染铝剂量的增加,各组小鼠偏好指数、辨别指数逐渐下降（F=5.857、13.849,均P<0.05）。透射电镜结果显示,对照组线粒体结构完整、外膜和嵴清晰可见,染铝组线粒体呈现空泡样改变,正常的线粒体结构消失。随着染铝剂量的增加,小鼠海马mtDNA含量、ATP含量逐渐降低（F=313.923、89.887,均P<0.05）。与对照组（1.00±0.00）相比,染铝组海马PGC-1α、NRF-1和TFAM mRNA的表达量均出现下降的趋势,56 μmol/kg Al（mal）₃组PGC-1α、NRF-1、TFAM mRNA水平显著降低为0.53±0.08、0.21±0.08、0.42±0.06（P<0.05）。与对照组（1.00±0.00）相比,染铝组海马PGC-1α、NRF-1和TFAM的蛋白表达量均出现下降的趋势,56 μmol/kg Al（mal）₃组海马PGC-1α、NRF-1和TFAM的蛋白表达显著降低至0.66±0.15、0.50±0.22、0.60±0.77（P<0.05）,呈现一定的剂量反应关系。结论铝可致小鼠海马组织内线粒体生物发生相关信号通路PGC-1α-NRF-1-TFAM抑制,使神经元mtDNA数量下降而抑制细胞内线粒体生物发生,小鼠海马ATP 含量减少、海马神经元形态结构改变,进而导致小鼠学习记忆能力受损。

关键词: 铝, 线粒体生物发生, 过氧化物酶增殖体激活受体共激活因子-1α, 核呼吸因子1, 线粒体转录因子 A, 学习记忆

Abstract: Objective To explore the role of peroxisome proliferator-activated receptor gamma coactivator-1α（PGC-1α）-mediated mitochondrial biogenesis in aluminum-induced learning and memory impairment in mice. Methods The adult male SPF ICR mice were randomly divided into four groups：control group（saline group）, aluminum exposure groups[14, 28, 56 μmol/kg Al（mal）₃], which were exposed for three months.The new object recognition experiment was used to detect the changes of learning and memory ability of mice. The changes of mitochondrial structure in hippocampal neurons were observed by transmission electron microscope. The content of adenosine triphosphate（ATP） in hippocampus of mice was detected by corresponding kit. The mRNA contents of PGC-1α, nuclear respiratory factor 1（NRF-1） and mitochondrial transcription factor A（TFAM） and mitochondrial DNA（mtDNA） contents were detected by reverse transcription-polymerase chain reaction（RT-PCR）. The Western blotting was used to detect the expression of PGC-1α,TFAM and NRF-1 in hippocampus. Results The experimental results of new object recognition showed that the preference index and discrimination index of mice in each group decreased gradually with the increase of aluminum exposure dose（F=5.857,13.849, both P<0.05）. The results of transmission electron microscope showed that the structure of mitochondria in the control group was complete, the outer membrane and crista were clearly visible, and the mitochondria in the aluminum exposed groups showed vacuolar changes, and the normal mitochondrial structure disappeared. The contents of mtDNA and ATP in hippocampus of mice decreased gradually with the increase of aluminum exposure dose（F=313.923, 89.887,both P<0.05）. Compared with the control group（1.00±0.00）,the expressions of PGC-1α,NRF-1 and TFAM mRNA in hippocampal neurons in aluminum exposure groups all showed a downward trend, and the levels of PGC-1α,NRF-1 and TFAM mRNA in 56 μmol/kg Al（mal）₃ group were significantly reduced to 0.53±0.08,0.21±0.08,0.42±0.06（P<0.05）. Compared with the control group（1.00±0.00）,the protein expressions of PGC-1α,NRF-1 and TFAM in the aluminum exposed groups all showed a downward trend, and the protein expressions of PGC-1α,NRF-1 and TFAM in the 56 μmol/kg Al（mal）₃ group decreased significantly to 0.66±0.15,0.50±0.22,0.60±0.77（P<0.05）, showing a dose-response relationship. Conclusion Aluminum can inhibit the signal pathway PGC-1α-NRF-1-TFAM related to mitochondrial biogenesis in the hippocampus of mice, decrease the number of mtDNA in neurons and inhibit intracellular mitochondrial biogenesis,reduce the ATP content in mitochondria,change the morphological structure of hippocampal neurons in mice,and then damage the learning and memory ability of mice.

Key words: Aluminum, Mitochondrial biogenesis, Peroxisome proliferator-activated receptor gamma coactivator-1α, Nuclear respiratory factor 1, Mitochondrial transcription factor A, Learning and memory

中图分类号:

R-332

贺小玉, 向长鑫, 王茹, 刘洋, 殷金珠, 张慧芳. PGC-1α介导的线粒体生物发生在铝致小鼠学习记忆能力损伤中的作用研究. [J]职业与健康, 2024, 40(8): 1013-1019.

HE Xiaoyu, XIANG Changxin, WANG Ru, LIU Yang, YIN Jinzhu, ZHANG Huifang. Role of PGC-1α-mediated mitochondrial biogenesis in aluminum-induced learning and memory impairment in mice. [J]OCCUPATION AND HEALTH, 2024, 40(8): 1013-1019.

参考文献

[1] KAWAHARA M,KATO-NEGISHI M.Link between aluminum and the pathogenesis of alzheimer's disease:The integration of the aluminum and amyloid cascade hypotheses[J].Int J Alzheimers Dis,2011,2011: 276393.
[2] KLOTZ K,WEISTENHÖFER W,NEFF F,et al.The health effects of aluminum exposure[J].Dtsch Arztebl Int,2017,114(39):653-659.
[3] BANKS W A,KASTIN A J.Aluminum-induced neurotoxicity:Alterations in membrane function at the blood-brain barrier[J].Neurosci Biobehav Rev,1989,13(1):47-53.
[4] KUMAR V,GILL K D.Oxidative stress and mitochondrial dysfunction in aluminium neurotoxicity and its amelioration:A review[J].Neurotoxicology,2014,41:154-66.
[5] GRIMM A,ECKERT A.Brain aging and neurodegeneration:From a mitochondrial point of view[J].J Neurochem,2017,143(4):418-431.
[6] YAN M H,WANG X,ZHU X.Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease[J].Free Radic Biol Med,2013,62:90-101.
[7] GOLPICH M,AMINI E,MOHAMED Z,et al.Mitochondrial Dysfunction and biogenesis in neurodegenerative diseases:pathogenesis and treatment[J].CNS Neurosci Ther,2017,23(1):5-22.
[8] FIENI F,LEE S B,JAN Y N,et al.Activity of the mitochondrial calcium uniporter varies greatly between tissues[J].Nat Commun,2012,3:1317.
[9] KOCH R E,JOSEFSON C C,HILL G E.Mitochondrial function,ornamentation,and immunocompetence[J].Biol Rev Camb Philos Soc,2017 92(3):1459-1474.
[10] FANG D,MALDONADO E N.VDAC Regulation: A Mitochondrial target to stop cell proliferation[J].Adv Cancer Res,2018,138:41-69.
[11] LIN M T,BEAL M F.Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases[J].Nature,2006,443(7113):787-795.
[12] JORNAYVAZ F R,SHULMAN G I.Regulation of mitochondrial biogenesis[J].Essays Biochem,2010,47:69-84.
[13] CARDANHO-RAMOS C,MORAIS V A.Mitochondrial biogenesis in Neurons: How and Where[J].Int J Mol Sci,2021,22(23):13059.
[14] SCARPULLA R C.Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network[J].Biochim Biophys Acta,2011,1813(7):1269-1278.
[15] PUIGSERVER P,SPIEGELMAN B M.Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha(PGC-1 alpha):Transcriptional coactivator and metabolic regulator[J].Endocr Rev,2003,24(1):78-90.
[16] VIRBASIUS J V,SCARPULLA R C.Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors:A potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis[J].Proc Natl Acad Sci USA,1994,91(4):1309-1313.
[17] ONYANGO I G,LU J,RODOVA M,et al.Regulation of neuron mitochondrial biogenesis and relevance to brain health[J].Biochim Biophys Acta,2010,1802(1):228-234.
[18] BONDY S C.The neurotoxicity of environmental aluminum is still an issue[J].Neurotoxicology,2010,31(5):575-581.
[19] LI H,XUE X,LI L,et al.Aluminum-induced synaptic plasticity impairment via PI3K-Akt-mTOR signaling pathway[J].Neurotox Res,2020,37(4):996-1008.
[20] ZHANG H,YANG X,QIN X,et al.Caspase-3 is Involved in Aluminum-Induced impairment of long-term potentiation in rats through the Akt/GSK-3β pathway[J].Neurotox Res,2016,29(4):484-494.
[21] CRISTÓVÃO J,SANTOS R,GOMES C M.Metals and neuronal metal binding proteins implicated in Alzheimer's Disease[J].Oxid Med Cell Longev,2016,2016: 9812178.
[22] MARTÍNEZ-REYES I,CHANDEL N S.Mitochondrial TCA cycle metabolites control physiology and disease[J].Nat Commun,2020,11(1):102-113.
[23] DASKALAKI I,TAVERNARAKIS N.Mitochondrial biogenesis in organismal senescence and neurodegeneration[J].Mech Ageing Dev,2020 191:111345.
[24] ANZELL A R,MAIZY R,PRZYKLENK K,et al.Mitochondrial Quality Control and Disease:Insights into Ischemia-Reperfusion Injury[J].Mol Neurobiol,2018,55(3):2547-2564.
[25] SEDLACKOVA L,KOROLCHUK V I.Mitochondrial quality control as a key determinant of cell survival[J].BA-Mol C R,2019,1866(4):575-587.
[26] MURPHY M P,HARTLEY R C.Mitochondria as a therapeutic target for common pathologies[J].Nat Rev Drug Discov,2018,17(12):865-886.
[27] POPOV L D.Mitochondrial biogenesis:An update[J].J Cell Mol Med,2020,24(9):4892-4899.
[28] LEMIRE J,MAILLOUX R,PUISEUX-DAO S,et al.Aluminum-induced defective mitochondrial metabolism perturbs cytoskeletal dynamics in human astrocytoma cells[J].J Neurosci Res,2009,87(6): 1474-1483.
[29] NIERENBERG A A,GHAZNAVI S A,SANDE MATHIAS I,et al.Peroxisome proliferator-activated receptor gamma coactivator-1 alpha as a novel target for bipolar disorder and other neuropsychiatric disorders[J].Biol Psychiatry,2018,83(9):761-769.
[30] UITTENBOGAARD M,CHIARAMELLO A.Mitochondrial biogenesis: a therapeutic target for neurodevelopmental disorders and neurodegenerative diseases[J].Curr Pharm Des,2014,20(35):5574-5593.
[31] LI P A,HOU X,HAO S.Mitochondrial biogenesis in neurodegeneration[J].J Neurosci Res,2017,95(10):2025-2029.
[32] VON BOHLEN UND HALBACH O,VON BOHLEN UND HALBACH V.BDNF effects on dendritic spine morphology and hippocampal function[J].Cell Tissue Res,2018,373(3):729-471.