Farias Hémelin Resende, Ramos Jessica Marques Obelar, Griesang Caroline Tainá, Santos Lucas, Junior Osmar Vieira Ramires, Souza Debora Guerini, Ferreira Fernanda Silva, Somacal Sabrina, Martins Leo Anderson Meira, de Souza Diogo Onofre Gomes, Moreira José Cláudio Fonseca, Wyse Angela T S, Guma Fátima Theresinha Costa Rodrigues, de Oliveira Jade
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande Do Sul (UFRGS), Porto Alegre, RS, Brazil.
Programa de Pós-Graduação em Biologia Celular e Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Mol Neurobiol. 2025 Jun;62(6):6939-6950. doi: 10.1007/s12035-024-04476-y. Epub 2024 Sep 20.
Hypercholesterolemia has been associated with cognitive dysfunction and neurodegenerative diseases. Moreover, this metabolic condition disrupts the blood-brain barrier, allowing low-density lipoprotein (LDL) to enter the central nervous system. Thus, we investigated the effects of LDL exposure on mitochondrial function in a mouse hippocampal neuronal cell line (HT-22). HT-22 cells were exposed to human LDL (50 and 300 μg/mL) for 24 h. After this, intracellular lipid droplet (LD) content, cell viability, cell death, and mitochondrial parameters were assessed. We found that the higher LDL concentration increases LD content compared with control. Both concentrations increased the number of Annexin V-positive cells, indicating apoptosis. Moreover, in mitochondrial parameters, the LDL exposure on hippocampal neuronal cell line leads to a decrease in mitochondrial complexes I and II activities in both concentrations tested and a reduction in Mitotracker™ Red fluorescence and Mitotracker™ Red and Mitotracker™ Green ratio in the higher concentration, indicating mitochondrial impairment. The LDL incubation induces mitochondrial superoxide production and decreases superoxide dismutase activity in the lower concentration in HT-22 cells. Finally, LDL exposure increases the expression of genes associated with mitochondrial fusion (OPA1 and mitofusin 2) in the lower concentration. In conclusion, our findings suggest that LDL exposure induces mitochondrial dysfunction and modulates mitochondrial dynamics in the hippocampal neuronal cells.
高胆固醇血症与认知功能障碍和神经退行性疾病有关。此外，这种代谢状况会破坏血脑屏障，使低密度脂蛋白（LDL）进入中枢神经系统。因此，我们研究了LDL暴露对小鼠海马神经元细胞系（HT-22）线粒体功能的影响。将HT-22细胞暴露于人类LDL（50和300μg/mL）中24小时。之后，评估细胞内脂滴（LD）含量、细胞活力、细胞死亡和线粒体参数。我们发现，与对照组相比，较高的LDL浓度会增加LD含量。两种浓度均增加了膜联蛋白V阳性细胞的数量，表明细胞凋亡。此外，在测试的两种浓度下，LDL暴露于海马神经元细胞系均导致线粒体复合物I和II活性降低，在较高浓度下，Mitotracker™ Red荧光以及Mitotracker™ Red与Mitotracker™ Green的比率降低，表明线粒体受损。LDL孵育在较低浓度下可诱导HT-22细胞产生线粒体超氧化物并降低超氧化物歧化酶活性。最后，在较低浓度下，LDL暴露会增加与线粒体融合相关基因（OPA1和线粒体融合蛋白2）的表达。总之，我们的研究结果表明，LDL暴露会诱导线粒体功能障碍并调节海马神经元细胞中的线粒体动力学。
