Mitochondrial permeability transition regulator, cyclophilin D, is transcriptionally activated by C/EBP during adipogenesis.
Mitochondrial permeability transition regulator, cyclophilin D, is transcriptionally activated by C/EBP during adipogenesis.
复制标题
DOI：
10.1016/j.jbc.2023.105458
复制
发表时间：
2023-12
影响因子：
4.8
通讯作者：
Eliseev, Roman A
中科院分区：
文献类型：
--
作者：
Yu, Chen;Sautchuk, Rubens Jr;Martinez, John;Eliseev, Roman A
年龄相关的骨质流失与骨形成减少、骨吸收增加和骨髓脂肪积累有关。在衰老过程中，骨髓基质（又名间充质干）细胞（BMSC）的分化潜能从成骨谱系转向成脂谱系。在老化的骨组织中，我们之前观察到线粒体通透性转换孔（MPTP）的病理性开放，导致线粒体功能障碍、氧化磷酸化解偶联和细胞死亡。亲环蛋白 D (CypD) 是一种线粒体蛋白，有助于打开 MPTP。我们之前发现，CypD 在 BMSC 成骨过程中下调，导致 MPTP 活性降低，从而保护线粒体免受功能障碍。然而，在脂肪形成过程中，线粒体功能和 CypD 表达的调节仍不清楚。在这项研究中，我们观察到 BMSC 在脂肪生成过程中增加了 CypD 表达和 MPTP 活性，激活了糖酵解，并破碎了线粒体网络。在此过程中，成脂 C/EBPα 充当 CypD 基因 Ppif 表达的转录激活剂。炎症相关转录因子 NF-κB 与 C/EBPα 诱导 Ppif 表达具有协同作用。总的来说，我们证明了脂肪生成过程中线粒体形态和功能的变化。我们还鉴定出 C/EBPα 是 CypD 的转录激活因子。在此过程中，C/EBPα 和 NF-κB p65 亚基协同激活 CypD，表明脂肪生成信号、炎症和 MPTP 功能获得之间存在潜在联系，从而改变衰老过程中的 BMSC 命运。
Age-related bone loss is associated with decreased bone formation, increased bone resorption, and accumulation of bone marrow fat. During aging, differentiation potential of bone marrow stromal (a.k.a. mesenchymal stem) cells (BMSCs) is shifted toward an adipogenic lineage and away from an osteogenic lineage. In aged bone tissue, we previously observed pathological opening of the mitochondrial permeability transition pore (MPTP) which leads to mitochondrial dysfunction, oxidative phosphorylation uncoupling, and cell death. Cyclophilin D (CypD) is a mitochondrial protein that facilitates opening of the MPTP. We found earlier that CypD is downregulated during osteogenesis of BMSCs leading to lower MPTP activity and, thus, protecting mitochondria from dysfunction. However, during adipogenesis, a fate alternative to osteogenesis, the regulation of mitochondrial function and CypD expression is still unclear. In this study, we observed that BMSCs have increased CypD expression and MPTP activity, activated glycolysis, and fragmented mitochondrial network during adipogenesis. Adipogenic C/EBPα acts as a transcriptional activator of expression of the CypD gene, Ppif, during this process. Inflammation-associated transcription factor NF-κB shows a synergistic effect with C/EBPα inducing Ppif expression. Overall, we demonstrated changes in mitochondrial morphology and function during adipogenesis. We also identified C/EBPα as a transcriptional activator of CypD. The synergistic activation of CypD by C/EBPα and the NF-κB p65 subunit during this process suggests a potential link between adipogenic signaling, inflammation, and MPTP gain-of-function, thus altering BMSC fate during aging.