Department of Neurosurgery, First Affiliated Hospital of Zhejiang Chinese Medicine University, 54 Youdian Lane, Hangzhou, 310006, China.
Department of Surgery, First Affiliated Hospital of Zhejiang Chinese Medicine University, 54 Youdian Lane, Hangzhou, 310006, China.
Mol Neurobiol. 2018 Apr;55(4):3499-3512. doi: 10.1007/s12035-017-0576-5. Epub 2017 May 15.
Metabolic defects are common pathological phenomena following traumatic brain injury (TBI) which contribute to poor prognosis. Brain-derived neurotrophic factor (BDNF) is an important regulator of neuronal survival, development, function, and plasticity. This study was designed to investigate the potential effects of BDNF on TBI-induced metabolic defects and their underlying molecular mechanisms. BDNF was added into cultured neurons to a concentration of 25, 50, and 100 ng/ml, respectively, right after mechanical injury and metabolite levels were analyzed 4 h post injury. The mitochondrial phosphorylated cAMP response element-binding protein (pCREB) distribution and complex V synthesis, as well as their roles in metabolic defects, were evaluated. We found that exogenous BDNF improved metabolic defects, especially the uncoupling of oxidative phosphorylation. BDNF increased pCREB in mitochondrial inner membrane and matrix and promoted mitochondrial complex V synthesis. We also found that these results were negatively regulated by the mitochondrial permeability transition pore (MPTP) antagonist CsA and positively regulated by the MPTP agonist atractyloside. BDNF's protectional effects on metabolic defects were abolished by CREB knockout. When administrated in a dominant interfering CREB mutant (A-CREB) model, mitochondrial pCREB accumulation could still be observed, but the synthesis of complex V and alleviation of metabolic defects were repressed. Our data demonstrate that exogenous BDNF mitigates neuronal metabolic defects following mechanical injury by promoting the pCREB accumulation in mitochondrial inner membrane and matrix, which is regulated by MPTP opening, thus facilitating the synthesis of mitochondrial complex V.
代谢缺陷是创伤性脑损伤 (TBI) 后的常见病理现象，这导致预后不良。脑源性神经营养因子 (BDNF) 是神经元存活、发育、功能和可塑性的重要调节因子。本研究旨在探讨 BDNF 对 TBI 诱导的代谢缺陷的潜在影响及其潜在的分子机制。在机械损伤后立即将 BDNF 添加到培养的神经元中，浓度分别为 25、50 和 100ng/ml，并在损伤后 4 小时分析代谢物水平。评估了线粒体磷酸化 cAMP 反应元件结合蛋白 (pCREB) 分布和复合物 V 的合成，以及它们在代谢缺陷中的作用。我们发现外源性 BDNF 可改善代谢缺陷，特别是氧化磷酸化的解偶联。BDNF 增加了线粒体内膜和基质中的 pCREB，并促进了线粒体复合物 V 的合成。我们还发现，这些结果受到线粒体通透性转换孔 (MPTP) 拮抗剂 CsA 的负调控和 MPTP 激动剂阿托他汀的正调控。CREB 敲除消除了 BDNF 对代谢缺陷的保护作用。当在显性干扰 CREB 突变体 (A-CREB) 模型中给药时，仍可观察到线粒体 pCREB 的积累，但复合物 V 的合成和代谢缺陷的缓解受到抑制。我们的数据表明，外源性 BDNF 通过促进线粒体内膜和基质中 pCREB 的积累来减轻机械损伤后的神经元代谢缺陷，这受 MPTP 开放的调节，从而促进线粒体复合物 V 的合成。
