Department of Pathology, Xi Jing Hospital, 4th Military Medical University, Xi'an, Shaanxi 710032, PR China.
Neuroscience. 2010 Aug 11;169(1):23-38. doi: 10.1016/j.neuroscience.2010.04.063. Epub 2010 May 18.
Nuclear respiratory factor 1 (NRF-1) is one of the key transcription factors implicated in mitochondrial biogenesis by activating the transcription of mitochondrial transcription factor A (mtTFA) and subunit genes of respiratory enzymes. NRF-1 transactivation activity can be enhanced by interaction with transcription coactivator peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha). The expression of PGC-1alpha, NRF-1 and mtTFA in neurons is known to be tightly regulated by neuronal activity. However, the coupling signaling mechanism is poorly understood. Here, we use primary cultures of rat visual cortical neurons and a rat model of monocular deprivation (MD) to investigate whether AMP-activated protein kinase (AMPK) is implicated in mediating activity-dependent regulation of PGC-1alpha and NRF-1 expression in neurons. We find that KCl depolarization rapidly activates AMPK and significantly increases PGC-1alpha, NRF-1, and mtTFA levels with increased ATP production in neuron cultures. Similarly, pharmacological activation of AMPK with 5'-aminoimidazole-4-carboxamide riboside (AICAR) or resveratrol also markedly increases PGC-1alpha and NRF-1 mRNA levels in neuron cultures. All these effects can be completely blocked by an AMPK inhibitor, Compound C. Conversely, 1 week of MD significantly reduces AMPK phosphorylation and activity, dramatically down-regulates PGC-1alpha and NRF-1 expression in deprived primary visual cortex. Administration of resveratrol in vivo significantly activates AMPK activity and attenuates the effects of MD on mitochondria by significant increase in PGC-1alpha and NRF-1 levels, mitochondria amount, and coupled respiration. These results strongly indicate that AMPK is an essential upstream mediator that couples neuronal activity to mitochondrial energy metabolism by regulation of PGC-1alpha-NRF-1 pathway in neurons.
核呼吸因子 1（NRF-1）是一种关键的转录因子，通过激活线粒体转录因子 A（mtTFA）和呼吸酶亚基基因的转录，参与线粒体生物发生。NRF-1 的转录激活活性可以通过与转录共激活因子过氧化物酶体增殖物激活受体γ共激活因子 1α（PGC-1α）相互作用而增强。神经元中 NRF-1、PGC-1α 和 mtTFA 的表达受神经元活动的严格调控。然而，其偶联信号机制尚不清楚。在这里，我们使用大鼠视皮层神经元的原代培养物和单侧眼剥夺（MD）大鼠模型来研究 AMP 激活的蛋白激酶（AMPK）是否参与介导神经元中活性依赖性的 PGC-1α 和 NRF-1 表达的调节。我们发现，KCl 去极化可迅速激活 AMPK，显著增加神经元培养物中的 PGC-1α、NRF-1 和 mtTFA 水平，并增加 ATP 的产生。同样，用 5'-氨基咪唑-4-羧酰胺核苷（AICAR）或白藜芦醇药理学激活 AMPK 也可显著增加神经元培养物中 PGC-1α 和 NRF-1 的 mRNA 水平。所有这些作用都可以被 AMPK 抑制剂 Compound C 完全阻断。相反，1 周的 MD 显著降低了 AMPK 的磷酸化和活性，显著下调了剥夺的初级视皮层中的 PGC-1α 和 NRF-1 的表达。体内给予白藜芦醇可显著激活 AMPK 活性，并通过显著增加 PGC-1α 和 NRF-1 水平、线粒体数量和偶联呼吸来减轻 MD 对线粒体的影响。这些结果强烈表明，AMPK 是一种必需的上游调节剂，通过调节神经元中的 PGC-1α-NRF-1 通路，将神经元活动与线粒体能量代谢偶联。
