可溶性腺苷酸环化酶介导的cAMP信号以及PKA和EPAC在脑线粒体功能中的假定作用。,Journal of Neuroscience Research

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可溶性腺苷酸环化酶介导的cAMP信号以及PKA和EPAC在脑线粒体功能中的假定作用。
Journal of Neuroscience Research ( IF 2.9 ) Pub Date : 2019-06-06 , DOI: 10.1002/jnr.24477
Emil Jakobsen ₁ , Sofie C Lange ₁ , Lasse K Bak ₁

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线粒体在包括脑细胞在内的大多数细胞中产生大量的ATP。调节这种复杂的设备以适应电池的能量需求是一个复杂的过程，我们尚未完全了解。在这种情况下，已建议3'，5'-环AMP（cAMP）在信号代谢耦合和线粒体ATP产生的调节中起重要作用。在细胞中，cAMP信号可能会从胞质侧影响线粒体，但最近，有人提出在线粒体基质中由可溶性腺苷酸环化酶（sAC）产生的cAMP信号可调节呼吸作用，从而调节ATP的产生。但是，关于脑线粒体的这些过程知之甚少，由于已经暗示了蛋白激酶A（PKA）和被cAMP 1激活的交换蛋白（EPAC1）都涉及到，因此在基质内产生的cAMP信号的效应子还不是很清楚。在这里，我们回顾当前的知识，并将其与脑线粒体相关。此外，基于对孤立的小鼠大脑皮质线粒体中呼吸，膜电位和ATP产生的测量，我们显示sAC，PKA或EPAC抑制剂以不同的方式影响线粒体功能。总之，我们建议脑线粒体确实通过sAC介导的cAMP信号调节其功能，并且PKA和EPAC均可参与sAC的下游。最后，由于线粒体功能异常在一系列神经系统疾病中的作用，

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Soluble adenylyl cyclase-mediated cAMP signaling and the putative role of PKA and EPAC in cerebral mitochondrial function.

Mitochondria produce the bulk of the ATP in most cells, including brain cells. Regulating this complex machinery to match the energetic needs of the cell is a complicated process that we have yet to understand in its entirety. In this context, 3',5'-cyclic AMP (cAMP) has been suggested to play a seminal role in signaling-metabolism coupling and regulation of mitochondrial ATP production. In cells, cAMP signals may affect mitochondria from the cytosolic side but more recently, a cAMP signal produced within the matrix of mitochondria by soluble adenylyl cyclase (sAC) has been suggested to regulate respiration and thus ATP production. However, little is known about these processes in brain mitochondria, and the effectors of the cAMP signal generated within the matrix are not completely clear since both protein kinase A (PKA) and exchange protein activated by cAMP 1 (EPAC1) have been suggested to be involved. Here, we review the current knowledge and relate it to brain mitochondria. Further, based on measurements of respiration, membrane potential, and ATP production in isolated mouse brain cortical mitochondria we show that inhibitors of sAC, PKA, or EPAC affect mitochondrial function in distinct ways. In conclusion, we suggest that brain mitochondria do regulate their function via sAC-mediated cAMP signals and that both PKA and EPAC could be involved downstream of sAC. Finally, due to the role of faulty mitochondrial function in a range of neurological diseases, we expect that the function of sAC-cAMP-PKA/EPAC signaling in brain mitochondria will likely attract further attention.

更新日期：2019-11-01

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