The downregulation of AMP-activated protein kinase (AMPK) activity contributes to numerous pathologies. Recent reports suggest that the elevation of cellular cAMP promotes AMPK activity. However, the source of the cAMP pool that controls AMPK activity remains unknown. Mammalian cells possess two cAMP sources: membrane-bound adenylyl cyclase (tmAC) and intracellularly localized, type 10 soluble adenylyl cyclase (sAC). Due to the localization of sAC and AMPK in similar intracellular compartments, we hypothesized that sAC may control AMPK activity. In this study, sAC expression and activity were manipulated in H9C2 cells, adult rat cardiomyocytes or endothelial cells. sAC knockdown depleted the cellular cAMP content and decreased AMPK activity in an EPAC-dependent manner. Functionally, sAC knockdown reduced cellular ATP content, increased mitochondrial ROS formation and led to mitochondrial depolarization. Furthermore, sAC downregulation led to EPAC-dependent mitophagy disturbance, indicated by an increased mitochondrial mass and unaffected mitochondrial biogenesis. Consistently, sAC overexpression or stimulation with bicarbonate significantly increased AMPK activity and cellular ATP content. In contrast, tmAC inhibition or stimulation produced no effect on AMPK activity. Therefore, the sAC-EPAC axis may regulate basal and induced AMPK activity and support mitophagy, cellular energy and redox homeostasis. The study argues for sAC as a potential target in treating pathologies associated with AMPK downregulation.

中文翻译：

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10 型腺苷酸环化酶对 AMPK 活性的调节：对线粒体生物学、细胞氧化还原和能量稳态的贡献。


AMP 激活蛋白激酶 (AMPK) 活性的下调会导致多种病理。最近的报告表明细胞 cAMP 的升高可促进 AMPK 活性。然而，控制 AMPK 活性的 cAMP 池的来源仍然未知。哺乳动物细胞拥有两种 cAMP 来源：膜结合腺苷酸环化酶 (tmAC) 和细胞内定位的 10 型可溶性腺苷酸环化酶 (sAC)。由于 sAC 和 AMPK 位于相似的细胞内区室中，我们假设 sAC 可能控制 AMPK 活性。在这项研究中，我们对 H9C2 细胞、成年大鼠心肌细胞或内皮细胞中的 sAC 表达和活性进行了操作。 sAC 敲除会消耗细胞 cAMP 含量并以 EPAC 依赖性方式降低 AMPK 活性。从功能上来说，sAC 敲低降低了细胞 ATP 含量，增加了线粒体 ROS 的形成并导致线粒体去极化。此外，sAC 下调导致 EPAC 依赖性线粒体自噬紊乱，表现为线粒体质量增加和线粒体生物发生未受影响。一致地，sAC 过度表达或用碳酸氢盐刺激显着增加 AMPK 活性和细胞 ATP 含量。相反，tmAC 抑制或刺激对 AMPK 活性没有影响。因此，sAC-EPAC 轴可以调节基础和诱导的 AMPK 活性，并支持线粒体自噬、细胞能量和氧化还原稳态。该研究认为 sAC 是治疗 AMPK 下调相关病理的潜在靶点。