Torres-López María, González-Rodríguez Patricia, Colinas Olalla, Rho Hee-Sool, Torres-Torrelo Hortensia, Castellano Antonio, Gao Lin, Ortega-Sáenz Patricia, López-Barneo José
Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
Departamento de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain.
J Physiol. 2025 Mar;603(5):1091-1107. doi: 10.1113/JP287130. Epub 2025 Feb 12.
The carotid body (CB) is the main oxygen (O) sensing organ that mediates reflex hyperventilation and increased cardiac output in response to hypoxaemia. Acute O sensing is an intrinsic property of CB glomus cells, which contain special mitochondria to generate signalling molecules (NADH and HO) that modulate membrane K channels in response to lowered O tension (hypoxia). In parallel with these membrane-associated events, glomus cells are highly sensitive to mitochondrial electron transport chain (ETC) inhibitors. It was suggested that a decrease in oxidative production of ATP is a critical event mediating hypoxia-induced cell depolarization. Here, we show that rotenone [an inhibitor of mitochondrial complex (MC) I] activates rat and mouse glomus cells but abolishes their responsiveness to hypoxia. Rotenone does not prevent further activation of the cells by cyanide (a blocker of MCIV) or glucose deprivation. Responsiveness to glucose deprivation is enhanced in O-insenstive glomus cells with genetic disruption of MCI. These findings suggest that acute O sensing requires a functional MCI but that a decrease in intracellular ATP, presumably produced by the simultaneous inhibition of MCI and MCIV, is not involved in hypoxia signalling. In support of this concept, ATP levels in single glomus cells were unaltered by hypoxia, but rapidly declined following exposure of the cells to low glucose or to inhibitors of oxidative phosphorylation. These observations indicate that a reduction in intracellular ATP does not participate in physiological acute O sensing. However, local decreases in ATP of glycolytic origin may contribute to low glucose signalling in glomus cells. KEY POINTS: The carotid body contains oxygen-sensitive glomus cells with specialized mitochondria that generate signalling molecules (NADH and HO) to inhibit membrane K channels in response to hypoxia. Glomus cells are highly sensitive to electron transport chain (ETC) blockers. It was suggested that a decrease in intracellular ATP is the main signal inducing K channel inhibition and depolarization in response to hypoxia or ETC blockade. Rotenone, an inhibitor of mitochondrial complex (MC) I, activates glomus cells but abolishes their responsiveness to hypoxia. However, rotenone does not prevent further activation of glomus cells by cyanide (an MCIV blocker) or glucose deprivation. Single-cell ATP levels were unaltered by hypoxia, but decreased rapidly following exposure of glomus cells to 0 mM glucose or inhibitors of oxidative phosphorylation. A reduction in intracellular ATP does not participate in signalling acute hypoxia. However, it may contribute to hypoglycaemia signalling in glomus cells.
颈动脉体（CB）是主要的氧（O）传感器官，可介导反射性过度通气和因低氧血症导致的心输出量增加。急性氧传感是CB球细胞的固有特性，这些细胞含有特殊的线粒体以生成信号分子（NADH和HO），从而在氧张力降低（缺氧）时调节膜钾通道。与这些膜相关事件同时发生的是，球细胞对线粒体电子传递链（ETC）抑制剂高度敏感。有人提出，ATP氧化产生的减少是介导缺氧诱导细胞去极化的关键事件。在此，我们表明鱼藤酮[线粒体复合物（MC）I的抑制剂]可激活大鼠和小鼠的球细胞，但会消除它们对缺氧的反应性。鱼藤酮不会阻止氰化物（MCIV的阻断剂）或葡萄糖剥夺对细胞的进一步激活。在MCI基因破坏的氧不敏感球细胞中，对葡萄糖剥夺的反应性增强。这些发现表明，急性氧传感需要功能性的MCI，但细胞内ATP的减少（可能是由MCI和MCIV的同时抑制产生的）并不参与缺氧信号传导。支持这一概念的是，单个球细胞中的ATP水平不会因缺氧而改变，但在细胞暴露于低葡萄糖或氧化磷酸化抑制剂后会迅速下降。这些观察结果表明，细胞内ATP的减少不参与生理性急性氧传感。然而，糖酵解来源的ATP局部减少可能有助于球细胞中的低葡萄糖信号传导。要点：颈动脉体含有对氧敏感的球细胞，这些细胞具有特殊的线粒体，可生成信号分子（NADH和HO）以在缺氧时抑制膜钾通道。球细胞对电子传递链（ETC）阻断剂高度敏感。有人提出，细胞内ATP的减少是响应缺氧或ETC阻断诱导钾通道抑制和去极化的主要信号。鱼藤酮，一种线粒体复合物（MC）I的抑制剂，可激活球细胞，但会消除它们对缺氧的反应性。然而，鱼藤酮不会阻止氰化物（一种MCIV阻断剂）或葡萄糖剥夺对球细胞的进一步激活。单细胞ATP水平不会因缺氧而改变，但在球细胞暴露于0 mM葡萄糖或氧化磷酸化抑制剂后会迅速下降。细胞内ATP的减少不参与急性缺氧信号传导。然而，它可能有助于球细胞中的低血糖信号传导。
