Center for Autophagy Research.
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
JCI Insight. 2020 Jan 16;5(1):133282. doi: 10.1172/jci.insight.133282.
Autosis is a distinct form of cell death that requires both autophagy genes and the Na+,K+-ATPase pump. However, the relationship between the autophagy machinery and Na+,K+-ATPase is unknown. We explored the hypothesis that Na+,K+-ATPase interacts with the autophagy protein Beclin 1 during stress and autosis-inducing conditions. Starvation increased the Beclin 1/Na+,K+-ATPase interaction in cultured cells, and this was blocked by cardiac glycosides, inhibitors of Na+,K+-ATPase. Increases in Beclin 1/Na+,K+-ATPase interaction were also observed in tissues from starved mice, livers of patients with anorexia nervosa, brains of neonatal rats subjected to cerebral hypoxia-ischemia (HI), and kidneys of mice subjected to renal ischemia/reperfusion injury (IRI). Cardiac glycosides blocked the increased Beclin 1/Na+,K+-ATPase interaction during cerebral HI injury and renal IRI. In the mouse renal IRI model, cardiac glycosides reduced numbers of autotic cells in the kidney and improved clinical outcome. Moreover, blockade of endogenous cardiac glycosides increased Beclin 1/Na+,K+-ATPase interaction and autotic cell death in mouse hearts during exercise. Thus, Beclin 1/Na+,K+-ATPase interaction is increased in stress conditions, and cardiac glycosides decrease this interaction and autosis in both pathophysiological and physiological settings. This crosstalk between cellular machinery that generates and consumes energy during stress may represent a fundamental homeostatic mechanism.
自噬性细胞死亡是一种独特的细胞死亡形式，需要自噬基因和 Na+，K+-ATP 酶泵的共同参与。然而，自噬机制与 Na+，K+-ATP 酶之间的关系尚不清楚。我们提出假说，即在应激和诱导自噬发生的条件下，Na+，K+-ATP 酶与自噬蛋白 Beclin 1 相互作用。饥饿可增加培养细胞中 Beclin 1/Na+，K+-ATP 酶的相互作用，而 Na+，K+-ATP 酶的抑制剂（如强心苷）可阻断这一作用。在饥饿小鼠的组织、神经性厌食症患者的肝脏、新生大鼠脑缺氧缺血（HI）以及小鼠肾缺血再灌注损伤（IRI）的组织中，也观察到 Beclin 1/Na+，K+-ATP 酶相互作用的增加。在脑 HI 损伤和肾 IRI 中，强心苷可阻断 Beclin 1/Na+，K+-ATP 酶相互作用的增加。在小鼠肾 IRI 模型中，强心苷可减少肾组织中自噬细胞的数量，并改善临床结局。此外，内源性强心苷的阻断可增加运动小鼠心脏中 Beclin 1/Na+，K+-ATP 酶的相互作用和自噬性细胞死亡。因此，在应激条件下，Beclin 1/Na+，K+-ATP 酶的相互作用增加，而强心苷可减少这种相互作用和自噬，这在生理和病理状态下均有体现。这种在应激时产生和消耗能量的细胞机制之间的串扰可能代表了一种基本的稳态机制。
