期刊
JCI INSIGHT
卷 5, 期 1, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.133282
关键词
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资金
- NIH [R01 CA109618, U19 AI109725, U19 AI142784, R01 DK091392, R01 DK092461, 5P30 CA124543, R01 HL138720]
- Cancer Prevention Research Institute of Texas grant [RP120718]
- Fondation Leducq grant [15CBD04]
- Pak Foundation for Endowed Professors Collaborative Research Support
- Institut National de la Sante et de la Recherche Medicale (ATIP AVENIR)
- Agence Nationale pour la Recherche [ANR-14-CE12-0011, ANR-14-CE35-0022, ANR-18-CE14-0006-01]
- Swiss National Foundation [310030, 163064, 182332]
- Fondation Motrice grant
- Agence Nationale de la Recherche (ANR) [ANR-18-CE14-0006, ANR-14-CE35-0022] Funding Source: Agence Nationale de la Recherche (ANR)
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 I during stress and autosis-inducing conditions. Starvation increased the Bedin 1/Na+, K+-ATPase interaction in cultured cells, and this was blocked by cardiac glycosides, inhibitors of Na+, K+-ATPase. Increases in Beclin I/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 hypoxiaischemia (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.
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