Journal Article

Autosis is a Na⁺,K⁺-ATPase–regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia–ischemia

Zhang, Liying, Sumpter, Rhea M., Posner, Bruce, Shaw, Stanley Y., Liu, Yang, Ginet, Vanessa, Green, Douglas R., Clarke, Peter G. H., Shoji-Kawata, Sanae, Tran, Khoa A., Xavier, Ramnik J., Puyal, Julien, Wei, Yongjie, Levine, Beth

2013

Overview

A long-standing controversy is whether autophagy is a bona fide cause of mammalian cell death. We used a cell-penetrating autophagy-inducing peptide, Tat-Beclin 1, derived from the autophagy protein Beclin 1, to investigate whether high levels of autophagy result in cell death by autophagy. Here we show that Tat-Beclin 1 induces dose-dependent death that is blocked by pharmacological or genetic inhibition of autophagy, but not of apoptosis or necroptosis. This death, termed “autosis,” has unique morphological features, including increased autophagosomes/autolysosomes and nuclear convolution at early stages, and focal swelling of the perinuclear space at late stages. We also observed autotic death in cells during stress conditions, including in a subpopulation of nutrient-starved cells in vitro and in hippocampal neurons of neonatal rats subjected to cerebral hypoxia–ischemia in vivo. A chemical screen of ∼5,000 known bioactive compounds revealed that cardiac glycosides, antagonists of Na ⁺,K ⁺-ATPase, inhibit autotic cell death in vitro and in vivo. Furthermore, genetic knockdown of the Na ⁺,K ⁺-ATPase α1 subunit blocks peptide and starvation-induced autosis in vitro. Thus, we have identified a unique form of autophagy-dependent cell death, a Food and Drug Administration-approved class of compounds that inhibit such death, and a crucial role for Na ⁺,K ⁺-ATPase in its regulation. These findings have implications for understanding how cells die during certain stress conditions and how such cell death might be prevented.

• Publisher: National Academy of Sciences,NATIONAL ACADEMY OF SCIENCES,National Acad Sciences
• Subject: Animals / antagonists / Apoptosis / autophagy / Autophagy - drug effects / Biological Sciences / Brain hypoxia / Brain Ischemia - metabolism / Brain Ischemia - pathology / Cardiac glycosides / Cardiac Glycosides - pharmacology / Cell death / Cell lines / Cell nucleus / Cell-Penetrating Peptides - pharmacology / death / dose response / HeLa Cells / Humans / mammals / neonates / Nerve Tissue Proteins - metabolism / Neurons / peptides / Rats / Small interfering RNA / sodium / Sodium-Potassium-Exchanging ATPase - antagonists & inhibitors / Sodium-Potassium-Exchanging ATPase - metabolism / Starvation