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

Y Liu, S Shoji-Kawata, RM Sumpter Jr… - Proceedings of the …, 2013 - National Acad Sciences
Y Liu, S Shoji-Kawata, RM Sumpter Jr, Y Wei, V Ginet, L Zhang, B Posner, KA Tran…
Proceedings of the National Academy of Sciences, 2013National Acad Sciences
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 …
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.
National Acad Sciences