Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2015 Mar;22(3):367-76.
doi: 10.1038/cdd.2014.143. Epub 2014 Sep 26.

Autosis and autophagic cell death: the dark side of autophagy

Y Liu  1 , B Levine  2
Affiliations
Review

Autosis and autophagic cell death: the dark side of autophagy

Y Liu et al. Cell Death Differ. 2015 Mar.

Abstract

It is controversial whether cells truly die via autophagy or whether - in dying cells - autophagy is merely an innocent bystander or a well-intentioned 'Good Samaritan' trying to prevent inevitable cellular demise. However, there is increasing evidence that the genetic machinery of autophagy may be essential for cell death in certain settings. We recently identified a novel form of autophagy gene-dependent cell death, termed autosis, which is mediated by the Na(+),K(+)-ATPase pump and has unique morphological features. High levels of cellular autophagy, as occurs with treatment with autophagy-inducing peptides, starvation, or in vivo during certain types of ischemia, can trigger autosis. These findings provide insights into the mechanisms and strategies for prevention of cell death during extreme stress conditions.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Schematic overview of the autophagy pathway. Autophagy is a catabolic process in which damaged or redundant cellular organelles or exogenous pathogens are degraded by autophagosomes. The formation of the autophagosome includes vesicle nucleation, vesicle elongation, and vesicle completion, which are tightly regulated by various autophagy-related proteins, some of which are listed in the figure. The mature autophagosome then fuses with the lysosome to form an autolysosome. Inside the autolysosome, the sequestered contents are degraded
Figure 2
Figure 2
Morphological features of autosis. (a) Representative light microscopic image of an autotic HeLa cell during starvation. Arrow shows area of focal nuclear concavity with adjacent focal ballooning of perinuclear space. (b–d) Representative electron microscopic images of different stages of autotic cell death; including (b) a cell in an early stage of autosis (referred to as phase 1a) with nuclear membrane convolution, mild chromatin condensation, numerous autophagosomes, and autolyososomes, dilated and fragmented ER, and electron-dense mitochondria; (c) a cell in a mid-stage of autosis (referred to as phase 1b) with separation of the inner and outer nuclear membrane, the presence of membrane-bound densities in the perinuclear space; and (d) a cell in the final stage of autosis (referred to as phase 2) with focal nuclear concavity, focal ballooning of the perinuclear space (which is empty) and disappearance of cellular organelles such as ER, autophagosomes, and autolysosomes. N, nucleus; PNS, perinuclear space
Figure 3
Figure 3
Multiple functions of Na+,K+-ATPase. Na+,K+-ATPase is a ubiquitous plasma membrane protein complex (consisting of α- and β-subunits) which functions in ion homeostasis by pumping Na+ out of cells and pumping K+ into cells. The ion pump function of Na+,K+-ATPase maintains the cell membrane potential, which is specifically inhibited by cardiac glycosides. In addition to its ion transporter function, Na+,K+-ATPase functions as a signalosome, recruiting diverse signaling molecules to initiate a series of signaling pathways. Na+,K+-ATPase also regulates the cytoskeleton, tight junctions, cell motility, and cell polarity
Figure 4
Figure 4
Summary of autosis inducers, mediators, and known pathophysiological contexts. Autosis is a novel form of autophagy-dependent, non-apoptotic cell death, which is induced by autophagy-inducing peptides, starvation, and hypoxia-ischemia. This process requires the core autophagy machinery and Na+,K+-ATPase. Thus far, it is known to contribute to cerebral infarct size in rodent neonatal cerebral hypoxia-ischemia. Cardiac glycosides, antagonists of Na+,K+-ATPase, inhibit autosis induced by peptides, starvation, and hypoxia-ischemia, and reduce cerebral infarct size in rodent neonatal cerebral hypoxia-ischemia
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Clarke PG. Developmental cell death: morphological diversity and multiple mechanisms. Anat Embryol (Berl) 1990;181:195–213. - PubMed
    1. Schweichel JU, Merker HJ. The morphology of various types of cell death in prenatal tissues. Teratology. 1973;7:253–266. - PubMed
    1. Levine B, Yuan J. Autophagy in cell death: an innocent convict. J Clin Invest. 2005;115:2679–2688. - PMC - PubMed
    1. Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ. 2012;19:107–120. - PMC - PubMed
    1. Liu Y, Shoji-Kawata S, Sumpter RM, Jr, Wei Y, Ginet V, Zhang L, et al. Autosis is a Na+,K+-ATPase-regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia-ischemia. Proc Natl Acad Sci USA. 2013;110:20364–20371. - PMC - PubMed

Publication types

  NODES
INTERN 4
twitter 2