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Autosis is a Na + ,K + -ATPase–regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia–ischemia
Open accessAbstract
Significance: We show that the selective overactivation of autophagy can cause cell death with unique morphological features distinct from apoptosis or necrosis. This unique type of autophagic cell death, termed “autosis,” occurs not only in vitro but also in vivo in cerebral hypoxia–ischemia. Moreover, autosis is inhibited both in vitro and in vivo by cardiac glycosides, which are Na + ,K + -ATPase antagonists used in clinical medicine. Our findings contribute to the basic understanding of cell-death mechanisms and suggest strategies for protecting cells against stresses such as hypoxia–ischemia.
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In the citing paper
“Corroborating the physiological relevance of this process, the administration of Na+/K+-ATPase inhibitors such as cardiac glycosides, confers neuroprotection in a rat model of neonatal hypoxia-ischemia [851].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [851]
In the citing paper
“Autosis is a specific variant of autophagy-dependent cell death that relies on the plasma membrane Na+/K+-ATPase [851].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [851]
In the citing paper
“On the one hand, RCD constitutes a primary etiological determinant in diseases associated with the irreversible loss of post-mitotic tissues (e.g., myocardial infarction, neurodegeneration) [687, 752, 851, 869, 1035, 1036].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [851]
In the citing paper
“We found that GC reduced the autophagic gene expression including key genes associated with autophagy induction, such as Atg7 and Beclin 1[45], by 1-5 folds”
From Prevention of glucocorticoid induced bone changes with beta-ecdysone (2015) · cites this paper as [45]
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Lumkwana, D., du Toit, A., Kinnear, C. J., & Loos, B. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.03.006 · Cited by 69
Hwang, I., Kim, B.-S., Lee, H. Y., Cho, S. W., Lee, S. E., & Ahn, J. (2023) · Autophagy · doi:10.1080/15548627.2023.2259215 · Cited by 67
“Interestingly, we found that mRNA and protein levels of Pa2g4 were highly upregulated within 24 h and then gradually diminished for 72 h. PA2G4/EBP1 levels were inversely correlated with those of active CASP3 (caspase 3) or BAX, which are hallmarks of cell death [25] (Figure 1B).”
BackgroundTargeting Na+/K+‐translocating adenosine triphosphatase in cancer treatment
Durlacher, C. T., Chow, K., Chen, X., He, Z., Zhang, X., Yang, T., & Zhou, S. (2015) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/1440-1681.12385 · Cited by 65
“Autophagy is a primary morphologically distinctive mode of programmed cell death; it is an important process involving the engulfment and degradation of non-essential or abnormal cellular organelles and proteins in living cells.51–53 Inhibition of Na+/K+ATPase can induce or inhibit autophagy in various cancer cells.54…”
BackgroundComprehensive autophagy evaluation in cardiac disease models
Kaludercic, N., Maiuri, M. C., Kaushik, S., Fernández, Á. F., de Bruijn, J., Castoldi, F., Chen, Y., Ito, J., Mukai, R., Murakawa, T., et al. (2020) · Cardiovascular Research · doi:10.1093/cvr/cvz233 · Cited by 64
“This form of cell death, specifically relying on the Naþ/Kþ-ATPase, was termed autosis.(65) Consistent with the physiological relevance of this process, administration of Naþ/Kþ-ATPase inhibitors, such as cardiac glycosides, confers neuroprotection in a rat model of neonatal hypoxia–ischaemia.”
BackgroundInvolvement of the Actin Machinery in Programmed Cell Death
Ren, W., Zhao, W., Cao, L., & Huang, J. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.634849 · Cited by 67
“Autosis is a specific form of autophagy-dependent cell death induced by starvation or an autophagy-inducing cellpermeable peptide, Tat-Beclin 1 (Figure 9) (Liu et al., 2013; Zhang et al., 2015; Fernandez et al., 2020).”
BackgroundRIP3 Regulates Autophagy and Promotes Coxsackievirus B3 Infection of Intestinal Epithelial Cells
Harris, K. G., Morosky, S. A., Drummond, C., Patel, M., Kim, C., Stolz, D. B., Bergelson, J. M., Cherry, S. R., & Coyne, C. B. (2015) · Cell Host & Microbe · doi:10.1016/j.chom.2015.07.007 · Cited by 64
“…accompanying cell death (Mariño et al., 2014), and a subset of cases in which cell death is actually dependent upon autophagy (Elgendy et al., 2011; Liu et al., 2013; Yu er Inc. Approximately 2–4 hpi, RIP3 contributes to the establishment of viral replication factories (green dashed arrows)…”
BackgroundEntosis: The emerging face of non-cell-autonomous type IV programmed death
Martins, I., Raza, S. Q., Voisin, L., Dakhli, H., Law, F., de Jong, D., Allouch, A., Thoreau, M., Brenner, C., Deutsch, É., et al. (2017) · Biomedical Journal · doi:10.1016/j.bj.2017.05.001 · Cited by 70
“Autotic death is characterized by focal plasma membrane rupture, nuclear membrane convolution and shrinkage, focal swelling of the perinuclear space and thedisappearance of endoplasmic reticulum [25,26].”
BackgroundCurrent questions and possible controversies in autophagy
Lindqvist, L., Simon, A. K., & Baehrecke, E. H. (2015) · Cell Death Discovery · doi:10.1038/cddiscovery.2015.36 · Cited by 62
Therapeutic modulation of autophagy: which disease comes first?
Maiuri, M. C., & Kroemer, G. (2019) · Cell Death and Differentiation · doi:10.1038/s41418-019-0290-0 · Cited by 66
Sharifi, M., Hosseinali, S. H., Saboury, A. A., Szegezdi, É., & Falahati, M. (2019) · Journal of Controlled Release · doi:10.1016/j.jconrel.2019.02.007 · Cited by 62
cGAS‐STING signaling in cell death: Mechanisms of action and implications in pathologies
Xu, Y., Chen, C., Liao, Z., & Xu, P. (2023) · European Journal of Immunology · doi:10.1002/eji.202350386 · Cited by 65
Cell death induced autophagy contributes to terminal differentiation of skin and skin appendages
Koenig, U., Robenek, H., Barresi, C., Brandstetter, M., Resch, G. P., Gröger, M., Pap, T., & Hartmann, C. (2019) · Autophagy · doi:10.1080/15548627.2019.1646552 · Cited by 64
“Two phases were morphologically characterized in a Tat-BECN1 induced CDA model (termed autosis) in HeLa cells.”
BackgroundInfluentialDying to Be Noticed: Epigenetic Regulation of Immunogenic Cell Death for Cancer Immunotherapy
Cruickshank, B. M., Giacomantonio, M., Marcato, P., McFarland, S. A., Pol, J. G., & Gujar, S. A. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00654 · Cited by 62
Phosphoinositides: multipurpose cellular lipids with emerging roles in cell death
Phan, T. K., Williams, S. A., Bindra, G. K., Lay, F. T., Poon, I. K. H., & Hulett, M. D. (2019) · Cell Death and Differentiation · doi:10.1038/s41418-018-0269-2 · Cited by 63
“Membrane rupture and accumulation of autophagolysosomes are some typical ACD characteristics. e Pyroptosis.”
InfluentialRegulation of Apoptosis by Autophagy to Enhance Cancer Therapy.
Tompkins, K. D., & Thorburn, A. M. (2019) · Europe PMC (PubMed Central) · Cited by 59
Song, D., Zhang, T.-T., Chen, J.-L., Xia, Y., Qin, Z., Waeber, C., & Sheng, R. (2017) · Cell Death and Disease · doi:10.1038/cddis.2017.289 · Cited by 60
“between Beclin-1 and Bcl-2/Bcl-XL to activate autophagy through the BH3 domains.(47,52) BNIP3, a BH3 domain-”
BackgroundMethodYAP plays a crucial role in the development of cardiomyopathy in lysosomal storage diseases
Ikeda, S., Nah, J., Shirakabe, A., Zhai, P., Oka, S., Sciarretta, S., Guan, K., Shimokawa, H., & Sadoshima, J. (2020) · Journal of Clinical Investigation · doi:10.1172/jci143173 · Cited by 57
“Although we have conducted an extensive search for the morphological features of autosis in CMs using electron microscopy (36), thus far we have only been able to identify accumulation of autophagosomes, rather than a complete signature of autotic cell death, in RagA/B cKO mice.”
BackgroundRoles of ubiquitin in autophagy and cell death
Diaz, C. G., & Ikeda, F. (2018) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2018.09.004 · Cited by 64
Multiple forms of cell death: A focus on the PI3K/AKT pathway
Xu, J., Li, Y., Kang, M., Chang, C., Wei, H., Zhang, C., & Chen, Y. (2023) · Journal of Cellular Physiology · doi:10.1002/jcp.31087 · Cited by 60
Sorafenib-induced defective autophagy promotes cell death by necroptosis
Kharaziha, P., Chioureas, D., Baltatzis, G., Fonseca, P., Rodriguez, P. Q., Gogvadze, V. G., Lennartsson, L., Björklund, A.-C., Zhivotovsky, B., Grandér, D., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.5797 · Cited by 56
“Even though in most cases autophagy plays a cytoprotective role, there are several experimental evidences pointing towards to being a mechanism of cell death in a cell type and stress-specific manner [18-20].”
BackgroundThe interplay between cell death signaling pathways in the heart
Biala, A. K., & Kirshenbaum, L. A. (2014) · Trends in Cardiovascular Medicine · doi:10.1016/j.tcm.2014.08.002 · Cited by 59
Chandramouli, C., Reichelt, M. E., Curl, C. L., Varma, U., Bienvenu, L. A., Koutsifeli, P., Raaijmakers, A. J. A., Blasio, M. J. D., Qin, C. X., Jenkins, A. J., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-20703-8 · Cited by 56
The inducible role of autophagy in cell death: emerging evidence and future perspectives
Huang, X., Yan, H., Xu, Z., Yang, B., Luo, P., & He, Q. (2025) · Cell Communication and Signaling · doi:10.1186/s12964-025-02135-w · Cited by 64
“Autosis can be induced by nutrient starvation or autophagy-inducing peptide treat-ment in various cell lines (such as HeLa cells, U2OS cells, mouse embryonic fibroblasts (MEFs), and murine bone marrow-derived macrophages (BMDMs)), or by hypoxia-ischemia treatment in neonatal rat cerebra [17].”
Cui, Z., Wang, H., Li, S., Qin, T., Shi, H., Ma, J., Li, L., Yu, G., Jiang, T., & Li, C. (2021) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2021.09.008 · Cited by 57
Li, P., Shi, M., Maique, J., Shaffer, J., Yan, S. X., Moe, O. W., & Hu, M. C. (2020) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00504.2019 · Cited by 54
Bata, N., & Cosford, N. D. P. (2021) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.1c00130 · Cited by 60
Packer, M. (2023) · European Journal of Heart Failure · doi:10.1002/ejhf.3068 · Cited by 55
Au, A. K., Aneja, R. K., Bayır, H., Bell, M. J., Janesko‐Feldman, K. L., Kochanek, P. M., & Clark, R. S. B. (2016) · Neurocritical Care · doi:10.1007/s12028-016-0351-x · Cited by 55
“The presence of autophagy biomarkers beclin 1 or p62 in CSF after TBI may represent release during autophagic cell death or injury—termed ‘‘autosis’’ [27].”
BackgroundFernández, Á. F., Liu, Y., Ginet, V., Shi, M., Nah, J., Zou, Z., Zhou, A., Posner, B. A., Xiao, G., Tanguy, M., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.133282 · Cited by 58
“Together with our previous study (6), these results demonstrate that autosis occurs during ischemic injury and that cardiac glycosides may be”
BackgroundResultInfluentialSelf-citation
Metadata
- Authors
- Liu, Y., Shoji-Kawata, S., Sumpter, R. M., Wei, Y., Ginet, V., Zhang, L., Posner, B., Tran, K. A., Green, D. R., Xavier, R. J., Shaw, S. Y., Clarke, P. G. H., Puyal, J., & Levine, B.
- Affiliations
- Center for Autophagy Research,
- Howard Hughes Medical Institute (US)
- University of Lausanne (CH)
- Biochemistry, and
- Center for Systems Biology (US)
- St. Jude Children's Research Hospital (US)
- Broad Institute (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-11-25
- Volume
- 110
- Issue
- 51
- Pages
- 20364-20371
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3870705
- OpenAlex
- W2145084709
- Cited by
- 607
- References
- 35
- Citations by year
- 2026: 33 · 2025: 48 · 2024: 38 · 2023: 51 · 2022: 46 · 2021: 58 · 2020: 50 · 2019: 51 · 2018: 43 · 2017: 58 · 2016: 47 · 2015: 43 · 2014: 38
- FWCI
- 31.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- SERVAL (Université de Lausanne) (acceptedVersion, other-oa)
- IRIS (submittedVersion)
- Funders
- National Science Foundation (310030)
- Howard Hughes Medical Institute
- McKnight Foundation
- University of Texas Southwestern Medical Center
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (130769, 310030)
- Université de Lausanne
- National Institutes of Health (HHSN268201000044C, 5p01ca095471-10, 1P01CA95471-09)
- U.S. Public Health Service (R01 A140646)
- National Heart, Lung, and Blood Institute (HHSN268201000044C)
- National Cancer Institute (P01 CA95471, P01-CA095471, R01CA169291, CA109618, HHSN268201000044C, (CA142543), R01CA109618, P30CA142543)
- National Institute of Allergy and Infectious Diseases (R01AI040646, U54AI057156)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- autophagic cell death, Na+/K+-ATPase, Beclin-1, starvation, hypoxia-ischemia, hippocampal neurons, cardiac glycosides, Na+/K+-ATPase alpha1 subunit, autophagosomes, cell death regulation
- MeSH terms
- Sodium-Potassium-Exchanging ATPase, Animals, Autophagy, Cardiac Glycosides, Brain Ischemia, HeLa Cells, Humans, Nerve Tissue Proteins, Rats, Cell-Penetrating Peptides
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