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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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“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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“, 2012]) and autophagic cell death are now known to contribute to cell death induced by viral infection (Linkermann and Green, 2014) and nutrient deprivation (Gao et al., 2015; Liu et al., 2013) and to programmed cell death during development (Nelson et al.”
Autophagy, cell death, and cancer
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STING orchestrates the neuronal inflammatory stress response in multiple sclerosis
Woo, M. S., Mayer, C., Binkle-Ladisch, L., Sonner, J. K., Rosenkranz, S. C., Shaposhnykov, A., Rothammer, N., Tsvilovskyy, V., Lorenz, S., Raich, L., et al. (2024) · Cell · doi:10.1016/j.cell.2024.05.031 · Cited by 197
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Akimoto, M., Iizuka, M., Kanematsu, R., Yoshida, M., & Takenaga, K. (2015) · PLoS ONE · doi:10.1371/journal.pone.0126605 · Cited by 183
“This form of cell death coincides well with autosis, a recently characterized Na,K-ATPase-regulated form of cell death [36].”
BackgroundInfluentialMyocardial stress and autophagy: mechanisms and potential therapies
Delbridge, L. M. D., Mellor, K. M., TAYLOR, D. J., & Gottlieb, R. A. (2017) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2017.35 · Cited by 177
Autophagy induction stabilizes microtubules and promotes axon regeneration after spinal cord injury
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“In this study, we took advantage of Tat-beclin1 (Tat-Bec), a specific autophagy-inducing peptide (40), which has been used to enhance autophagy both in vitro and in vivo (41, 42).”
MethodGovender, J., Loos, B., Marais, E., & Engelbrecht, A. (2014) · Journal of Pineal Research · doi:10.1111/jpi.12176 · Cited by 182
“, there is cell death with autophagy but not by autophagy) [156].”
BackgroundInfluentialCrosstalk between cGAS–STING signaling and cell death
Murthy, A. M. V., Robinson, N., & Kumar, S. (2020) · Cell Death and Differentiation · doi:10.1038/s41418-020-00624-8 · Cited by 178
“For example, autosis is a specific form of ADCD that involves the Na/K-ATPase [139].”
BackgroundRecent insights into cell death and autophagy
Fitzwalter, B. E., & Thorburn, A. M. (2015) · FEBS Journal · doi:10.1111/febs.13515 · Cited by 177
Repair, Reuse, Recycle: The Expanding Role of Autophagy in Genome Maintenance
Hewitt, G., & Korolchuk, V. I. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2016.11.011 · Cited by 175
Autophagy as a pro‐death pathway
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Autophagy in Cell Life and Cell Death
Anding, A. L., & Baehrecke, E. H. (2015) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2015.07.012 · Cited by 164
“Additionally, Tat-Beclin 1, a cell-death-inducing peptide, was shown to induce a form of autophagy-dependent cell death known as autosis that was independent from the apoptotic and necroptotic machinery in mammalian cells (Liu et al., 2013).”
BackgroundCell Death in the Developing Brain after Hypoxia-Ischemia
Thornton, C., Leaw, B., Mallard, C. E., Nair, S., Jinnai, M., & Hagberg, H. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00248 · Cited by 166
“…show that HI in the immature brain can induce apoptosis (Edwards et al., 1997; Zhu et al., 2000; Northington et al., 2001), necroptosis/necrosis (Northington et al., 2011; Galluzzi et al., 2012a) as well as autophagic cell death/autosis (Koike et al., 2008; Ginet et al., 2009; Liu et al., 2013).”
BackgroundInfluentialNeuroprotection by selective neuronal deletion of Atg7 in neonatal brain injury
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Research progress on morphology and mechanism of programmed cell death
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“Autosis is a subtype of ADCD that relies on the plasma membrane Na + /K + -ATPase [43].”
BackgroundUpregulation of Rubicon promotes autosis during myocardial ischemia/reperfusion injury
Nah, J., Zhai, P., Huang, C.-Y., Fernández, Á. F., Mareedu, S., Levine, B., & Sadoshima, J. (2020) · Journal of Clinical Investigation · doi:10.1172/jci132366 · Cited by 150
“Levine and colleagues showed that autosis is induced by hypoxia-ischemia in the neonatal mouse brain in vivo (11); howAlthough autophagy is generally protective, uncontrolled or excessive activation of autophagy can be detrimental.”
BackgroundInfluentialSelf-citationDiversity-Oriented Stapling Yields Intrinsically Cell-Penetrant Inducers of Autophagy
Peraro, L., Zou, Z., Makwana, K. M., Cummings, A. E., Ball, H. L., Yu, H., Lin, Y., Levine, B., & Kritzer, J. A. (2017) · Journal of the American Chemical Society · doi:10.1021/jacs.7b01698 · Cited by 148
Self-citationA compendium of kinetic modulatory profiles identifies ferroptosis regulators
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“Cultured cells that are starved or exposed to a Beclin1-derived peptide, neurons in cerebral ischemia, and hepatocytes of patients with severe anorexia nervosa exhibit hallmarks of autosis (Kheloufi et al. 2015, Liu et al. 2013, C. Xie et al. 2016).”
BackgroundAutophagy in neurodegeneration: New insights underpinning therapy for neurological diseases
Corti, O., Blomgren, K., Poletti, A., & Beart, P. M. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15002 · Cited by 141
“In 2013, a study was published demonstrating that selective over-activation of autophagy could cause a pattern of cell death with morphological characteristics different from apoptosis or necrosis, termed “autosis” (Liu et al. 2013) (Table 1).”
BackgroundSelf‐Assembled Autophagy‐Inducing Polymeric Nanoparticles for Breast Cancer Interference In‐Vivo
Wang, Y., Lin, Y., Qiao, Z., An, H., Qiao, S., Wang, L., Rajapaksha, R. P. Y. J., & Wang, H. (2015) · Advanced Materials · doi:10.1002/adma.201405926 · Cited by 141
Autophagy and the Kidney: Implications for Ischemia-Reperfusion Injury and Therapy
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Regorafenib induces lethal autophagy arrest by stabilizing PSAT1 in glioblastoma
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“Besides apoptosis, pathways that promote cell death include: autophagy-associated cell death [17], autosis [18], paraptosis [19], entosis [20], ferroptosis [21] and programmed necrosis [22], all of which can contribute to tumor inhibition.”
Programmed Cell Death and Inflammation: Winter Is Coming
Kolb, J. P., Oguin, T. H., Oberst, A., & Martinez, J. (2017) · Trends in Immunology · doi:10.1016/j.it.2017.06.009 · Cited by 136
“Morphologically, autosis is characterized by numerous autophagosomes, plasma membrane rupture, enhanced cell substrate adhesion, focal ballooning of perinuclear space, and disruption of endoplasmic reticulum [59].”
BackgroundKriel, J., & Loos, B. (2019) · Cell Death and Differentiation · doi:10.1038/s41418-018-0267-4 · Cited by 134
Mechanisms of Regulated Cell Death: Current Perspectives
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Ceramide induced mitophagy and tumor suppression
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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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