Upregulation of Rubicon promotes autosis during myocardial ischemia/reperfusion injury

Jihoon Nah, Peiyong Zhai, Chun Yang Huang, Álvaro F. Fernández, Satvik Mareedu, Beth Levine, Junichi Sadoshima

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Although autophagy is generally protective, uncontrolled or excessive activation of autophagy can be detrimental. However, it is often difficult to distinguish death by autophagy from death with autophagy, and whether autophagy contributes to death in cardiomyocytes (CMs) is still controversial. Excessive activation of autophagy induces a morphologically and biochemically defined form of cell death termed autosis. Whether autosis is involved in tissue injury induced under pathologically relevant conditions is poorly understood. In the present study, myocardial ischemia/reperfusion (I/R) induced autosis in CMs, as evidenced by cell death with numerous vacuoles and perinuclear spaces, and depleted intracellular membranes. Autosis was observed frequently after 6 hours of reperfusion, accompanied by upregulation of Rubicon, attenuation of autophagic flux, and marked accumulation of autophagosomes. Genetic downregulation of Rubicon inhibited autosis and reduced I/R injury, whereas stimulation of autosis during the late phase of I/R with Tat-Beclin 1 exacerbated injury. Suppression of autosis by ouabain, a cardiac glycoside, in humanized Na+,K+-ATPase-knockin mice reduced I/R injury. Taken together, these results demonstrate that autosis is significantly involved in I/R injury in the heart and triggered by dysregulated accumulation of autophagosomes due to upregulation of Rubicon.

Original languageEnglish (US)
Pages (from-to)2978-2991
Number of pages14
JournalJournal of Clinical Investigation
Volume130
Issue number6
DOIs
StatePublished - Jun 1 2020

ASJC Scopus subject areas

  • Medicine(all)

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    Nah, J., Zhai, P., Huang, C. Y., Fernández, Á. F., Mareedu, S., Levine, B., & Sadoshima, J. (2020). Upregulation of Rubicon promotes autosis during myocardial ischemia/reperfusion injury. Journal of Clinical Investigation, 130(6), 2978-2991. https://doi.org/10.1172/JCI132366