Tfeb-Mediated Transcriptional Regulation of Autophagy Induces Autosis during Ischemia/Reperfusion in the Heart
1
Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
2
School of Biological Science, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea
3
Cardiovascular Research Institute, Rutgers New Jersey Medical School, 185 South Orange Ave., MSB G609, Newark, NJ 07103, USA
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Academic Editor: Antonio Rodríguez-Sinovas
Cells 2022, 11(2), 258; https://doi.org/10.3390/cells11020258
Received: 10 October 2021
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Revised: 2 January 2022
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Accepted: 11 January 2022
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Published: 13 January 2022
(This article belongs to the Special Issue Mechanisms of Ischemic Heart Injury)
Autosis is a unique form of cell death with characteristic morphological and biochemical features caused by dysregulated autophagy. Autosis is observed in the heart during the late phase of ischemia/reperfusion (I/R), when marked accumulation of autophagosomes is induced. We previously showed that the excessive accumulation of autophagosomes promotes autosis in cardiomyocytes. Although the inhibition of autophagic flux via the upregulation of Rubicon induces the accumulation of autophagosomes during I/R, it appears that additional mechanisms exacerbating autophagosome accumulation are required for the induction of autosis. Here, we show that Tfeb contributes to the induction of autosis during the late phase of I/R in the heart. During myocardial reperfusion, Tfeb is activated and translocated into the nucleus, which in turn upregulates genes involved in autophagy and lysosomal function. The overexpression of Tfeb enhanced cardiomyocyte death induced by a high dose of TAT-Beclin 1, an effect that was inhibited by the downregulation of Atg7. Conversely, the knockdown of Tfeb attenuated high-dose TAT-Beclin1-induced death in cardiomyocytes. Although the downregulation of Tfeb in the heart significantly decreased the number of autophagic vacuoles and inhibited autosis during I/R, the activation of Tfeb activity via 3,4-dimethoxychalcone, an activator of Tfeb, aggravated myocardial injury during I/R. These findings suggest that Tfeb promotes cardiomyocyte autosis during the late phase of reperfusion in the heart.
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Keywords:
autophagic cell death; autosis; Tfeb; ischemia/reperfusion
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MDPI and ACS Style
Nah, J.; Sung, E.-A.; Zhai, P.; Zablocki, D.; Sadoshima, J. Tfeb-Mediated Transcriptional Regulation of Autophagy Induces Autosis during Ischemia/Reperfusion in the Heart. Cells 2022, 11, 258. https://doi.org/10.3390/cells11020258
AMA Style
Nah J, Sung E-A, Zhai P, Zablocki D, Sadoshima J. Tfeb-Mediated Transcriptional Regulation of Autophagy Induces Autosis during Ischemia/Reperfusion in the Heart. Cells. 2022; 11(2):258. https://doi.org/10.3390/cells11020258
Chicago/Turabian StyleNah, Jihoon, Eun-Ah Sung, Peiyong Zhai, Daniela Zablocki, and Junichi Sadoshima. 2022. "Tfeb-Mediated Transcriptional Regulation of Autophagy Induces Autosis during Ischemia/Reperfusion in the Heart" Cells 11, no. 2: 258. https://doi.org/10.3390/cells11020258
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