| Autor: |
Xiucui Ma, Haiyan Liu, Murphy, John T., Foyil, Sarah R., Godar, Rebecca J., Abuirqeba, Haedar, Weinheimer, Carla J., Barger, Philip M., Diwan, Abhinav |
| Předmět: |
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| Zdroj: |
Molecular & Cellular Biology; Mar2015, Vol. 35 Issue 6, p956-976, 21p |
| Abstrakt: |
In cardiac ischemia-reperfusion injury, reactive oxygen species (ROS) generation and upregulation of hypoxia-inducible protein, BNIP3, results in mitochondrial permeabilization; but impairment in autophagic removal of damaged mitochondria provokes programmed cardiomyocyte death. BNIP3 expression and ROS generation result in upregulation of BECLIN-1 protein abundance associated with transcriptional suppression of autophagy-lysosome proteins and reduced activation of transcription factor EB (TFEB), a master regulator of autophagy-lysosome machinery. Partial BECLIN-1 knockdown transcriptionally stimulates lysosome biogenesis and autophagy via mTOR inhibition and activation of TFEB, to enhance removal of depolarized mitochondria. TFEB activation concomitantly stimulates mitochondrial biogenesis via PGC1α induction to restore normally polarized mitochondria and attenuate BNIP3 and hypoxia-reoxygenation-induced cell death. Conversely, overexpression of BECLIN-1 activates mTOR to inhibit TFEB resulting in decline in lysosome numbers and suppression of PGC1α transcription. Importantly, knockdown of endogenous TFEB or PGC1α results in a complete or partial loss of the cytoprotective effects of partial BECLIN-1 knockdown, respectively, indicating a critical role for both mitochondrial autophagy and biogenesis in ensuring cellular viability. These studies uncover a transcriptional feedback loop for BECLIN-1-mediated regulation of TFEB activation, and implicate a central role for TFEB in coordinating mitochondrial autophagy with biogenesis to restore normally polarized mitochondria, and prevent ischemia-reperfusion-induced cardiomyocyte death. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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