Regulation of the transcription factor EB-PGC1α axis by beclin-1 controls mitochondrial quality and cardiomyocyte death under stress

Mol Cell Biol. 2015 Mar;35(6):956-76. doi: 10.1128/MCB.01091-14. Epub 2015 Jan 5.


In cardiac ischemia-reperfusion injury, reactive oxygen species (ROS) generation and upregulation of the hypoxia-inducible protein BNIP3 result 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, a protein associated with transcriptional suppression of autophagy-lysosome proteins and reduced activation of transcription factor EB (TFEB), a master regulator of the autophagy-lysosome machinery. Partial beclin-1 knockdown transcriptionally stimulates lysosome biogenesis and autophagy via mTOR inhibition and activation of TFEB, enhancing 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 declines in lysosome numbers and suppression of PGC1α transcription. Importantly, knockdown of endogenous TFEB or PGC1α results in a complete or partial loss, respectively, of the cytoprotective effects of partial beclin-1 knockdown, 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Autophagy / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Cell Death / genetics*
  • Cells, Cultured
  • HEK293 Cells
  • Humans
  • Lysosomes / genetics
  • Lysosomes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Myocytes, Cardiac / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury / genetics
  • Reperfusion Injury / metabolism
  • Stress, Physiological / genetics*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic / genetics


  • Apoptosis Regulatory Proteins
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Transcription Factors