title: Regulation of the transcription factor EB-PGC1α axis by beclin-1 controls mitochondrial quality and cardiomyocyte death under stress.
abstract: 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.
authors.affiliation: Division of Cardiology and Center for Cardiovascular Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA John Cochran VA Medical Center, St. Louis, Missouri, USA.
authors.forename: Xiucui
authors.initials: X
authors.lastname: Ma
authors.affiliation: Division of Cardiology and Center for Cardiovascular Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA John Cochran VA Medical Center, St. Louis, Missouri, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Liu
authors.affiliation: Division of Cardiology and Center for Cardiovascular Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Murphy
authors.affiliation: Division of Cardiology and Center for Cardiovascular Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA John Cochran VA Medical Center, St. Louis, Missouri, USA.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Foyil
authors.affiliation: Division of Cardiology and Center for Cardiovascular Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA John Cochran VA Medical Center, St. Louis, Missouri, USA.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Godar
authors.affiliation: Division of Cardiology and Center for Cardiovascular Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Haedar
authors.initials: H
authors.lastname: Abuirqeba
authors.affiliation: Division of Cardiology and Center for Cardiovascular Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Carla J
authors.initials: CJ
authors.lastname: Weinheimer
authors.affiliation: Division of Cardiology and Center for Cardiovascular Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Barger
authors.affiliation: Division of Cardiology and Center for Cardiovascular Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA John Cochran VA Medical Center, St. Louis, Missouri, USA adiwan@dom.wustl.edu.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Diwan
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy / Q000235:genetics; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics*; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D014157:Transcription Factors