title: Thyroid hormone induction of mitochondrial activity is coupled to mitophagy via ROS-AMPK-ULK1 signaling.
abstract: Currently, there is limited understanding about hormonal regulation of mitochondrial turnover. Thyroid hormone (T3) increases oxidative phosphorylation (OXPHOS), which generates reactive oxygen species (ROS) that damage mitochondria. However, the mechanism for maintenance of mitochondrial activity and quality control by this hormone is not known. Here, we used both in vitro and in vivo hepatic cell models to demonstrate that induction of mitophagy by T3 is coupled to oxidative phosphorylation and ROS production. We show that T3 induction of ROS activates CAMKK2 (calcium/calmodulin-dependent protein kinase kinase 2, β) mediated phosphorylation of PRKAA1/AMPK (5' AMP-activated protein kinase), which in turn phosphorylates ULK1 (unc-51 like autophagy activating kinase 1) leading to its mitochondrial recruitment and initiation of mitophagy. Furthermore, loss of ULK1 in T3-treated cells impairs both mitophagy as well as OXPHOS without affecting T3 induced general autophagy/lipophagy. These findings demonstrate a novel ROS-AMPK-ULK1 mechanism that couples T3-induced mitochondrial turnover with activity, wherein mitophagy is necessary not only for removing damaged mitochondria but also for sustaining efficient OXPHOS.
authors.affiliation: a Program of Cardiovascular and Metabolic Disorders; Duke-NUS Graduate Medical School ; Singapore.
authors.forename: Rohit A
authors.initials: RA
authors.lastname: Sinha
authors.forename: Brijesh K
authors.initials: BK
authors.lastname: Singh
authors.forename: Jin
authors.initials: J
authors.lastname: Zhou
authors.forename: Yajun
authors.initials: Y
authors.lastname: Wu
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Farah
authors.forename: Kenji
authors.initials: K
authors.lastname: Ohba
authors.forename: Ronny
authors.initials: R
authors.lastname: Lesmana
authors.forename: Jessica
authors.initials: J
authors.lastname: Gooding
authors.forename: Boon-Huat
authors.initials: BH
authors.lastname: Bay
authors.forename: Paul M
authors.initials: PM
authors.lastname: Yen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog; D002118:Calcium / Q000737:chemistry; D056945:Hep G2 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D063306:Mitophagy; D018384:Oxidative Stress; D010100:Oxygen / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D013481:Superoxides; D037042:Thyroid Hormone Receptors beta / Q000378:metabolism; D014284:Triiodothyronine / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine; D013481:Superoxides; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C484754:ULK1 protein, human; C112444:Ulk1 protein, mouse; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human; D010100:Oxygen; D002118:Calcium
keywords: PRKAA1/AMPK; ROS; T3; ULK1; autophagy; liver; mitochondria; mitophagy