title: Endoplasmic Reticulum Stress Enhances Mitochondrial Metabolic Activity in Mammalian Adrenals and Gonads.
abstract: The acute response to stress consists of a series of physiological programs to promote survival by generating glucocorticoids and activating stress response genes that increase the synthesis of many chaperone proteins specific to individual organelles. In the endoplasmic reticulum (ER), short-term stress triggers activation of the unfolded protein response (UPR) module that either leads to neutralization of the initial stress or adaptation to it; chronic stress favors cell death. UPR induces expression of the transcription factor, C/EBP homology protein (CHOP), and its deletion protects against the lethal consequences of prolonged UPR. Here, we show that stress-induced CHOP expression coincides with increased metabolic activity. During stress, the ER and mitochondria come close to each other, resulting in the formation of a complex consisting of the mitochondrial translocase, translocase of outer mitochondrial membrane 22 (Tom22), steroidogenic acute regulatory protein (StAR), and 3β-hydroxysteroid dehydrogenase type 2 (3βHSD2) via its intermembrane space (IMS)-exposed charged unstructured loop region. Stress increased the circulation of phosphates, which elevated pregnenolone synthesis by 2-fold by increasing the stability of 3βHSD2 and its association with the mitochondrion-associated ER membrane (MAM) and mitochondrial proteins. In summary, cytoplasmic CHOP plays a central role in coordinating the interaction of MAM proteins with the outer mitochondrial membrane translocase, Tom22, to activate metabolic activity in the IMS by enhanced phosphate circulation.
authors.affiliation: Laboratory of Biochemistry and Cell Biology, Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia, USA.
authors.forename: Manoj
authors.initials: M
authors.lastname: Prasad
authors.affiliation: Department of Pathology, Mercer University School of Medicine, Macon, Georgia, USA.
authors.forename: Anna N
authors.initials: AN
authors.lastname: Walker
authors.affiliation: Laboratory of Biochemistry and Cell Biology, Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia, USA.|Memorial University Medical Center, Anderson Cancer Institute, Savannah, Georgia, USA.
authors.forename: Jasmeet
authors.initials: J
authors.lastname: Kaur
authors.affiliation: Division of Basic Medical Sciences, Mercer University School of Medicine, Macon, Georgia, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Thomas
authors.affiliation: Division of Basic Medical Sciences, Mercer University School of Medicine, Macon, Georgia, USA.
authors.forename: Shirley A
authors.initials: SA
authors.lastname: Powell
authors.affiliation: Pediatric Endocrinology Diabetology & Metabolism, University Children's Hospital Bern, Bern, Switzerland.
authors.forename: Amit V
authors.initials: AV
authors.lastname: Pandey
authors.affiliation: Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Randy M
authors.initials: RM
authors.lastname: Whittal
authors.affiliation: Memorial University Medical Center, Anderson Cancer Institute, Savannah, Georgia, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Burak
authors.affiliation: Memorial University Medical Center, Anderson Cancer Institute, Savannah, Georgia, USA.
authors.forename: Guy
authors.initials: G
authors.lastname: Petruzzelli
authors.affiliation: Laboratory of Biochemistry and Cell Biology, Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia, USA bose_hs@mercer.edu.|Memorial University Medical Center, Anderson Cancer Institute, Savannah, Georgia, USA.
authors.forename: Himangshu S
authors.initials: HS
authors.lastname: Bose
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000737:chemistry / Q000378:metabolism; D000311:Adrenal Glands / Q000378:metabolism*; D000818:Animals; D003593:Cytoplasm / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D006066:Gonads / Q000378:metabolism*; D008297:Male; D008322:Mammals / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D013312:Stress, Physiological; D051742:Transcription Factor CHOP / Q000378:metabolism; D056811:Unfolded Protein Response; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: C497250:Ddit3 protein, mouse; D033681:Mitochondrial Membrane Transport Proteins; D010710:Phosphates; D010750:Phosphoproteins; C000609269:Tom22 protein, mouse; D000098682:Steroidogenic Acute Regulatory Protein; D051742:Transcription Factor CHOP; D015096:3-Hydroxysteroid Dehydrogenases