Mitochondrial metabolic regulation by GRP78

ER chaperone GRP78 is the central regulator of adrenals and gonadal steroid synthesis for mammalian survival. Steroids, essential for mammalian survival, are initiated by cholesterol transport by steroidogenic acute regulatory protein (StAR). Appropriate protein folding is an essential requirement of activity. Endoplasmic reticulum (ER) chaperones assist in folding of cytoplasmic proteins, whereas mitochondrial chaperones fold only mitochondrial proteins. We show that glucose regulatory protein 78 (GRP78), a master ER chaperone, is also present at the mitochondria-associated ER membrane (MAM), where it folds StAR for delivery to the outer mitochondrial membrane. StAR expression and activity are drastically reduced following GRP78 knockdown. StAR folding starts at the MAM region; thus, its cholesterol fostering capacity is regulated by GRP78 long before StAR reaches the mitochondria. In summary, GRP78 is an acute regulator of steroidogenesis at the MAM, regulating the intermediate folding of StAR that is crucial for its activity.

• Publication year

  2017

• Venue

  Science Advances

• Publication date

  2017-02-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1126/sciadv.1602038PMID 28275724PMCID 5325540
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• An Outer Mitochondrial Translocase, Tom22, Is Crucial for Inner Mitochondrial Steroidogenic Regulation in Adrenal and Gonadal Tissues

  2016cited by this paper
• Mitochondria-associated Endoplasmic Reticulum Membrane (MAM) Regulates Steroidogenic Activity via Steroidogenic Acute Regulatory Protein (StAR)-Voltage-dependent Anion Channel 2 (VDAC2) Interaction*

  2014influential reference
• MECHANISTIC SEQUENCE OF MITOCHONDRIAL CHOLESTEROL TRANSPORT BY StAR PROTEINS

  2013influential reference
• In Vivo Cross-linking Reveals Principally Oligomeric Forms of α-Synuclein and β-Synuclein in Neurons and Non-neural Cells*

  2013cited by this paper
• σ-1 Receptor at the Mitochondrial-Associated Endoplasmic Reticulum Membrane Is Responsible for Mitochondrial Metabolic Regulation

  2012cited by this paper
• Mitochondrial 3β-Hydroxysteroid Dehydrogenase Enzyme Activity Requires Reversible pH-dependent Conformational Change at the Intermembrane Space*

  2012cited by this paper
• Early steps in steroidogenesis: intracellular cholesterol trafficking

  2011cited by this paper
• Supplemental Figure : Manuscript title : Decreased Cytochrome C Oxidase IV ( COX IV ) Expression Reduces Steroidogenesis

  2011cited by this paper
• The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders.

  2011cited by this paper
• Inner Mitochondrial Translocase Tim50 Interacts with 3β-Hydroxysteroid Dehydrogenase Type 2 to Regulate Adrenal and Gonadal Steroidogenesis*

  2011influential reference
• Interactions between the endoplasmic reticulum, mitochondria, plasma membrane and other subcellular organelles.

  2009cited by this paper
• An ER-Mitochondria Tethering Complex Revealed by a Synthetic Biology Screen

  2009cited by this paper
• Cholesterol-induced fluid membrane domains: a compendium of lipid-raft ternary phase diagrams.

  2009cited by this paper
• Steroidogenic Activity of StAR Requires Contact with Mitochondrial VDAC1 and Phosphate Carrier Protein

  2008influential reference
• Folding, activity and import of steroidogenic acute regulatory protein into mitochondria changed by nicotine exposure.

  2007cited by this paper
• Structural and functional features and significance of the physical linkage between ER and mitochondria

  2006cited by this paper
• How principles of domain formation in model membranes may explain ambiguities concerning lipid raft formation in cells.

  2005cited by this paper
• A simplified method for the preparation of detergent-free lipid rafts Published, JLR Papers in Press, February 16, 2005. DOI 10.1194/jlr.D400041-JLR200

  2005cited by this paper
• pH-dependent Interactions of the Carboxyl-terminal Helix of Steroidogenic Acute Regulatory Protein with Synthetic Membranes*

  2005cited by this paper
• The role of the unfolded protein response in tumour development: friend or foe?

  2004cited by this paper
• Protein folding and misfolding

  2003cited by this paper
• For whom the bell tolls: protein quality control of the endoplasmic reticulum and the ubiquitin–proteasome connection

  2003cited by this paper
• Detergent-free domain isolated from Xenopus egg plasma membrane with properties similar to those of detergent-resistant membranes.

  2002cited by this paper
• Rapid regulation of steroidogenesis by mitochondrial protein import

  2002cited by this paper
• Molecular Chaperones in the Cytosol: from Nascent Chain to Folded Protein

  2002cited by this paper
• Binding of Steroidogenic Acute Regulatory Protein to Synthetic Membranes Suggests an Active Molten Globule*

  2001cited by this paper
• Aggresomes, inclusion bodies and protein aggregation.

  2000cited by this paper
• START: a lipid-binding domain in StAR, HD-ZIP and signalling proteins.

  1999cited by this paper
• The dimensions of the protein import channels in the outer and inner mitochondrial membranes.

  1999cited by this paper
• The active form of the steroidogenic acute regulatory protein, StAR, appears to be a molten globule.

  1999cited by this paper
• Electron microscopic tomography of rat‐liver mitochondria and their interactions with the endoplasmic reticulum

  1998cited by this paper
• Intracellular Cholesterol Trafficking

  1998influential reference
• The Hsp70 and Hsp60 chaperone machines.

  1998cited by this paper
• The pathophysiology and genetics of congenital lipoid adrenal hyperplasia.

  1996cited by this paper
• Regulation of the acute production of steroids in steroidogenic cells.

  1996cited by this paper
• The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR).

  1994cited by this paper
• Phospholipid synthesis in a membrane fraction associated with mitochondria.

  1990cited by this paper
• Coupled cell-free synthesis, segregation, and core glycosylation of a secretory protein.

  1978cited by this paper

• Computational characterization of GRP78 binding sites on mitochondrial GPX4: implications for targeting ferroptosis in triple-negative breast cancer

  2026cites this paper
• Mitochondria–ER crosstalk via MAMS: Bridging cellular homeostasis and cancer progression

  2026cites this paper
• The role of mitochondrial-associated endoplasmic reticulum membranes (MAMs) in diabetic microvascular complications: a review

  2025cites this paper
• Endoplasmic reticulum stress and steroidogenic dysfunction in Leydig cells: Molecular mechanisms of UPR-mediated testosterone regulation.

  2025cites this paper
• Adrenocortical Mitochondria-Associated Membranes: Isolation, Characterization, and Lipidoproteomic Response to Mitotane

  2025cites this paper
• Cholesterol Transport from ER to Outer Mitochondria by ERLIN2 in Steroid Metabolism.

  2025cites this paper
• Enzymes of the outer mitochondrial membrane regulating cholesterol and fatty acid metabolism in cancer.

  2025cites this paper
• STAR/STARD1: A mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.

  2025cites this paper
• Protocol for assessing mitochondrial cholesterol transport and protein molten globule state in steroidogenic and nonsteroidogenic systems

  2025cites this paper
• The role of mitochondria-endoplasmic reticulum crosstalk in colorectal cancer

  2025cites this paper
• Stress-induced translocation of the endoplasmic reticulum chaperone GRP78/BiP and its impact on human disease and therapy

  2025cites this paper
• Raphin‐1 mediates the survival and sensitivity to radiation of pediatric‐type diffuse high‐grade glioma via phosphorylated eukaryotic initiation factor 2α‐dependent and ‐independent processes

  2025cites this paper
• Lipid metabolism in the adrenal gland

  2025cites this paper
• STAR/STARD1: a mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy

  2025cites this paper
• PCSK9 Regulates Cardiac Mitochondrial Cholesterol by Promoting TSPO Degradation

  2025cites this paper
• Thirty years of StAR gazing. Expanding the universe of the steroidogenic acute regulatory protein

  2025cites this paper
• Loss of Myostatin Affects m6A Modification but Not Semen Characteristics in Bull Spermatozoa

  2025cites this paper
• Molecular characterization of the murine Leydig cell lines TM3 and MLTC-1

  2025cites this paper
• Dry molten globule conformational state of CYP11A1 (SCC) regulates the first step of steroidogenesis in the mitochondrial matrix

  2024cites this paper
• PTGS2/GRP78 Activation Triggers Endoplasmic Reticulum Stress Leading to Lipid Metabolism Disruption and Cell Apoptosis, Exacerbating Damage in Bovine Mastitis

  2024cites this paper
• MAM-mediated mitophagy and endoplasmic reticulum stress: the hidden regulators of ischemic stroke

  2024cites this paper
• Targeting endoplasmic reticulum stress as a potential therapeutic strategy for diabetic cardiomyopathy.

  2024cites this paper
• Interplay of α-Synuclein Oligomers and Endoplasmic Reticulum Stress in Parkinson'S Disease: Insights into Cellular Dysfunctions

  2024cites this paper
• Transcriptomic Analysis of Cardiac Tissues in a Rodent Model of Coronary Microembolization

  2024cites this paper
• Integrated stress response mediates HSP70 to inhibit testosterone synthesis in aging testicular Leydig cells.

  2024cites this paper
• GRP78 via releasing β-catenin from adherens junctions facilitates its interaction with STAT3 in mediating retinal neovascularization.

  2024cites this paper
• Targeting protein interaction networks in mitochondrial dynamics for neurodegenerative diseases

  2024cites this paper
• Steroidogenesis Upregulation through Mitochondria-Associated Endoplasmic Reticulum Membranes and Mitochondrial Dynamics in Rat Testes: The Role of D-Aspartate

  2024cites this paper
• Mitochondria-associated endoplasmic reticulum membranes: A promising toxicity regulation target.

  2023cites this paper
• The role of endoplasmic reticulum-mitochondria-associated membranes in diabetic kidney disease.

  2023cites this paper
• DJ-1 inhibits ferroptosis in cerebral ischemia-reperfusion via ATF4/HSPA5 pathway.

  2023cites this paper
• Novel tumor therapy strategies targeting endoplasmic reticulum-mitochondria signal pathwaysRunning title_ Tumor therapy based on ER-mitochondria interactions

  2023cites this paper
• The interaction network of the proteasome assembly chaperone PSMD9 regulates proteostasis

  2023cites this paper
• Mitochondria are midfield players in steroid synthesis.

  2023cites this paper
• Novel tumor therapy strategies targeting endoplasmic reticulum-mitochondria signal pathways.

  2023cites this paper
• Tom40 in cholesterol transport.

  2023cites this paper
• Protocol for direct measurement of stability and activity of mitochondria electron transport chain complex II

  2023cites this paper
• Pyk2 Regulates MAMs and Mitochondrial Dynamics in Hippocampal Neurons

  2022cites this paper
• Self-Reinforced Cancer Targeting (SRCT) Depending on Reciprocally Enhancing Feedback between Targeting and Therapy.

  2022cites this paper
• PKA/ATGL signaling pathway is involved in ER stress-mediated lipolysis in adipocytes of grass carp (Ctenopharyngodon idella)

  2022cites this paper
• Self-Activated Cascade Biocatalysis of Glucose Oxidase-Polycation-Iron Nanoconjugates Augments Cancer Immunotherapy.

  2022cites this paper
• Only one carbon difference determines the pro‐apoptotic activity of α‐tocopheryl esters

  2022cites this paper
• Androgen Metabolism and Response in Prostate Cancer Anti-Androgen Therapy Resistance

  2022cites this paper
• GRP78 Activity Moderation as a Therapeutic Treatment against Obesity

  2022cites this paper
• Ischemic-hypoxic preconditioning enhances the mitochondrial function recovery of transplanted olfactory mucosa mesenchymal stem cells via miR-181a signaling in ischemic stroke

  2021cites this paper
• The role of inactivated NF-κB in the occurrence of premature ovarian failure.

  2021cites this paper
• Endoplasmic Reticulum-Mitochondria Contacts: A Potential Therapy Target for Cardiovascular Remodeling-Associated Diseases

  2021cites this paper
• Insights into the Pathogenesis of Neurodegenerative Diseases: Focus on Mitochondrial Dysfunction and Oxidative Stress

  2021cites this paper
• Effects of High-Flux Dialysis Combined with Hemoperfusion on Serum GRP78 and miR-495-3p in Renal Failure Patients

  2021cites this paper
• Hepatokine Pregnancy Zone Protein Governs the Diet‐Induced Thermogenesis Through Activating Brown Adipose Tissue

  2021cites this paper
• Regulation of Estradiol Synthesis by Aromatase Interacting Partner in Breast (AIPB)

  2021influential citation
• Molecular Dysfunctions of Mitochondria-Associated Endoplasmic Reticulum Contacts in Atherosclerosis

  2021influential citation
• High-Throughput Screen Detects Calcium Signaling Dysfunction in Hutchinson-Gilford Progeria Syndrome

  2021cites this paper
• Turmeric and vitamin C mitigate testicular atrophy induced by lead diacetate via regulation of GRP‐78/17β‐HSD pathways in rat's model

  2021cites this paper
• Expression of the Endoplasmic Reticulum Stress Marker GRP78 in the Normal Retina and Retinal Degeneration Induced by Blue LED Stimuli in Mice

  2021cites this paper
• Distinctive functioning of STARD1 in the fetal Leydig cells compared to adult Leydig and adrenal cells. Impact of Hedgehog signaling via the primary cilium.

  2021cites this paper
• Electron Transport Chain Complex II Regulates Steroid Metabolism

  2020cites this paper
• Molecular Dysfunctions of Mitochondria-Associated Membranes (MAMs) in Alzheimer’s Disease

  2020influential citation
• Alzheimer’s Disease: Pathology, Diagnosis and Therapeutic Management

  2020cites this paper
• Inducing Endoplasmic Reticulum Stress to Expose Immunogens: A DNA Tetrahedron Nanoregulator for Enhanced Immunotherapy

  2020cites this paper
• STARD1 Functions in Mitochondrial Cholesterol Metabolism and Nascent HDL Formation. Gene Expression and Molecular mRNA Imaging Show Novel Splicing and a 1:1 Mitochondrial Association

  2020cites this paper
• Mitochondria-Associated Endoplasmic Reticulum Membranes in the Pathogenesis of Type 2 Diabetes Mellitus

  2020cites this paper
• Waterborne copper exposure up-regulated lipid deposition through the methylation of GRP78 and PGC1α of grass carp Ctenopharyngodon idella.

  2020cites this paper
• Modelling of dysregulated glucagon secretion in type 2 diabetes by considering mitochondrial alterations in pancreatic α-cells

  2020cites this paper
• StAR, a bridge from ApoE, LDL, and HDL cholesterol trafficking to mitochondrial metabolism

  2019cites this paper
• Role of HSP60 in Steroidogenesis and Reproduction

  2019cites this paper
• Possible Mechanisms for Maintenance and Regression of Corpus Luteum Through the Ubiquitin-Proteasome and Autophagy System Regulated by Transcriptional Factors

  2019cites this paper
• Proteomic Analysis of Porcine Pre-ovulatory Follicle Differentiation Into Corpus Luteum

  2019cites this paper
• Cyclooxygenase-2 modulates ER-mitochondria crosstalk to mediate superparamagnetic iron oxide nanoparticles induced hepatotoxicity: an in vitro and in vivo study

  2019cites this paper
• Mitochondrial Cholesterol in Alzheimer's Disease and Niemann–Pick Type C Disease

  2019cites this paper
• Mechanistic Connections between Endoplasmic Reticulum (ER) Redox Control and Mitochondrial Metabolism

  2019cites this paper
• Deficient pregnenolone synthesis associated with congenital adrenal hyperplasia and organelle dysfunction

  2019cites this paper
• Steroidogenic Acute Regulatory Protein: Structure, Functioning, and Regulation

  2019cites this paper
• Organization of Ovarian Steroidogenic Cells and Cholesterol Metabolism

  2019cites this paper
• Outside the Endoplasmic Reticulum: Non-Canonical GRP78 Signaling

  2019cites this paper
• ER-mitochondria interactions: Both strength and weakness within cancer cells.

  2019cites this paper
• The Interplay between Glucose-Regulated Protein 78 (GRP78) and Steroids in the Reproductive System

  2018influential citation
• Inner Mitochondrial Translocase Tim50 Is Central in Adrenal and Testicular Steroid Synthesis

  2018cites this paper
• Involvement of adenosine monophosphate activated kinase in interleukin‐6 regulation of steroidogenic acute regulatory protein and cholesterol side chain cleavage enzyme in the bovine zona fasciculata and zona reticularis

  2018cites this paper
• Lysosomal Cholesterol Hydrolysis Couples Efferocytosis to Anti-Inflammatory Oxysterol Production

  2018cites this paper
• Interaction of the cryptic fragment of myelin basic protein with mitochondrial voltage-dependent anion-selective channel-1 affects cell energy metabolism.

  2018influential citation
• Current knowledge on the acute regulation of steroidogenesis†

  2018cites this paper
• Steroidogenesis: Unanswered Questions.

  2017cites this paper
• Mutation Spectrum of STAR and the Founder Effect of p.Q258* in Korean Patients with Congenital Lipoid Adrenal Hyperplasia

  2017cites this paper
• Mutational analysis of rare subtypes of congenital adrenal hyperplasia in a highly inbred population.

  2017cites this paper
• Intracellular Cholesterol Trafficking and Impact in Neurodegeneration

  2017cites this paper
• De novo disruption of promoter and exon 1 of STAR gene reveals essential role for gonadal development

  2017cites this paper
• Mitochondria-Associated Membranes As Networking Platforms and Regulators of Cancer Cell Fate

  2017influential citation