Endoplasmic Reticulum Stress Enhances Mitochondrial Metabolic Activity in Mammalian Adrenals and Gonads

Author:

Prasad Manoj1,Walker Anna N.2,Kaur Jasmeet13,Thomas James L.4,Powell Shirley A.4,Pandey Amit V.5,Whittal Randy M.6,Burak William E.3,Petruzzelli Guy3,Bose Himangshu S.13

Affiliation:

1. Laboratory of Biochemistry and Cell Biology, Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia, USA

2. Department of Pathology, Mercer University School of Medicine, Macon, Georgia, USA

3. Memorial University Medical Center, Anderson Cancer Institute, Savannah, Georgia, USA

4. Division of Basic Medical Sciences, Mercer University School of Medicine, Macon, Georgia, USA

5. Pediatric Endocrinology Diabetology & Metabolism, University Children's Hospital Bern, Bern, Switzerland

6. Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada

Abstract

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.

Funder

National Institutes of Health

Anderson Cancer Institute, Memorial Health

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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