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Mitochondrial metabolic regulation by GRP78.
Manoj Prasad1, Kevin J Pawlak1, William E Burak2
1Laboratory of Biochemistry and Cell Biology, Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA.
Science Advances
|March 10, 2017
Summary
Glucose regulatory protein 78 (GRP78) chaperones steroidogenic acute regulatory protein (StAR) folding at the mitochondria-associated ER membrane (MAM). This process is crucial for steroidogenesis, regulating StAR activity before it reaches the mitochondria.
Area of Science:
- Cell Biology
- Biochemistry
- Endocrinology
Background:
- Steroidogenesis, vital for mammalian survival, relies on cholesterol transport mediated by the steroidogenic acute regulatory protein (StAR).
- Proper protein folding is critical for StAR activity, with endoplasmic reticulum (ER) chaperones handling cytoplasmic proteins and mitochondrial chaperones folding mitochondrial proteins.
Purpose of the Study:
- To investigate the role of glucose regulatory protein 78 (GRP78), a key ER chaperone, in the folding and regulation of StAR.
- To determine if GRP78 is involved in StAR processing at the mitochondria-associated ER membrane (MAM).
Main Methods:
- Studied the localization and function of GRP78 at the MAM.
- Utilized GRP78 knockdown to assess its impact on StAR expression and activity.
- Investigated the site of StAR folding initiation.
Main Results:
- GRP78 was found to be present at the MAM, where it facilitates the folding of StAR for subsequent delivery to the outer mitochondrial membrane.
- GRP78 knockdown led to a significant reduction in both StAR expression and activity.
- StAR folding was demonstrated to initiate at the MAM, indicating GRP78's regulatory role prior to mitochondrial import.
Conclusions:
- GRP78 acts as an acute regulator of steroidogenesis at the MAM.
- GRP78 regulates the intermediate folding of StAR at the MAM, a step essential for its biological activity and cholesterol transport function.
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