Mitochondrial metabolic regulation by GRP78.
Manoj PrasadKevin J PawlakWilliam E BurakElizabeth E PerryBrendan MarshallRandy M WhittalHimangshu S BosePublished in: Science advances (2017)
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.
Keyphrases
- endoplasmic reticulum
- endoplasmic reticulum stress
- oxidative stress
- single molecule
- cell surface
- liver failure
- molecular dynamics simulations
- transcription factor
- protein protein
- binding protein
- heat shock
- respiratory failure
- amino acid
- type diabetes
- blood pressure
- metabolic syndrome
- insulin resistance
- aortic dissection
- small molecule
- breast cancer cells
- estrogen receptor
- acute respiratory distress syndrome
- mechanical ventilation
- heat stress