Mitochondria maintain maturation and secretion of lipoprotein lipase in the endoplasmic reticulum
Résumé
Considering the physiological Ca 2+} dynamics within the endoplasmic reticulum (ER), it remains unclear how efficient protein folding is maintained in living cells. Thus, utilizing the strictly folding dependent activity and secretion of lipoprotein lipase (LPL), we evaluated the impact of ER Ca 2+} content and mitochondrial contribution to Ca 2+}-dependent protein folding. Exhaustive ER Ca 2+} depletion by inhibition of sarco/endoplasmic reticulum Ca 2+} ATPases caused strong but reversible reduction of cell associated and released activity of constitutive and adenovirus encoded human LPL in CHO-K1 and endothelial cells, respectively, which was not due to decline of mRNA or intracellular protein levels. In contrast, stimulation with the IP3-generating agonist histamine only moderately and transiently affected LPL maturation in endothelial cells that paralleled a basically preserved ER Ca 2+} content. However, in the absence of extracellular Ca 2+} or upon prevention of transmitochondrial Ca 2+} flux, LPL maturation discontinued upon histamine stimulation. Collectively, these data indicate that Ca 2+}-dependent protein folding in the ER is predominantly controlled by intraluminal Ca 2+} and largely maintained during physiological cell stimulation due to efficient ER Ca 2+} refilling. Since Ca 2+} entry and mitochondrial Ca 2+} homeostasis are crucial for continuous Ca 2+}-dependent protein maturation in the ER, their pathological alterations may result in dysfunctional protein folding.
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