title: Mitochondria maintain maturation and secretion of lipoprotein lipase in the endoplasmic reticulum.
abstract: Considering the physiological Ca2+ dynamics within the ER (endoplasmic reticulum), it remains unclear how efficient protein folding is maintained in living cells. Thus, utilizing the strictly folding-dependent activity and secretion of LPL (lipoprotein lipase), we evaluated the impact of ER Ca2+ content and mitochondrial contribution to Ca2+-dependent protein folding. Exhaustive ER Ca2+ depletion by inhibition of sarcoplasmic/endoplasmic reticulum Ca2+-ATPases caused strong, but reversible, reduction of cell-associated and released activity of constitutive and adenovirus-encoded human LPL in CHO-K1 (Chinese-hamster ovary K1) and endothelial cells respectively, which was not due to decline of mRNA or intracellular protein levels. In contrast, stimulation with the IP3 (inositol 1,4,5-trisphosphate)-generating agonist histamine only moderately and transiently affected LPL maturation in endothelial cells that paralleled a basically preserved ER Ca2+ content. However, in the absence of extracellular Ca2+ or upon prevention of transmitochondrial Ca2+ flux, LPL maturation discontinued upon histamine stimulation. Collectively, these data indicate that Ca2+-dependent protein folding in the ER is predominantly controlled by intraluminal Ca2+ and is largely maintained during physiological cell stimulation owing to efficient ER Ca2+ refilling. Since Ca2+ entry and mitochondrial Ca2+ homoeostasis are crucial for continuous Ca2+-dependent protein maturation in the ER, their pathological alterations may result in dysfunctional protein folding.
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University Graz, Harrachgasse 21/III, 8010 Graz, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Osibow
authors.forename: Sasa
authors.initials: S
authors.lastname: Frank
authors.forename: Roland
authors.initials: R
authors.lastname: Malli
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zechner
authors.forename: Wolfgang F
authors.initials: WF
authors.lastname: Graier
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D016466:CHO Cells / Q000378:metabolism; D002118:Calcium / Q000502:physiology*; D020013:Calcium Signaling; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D002998:Clonazepam / Q000031:analogs & derivatives / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D005822:Genetic Vectors; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000819:agonists; D008071:Lipoprotein Lipase / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology*; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013841:Thiazepines / Q000494:pharmacology
chemical_list: D006873:Hydroquinones; D011993:Recombinant Fusion Proteins; D013841:Thiazepines; C019359:2,5-di-tert-butylhydroquinone; D002998:Clonazepam; C079032:CGP 37157; D006632:Histamine; D015544:Inositol 1,4,5-Trisphosphate; D008071:Lipoprotein Lipase; D000252:Calcium-Transporting ATPases; D002118:Calcium