Mitochondria maintain maturation and secretion of lipoprotein lipase in the endoplasmic reticulum

Abstract

Considering the physiological Ca 2+ 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 Ca 2+ content and mitochondrial contribution to Ca 2+ -dependent protein folding. Exhaustive ER Ca 2+ depletion by inhibition of sarcoplasmic/ 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 (Chinesehamster ovary K1) and endothelial cells respectively, which was not due to decline of mRNA or intracellular protein levels. In contrast, stimulation with the IP 3 (inositol 1,4,5-trisphosphate)-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 is largely maintained during physiological cell stimulation owing to efficient ER Ca 2+ refilling. Since Ca 2+ entry and mitochondrial Ca 2+ homoeostasis are crucial for continuous Ca 2+ -dependent protein maturation in the ER, their pathological alterations may result in dysfunctional protein folding.

Rab32 Modulates Apoptosis Onset and Mitochondria-associated Membrane (MAM) Properties

“…Thus, ER oxidative protein folding appears to determine the properties of the MAM, a function that may explain the increased apposition between the ER and mitochondria upon ER stress (20). In line with these findings, a disruption of the MAM results in a reduced folding capacity of the ER, concomitant with ER stress (12,21,22).…”

Adipogenic potential of skeletal muscle satellite cells

“…Thus, both homodimers and folding intermediates are envisioned as being associated with chaperones and folding factors in the ER lumen, acting to stabilize and catalyze these two main steps in lipase maturation (Figure 4). Indeed, disruption of Ca 2+ levels in the ER, an ion required for proper chaperone function [72], causes cessation of LPL maturation until appropriate levels are restored [110]. …”

Mitochondrial Ca2+ uptake and not mitochondrial motility is required for STIM1-Orai1-dependent store-operated Ca2+ entry

“…The fundamental physiological relevance of SOCE is to ensure an appropriate ER Ca 2+ content even during and/or after cell stimulation with inositol 1,4,5-trisphosphate [Ins(1,4,5)P 3 ]-generating agonists. Accordingly, SOCE was shown to be physiologically relevant, particularly in view of the Ca 2+ dependency of the protein folding machinery within the ER (Osibow et al, 2006a) and to be established in certain lipid rafts as microdomains of Ca 2+ entry (Pani and Singh, 2009). Moreover, SOCE has been reported to significantly contribute to multiple cellular processes such as exocytosis (Fomina and Nowycky, 1999), transcription (Dolmetsch et al, 1998;Ishikawa et al, 2003), formation of second messengers (Lin et al, 2000) and cell death (Lampe et al, 1995), and is now considered as an important ubiquitous physiological mechanism in the regulation of Ca 2+ -dependent cell functions in nearly all cells of the human body.…”