Abstract
The endoplasmic reticulum (ER) is a dynamic organelle essential for intracellular homeostasis maintenance, controlling synthesis, the folding of secreted and membrane-bound proteins, and transport of Ca2+. During cellular stress, ER dysfunction leads to the activation of unfolded protein response (UPR) due to accumulated misfolded proteins in the ER. This condition is referred as ER stress. Mitochondria and ER form a site of close contact (the mitochondria-associated membrane, MAM) which is a major platform exerting important physiological roles in the regulation of intracellular Ca2+ homeostasis, lipid metabolism, mitochondrial fission, autophagosome formation, and apoptosis progression. Natural products have been receiving increasing attention for their ability to interfere with ER stress. Research works have focused on the capacity of these bioactive compounds to induce apoptosis by activating ER stress through the ER stress-mediated mitochondrial apoptotic pathway. In this review we discuss the role of natural products in the signaling communication between ER and mitochondria, focusing on the effects induced by ER stress including Ca2+ permeability transition and UPR signaling (protein kinase R-like ER kinase/mitofusin 2).
Highlights
Nature has been a source of bioactive compounds for millennia, with many useful drugs developed from plant sources
In this review we discuss the role of natural products in the signaling communication between endoplasmic reticulum (ER) and mitochondria, focusing on the effects induced by ER stress including Ca2+ permeability transition and unfolded protein response (UPR) signaling
The results showed how the HepG2 cells exhibited a gradual decrease in the Mfn2 protein levels and how small interfering RNA knock-down of Mfn2 resulted in a remarkable aggravation of ER stress through the inhibition of protein kinase B (Akt) phosphorylation
Summary
Nature has been a source of bioactive compounds for millennia, with many useful drugs developed from plant sources. Activating transcription factor 6 (ATF6), protein kinase R-like ER kinase (PERK), and inositol-requiring enzyme 1 (IRE1) are the three main transmembrane proteins initiating UPR signaling in ER stress response [5]. In normal conditions they are maintained in an inactive state. Several studies showed that natural compounds targeting components of UPR and reducing ER stress play an important role in heart failure, ischemic heart disease, and atherosclerosis, representing a potential approach to treat cardiovascular diseases [15]. Sustained high levels of Ca2+ in mitochondria cause the release of cytochrome c apoptotic protease activating factor-1 (Apaf-1), and ATP binds to procaspase 9, leading to apoptosome formation and activation of caspase 9, which in turn activates caspase 3, triggering death signals [22]
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