In mammals, ER stress represents a defense mechanism that helps the cells to adapt and survive. This process is referred to as ER-associated degradation (ERAD). The defective proteins are transported to the cytoplasm for degradation. During UPR ER, the sensor molecules anchored at the ER membrane, including inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6) and RNA-dependent protein kinase (PKR)-like ER kinase (PERK), are activated to transduce signals for the induction of various cellular responses. Increased demand for protein synthesis and aggregation of misfolded proteins are the main triggers for ER stress and unfolded protein response (UPR ER), a conserved transcriptional and translational program to stimulate chaperone production and restore proteostasis. ER also plays an essential role in regulating intracellular calcium homeostasis and lipid metabolism. Įndoplasmic reticulum (ER) is a membrane-bound organelle that controls the synthesis, folding, maturation and intracellular transport of proteins. However, accumulating evidence shows that alterations in mitochondria may evoke defense mechanisms to elicit coordinated protective effects on metabolic health and life span. The function of mitochondria decreases with advancing age, and dysfunctional mitochondria are implicated in the development and progression of metabolic diseases. Mitochondrial integrity is maintained through a series of quality control processes such as the mitochondrial unfolded protein response (UPR mt), antioxidant defense, fusion and fission, biogenesis and mitophagy-mediated removal. As an essential powerhouse of mammalian cells, the mitochondrion is crucial for functional regulation of cellular processes, including metabolism, proliferation, survival and death. Approximately 90% of cellular reactive oxygen species (ROS) are produced from mitochondria during the reactions of oxidative phosphorylation (OXPHOS) via the electron transport chain (ETC). In mammalian cells, the mitochondrion is the organelle specialized for energy production through the processes of oxidative phosphorylation, tricarboxylic acid (TCA) cycle and fatty acid β-oxidation.
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