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Related Concept Videos

The Unfolded Protein Response01:37

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The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
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Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
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After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
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Metabolism and the UPR(mt).

Yi-Fan Lin1, Cole M Haynes2

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The mitochondrial unfolded protein response (UPR(mt)) helps cells survive stress by repairing mitochondria. This review highlights its role in metabolic adaptations for recovery and cell-specific functions.

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Area of Science:

  • Cellular Biology
  • Mitochondrial Biology
  • Biochemistry

Background:

  • Mitochondrial dysfunction triggers the mitochondrial unfolded protein response (UPR(mt)) for cell survival and mitochondrial repair.
  • The UPR(mt) is crucial in bacterial infections, stem cell maintenance, and aging.
  • Previous research focused on UPR(mt) in restoring mitochondrial protein homeostasis via chaperones and proteases.

Purpose of the Study:

  • To review the metabolic adaptations mediated by the UPR(mt).
  • To explore how UPR(mt)-induced metabolic rewiring resolves mitochondrial unfolded protein stress.
  • To understand the contribution of UPR(mt) to cell-type-specific physiology.

Main Methods:

  • Literature review of studies on UPR(mt) and cellular metabolism.
  • Analysis of transcriptional targets of UPR(mt) related to metabolic pathways.
  • Integration of findings on UPR(mt) in various physiological and pathological contexts.

Main Results:

  • UPR(mt) activation leads to significant metabolic rewiring beyond protein homeostasis.
  • Specific metabolic pathways are modulated to support mitochondrial recovery and cellular adaptation.
  • These metabolic changes are critical for resolving unfolded protein stress and maintaining cell function.

Conclusions:

  • The UPR(mt) plays a vital role in metabolic adaptation, contributing to mitochondrial health.
  • Metabolic rewiring is a key mechanism by which UPR(mt) promotes cell survival and function.
  • Understanding UPR(mt)-mediated metabolic changes offers insights into treating mitochondrial diseases.