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The Unfolded Protein Response01:37

The Unfolded Protein Response

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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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Regulation of the Unfolded Protein Response01:31

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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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Export of Misfolded Proteins out of the ER01:32

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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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Mitochondrial Precursor Proteins01:39

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Mitochondrial precursors are partially unfolded or loosely folded polypeptide chains. Newly synthesized precursors are inhibited from spontaneously folding into their native conformation by the cytosolic chaperones, heat shock proteins 70 (Hsp70), and mitochondrial import stimulation factors (MSFs). Precursors bound to MSFs are guided to the TOM70-TOM37 receptors, while precursors bound to Hsp70  chaperones are targetted to TOM20-TOM22 receptor complexes.
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Mitochondrial Protein Sorting01:39

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Mitochondria are double-membrane organelles of the eukaryotes involved in cellular metabolism, signaling, ATP synthesis, and programmed cell death.  Each of these processes requires specific proteins and enzymes that must be correctly sorted to the right mitochondrial subcompartment for the proper functioning of the organelle.
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Translocation of Proteins into the Mitochondria01:19

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Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
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Mitochondrial UPR: A Double-Edged Sword.

Ye Tian1, Carsten Merkwirth1, Andrew Dillin1

  • 1Howard Hughes Medical Institute and Department of Molecular and Cell Biology, Glenn Center for Aging Research, University of California, Berkeley, Berkeley, CA 94720, USA.

Trends in Cell Biology
|July 11, 2016
PubMed
Summary
This summary is machine-generated.

The mitochondrial unfolded protein response aids mitochondria but unexpectedly preserves harmful mitochondrial DNA (mtDNA) mutations in C. elegans. This finding reveals new insights into mtDNA diseases and potential therapeutic targets.

Keywords:
ATFS-1OXPHOSUPR(mt)mitochondrial diseasemitochondrial heteroplasmymtDNA deletion

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Area of Science:

  • Mitochondrial Biology
  • Genetics
  • Cellular Stress Response

Background:

  • The mitochondrial unfolded protein response (UPR(mt)) is a protective pathway that helps dysfunctional mitochondria recover.
  • Mitochondrial DNA (mtDNA) mutations can lead to severe cellular dysfunction and disease.
  • Heteroplasmy, the presence of both normal and mutated mtDNA, presents unique challenges in understanding mitochondrial health.

Purpose of the Study:

  • To investigate the role of the UPR(mt) in managing mitochondrial dysfunction caused by mtDNA mutations.
  • To explore the consequences of UPR(mt) activation in the context of mtDNA heteroplasmy.
  • To identify potential therapeutic strategies for mtDNA-related disorders.

Main Methods:

  • Utilized a heteroplasmic Caenorhabditis elegans model with deleterious mtDNA mutations.
  • Induced and monitored the activation of the UPR(mt) pathway.
  • Assessed the impact of UPR(mt) on mtDNA integrity and organismal health.

Main Results:

  • UPR(mt) activation, while intended to restore mitochondrial function, inadvertently maintained and propagated the deleterious mtDNA mutations.
  • This propagation of mutated mtDNA by the UPR(mt) led to detrimental consequences for the organism.
  • The study highlights a paradoxical effect of a key cellular stress response.

Conclusions:

  • The UPR(mt) pathway's role in mtDNA heteroplasmy is more complex than previously understood.
  • Unexpectedly, UPR(mt) can exacerbate the propagation of harmful mtDNA mutations.
  • Targeting the UPR(mt) pathway may offer a novel therapeutic avenue for diseases linked to mtDNA mutations.