Related Experiment Video

Updated: Oct 28, 2025

Evaluation of the Impact of Protein Aggregation on Cellular Oxidative Stress in Yeast
11:04

Evaluation of the Impact of Protein Aggregation on Cellular Oxidative Stress in Yeast

Published on: June 23, 2018

7.5K

Effect of the mitochondrial unfolded protein response on hypoxic death and mitochondrial protein aggregation

Junyi Yan1,2,3, Chun-Ling Sun1,2, Seokyung Shin1,2,4

  • 1Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, WA, 98109, USA.

Cell Death & Disease
|July 16, 2021
PubMed

Insights

Hypoxia causes mitochondrial dysfunction and protein aggregation. While the mitochondrial unfolded protein response (UPRmt) mitigates aggregation, it doesn't guarantee protection against hypoxic cell death.

Area of Science:

  • Cellular biology
  • Mitochondrial function
  • Hypoxia research

Background:

  • Mitochondria are central to cellular oxygen consumption and are highly sensitive to hypoxia.
  • Hypoxia-induced mitochondrial dysfunction is a presumed driver of cellular pathology.
  • Early hypoxic events include disrupted mitochondrial proteostasis, UPRmt activation, and protein aggregation.

Purpose of the Study:

  • To investigate the relationship between hypoxic cell death, UPRmt activation, and hypoxia-induced mitochondrial protein aggregation (HIMPA) in *C. elegans*.
  • To determine if UPRmt activation is essential for or sufficient to confer resistance to hypoxic cell death.
  • To elucidate the protective role of UPRmt against specific hypoxic pathologies.

Main Methods:

  • Screening of RNAi and mutants in *C. elegans* for resistance to hypoxic cell death or UPRmt induction.
  • Analysis of hypoxia-induced mitochondrial protein aggregation (HIMPA).
  • Comparative assessment of UPRmt activation and hypoxic cell death resistance.

Main Results:

  • Resistance to hypoxic cell death consistently reduced HIMPA.
  • UPRmt activation consistently reduced HIMPA.
  • UPRmt activation was neither necessary nor sufficient for resistance to hypoxic death, and vice versa.

Conclusions:

  • UPRmt activation protects against mitochondrial protein aggregation during hypoxia.
  • UPRmt is not invariably protective against hypoxia-induced cell death.
  • Mitochondrial protein aggregation is a key early pathology in *C. elegans* hypoxia, distinct from cell death pathways.

More Related Videos

Isolation and Functional Analysis of Mitochondria from Cultured Cells and Mouse Tissue09:27

Isolation and Functional Analysis of Mitochondria from Cultured Cells and Mouse Tissue

Published on: March 23, 2015

40.0K
A Flow Cytometry-based Assay for Measuring Mitochondrial Membrane Potential in Cardiac Myocytes After Hypoxia/Reoxygenation07:14

A Flow Cytometry-based Assay for Measuring Mitochondrial Membrane Potential in Cardiac Myocytes After Hypoxia/Reoxygenation

Published on: July 13, 2018

14.7K

Related Concept Videos

Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

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...
2.7K
The Unfolded Protein Response01:37

The Unfolded Protein Response

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...
5.5K
Translocation of Proteins into the Mitochondria01:19

Translocation of Proteins into the Mitochondria

Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
9.3K
Mitochondrial Protein Sorting01:39

Mitochondrial Protein Sorting

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.
Most of these mitochondrial proteins are encoded by the nucleus and imported to the mitochondria as unfolded or loosely folded precursors. Mitochondrial precursors...
4.9K
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
7.2K
Mitochondrial Precursor Proteins01:39

Mitochondrial Precursor Proteins

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.
Most of the mitochondrial...
3.0K