ER Protein Processing Under Oxidative Stress: Implications and Prevention

Authors

Mahmoud F. Khalil, Department of Chemistry, University of Texas at El Paso, 500 W. University Ave., Chemistry and Computer Science Building 2.0202, 121 A Spiel Paso, El Paso, TX, 79968, USA.
Carlos Valenzuela, Department of Chemistry, University of Texas at El Paso, 500 W. University Ave., Chemistry and Computer Science Building 2.0202, 121 A Spiel Paso, El Paso, TX, 79968, USA.
Daniella Sisniega, Boston University School of Medicine, 72 E Concord St, Boston, MA, 02118, USA.
Rachid Skouta, Department of Chemistry, University of Texas at El Paso, 500 W. University Ave., Chemistry and Computer Science Building 2.0202, 121 A Spiel Paso, El Paso, TX, 79968, USA. rskouta@utep.edu.
Mahesh Narayan, Department of Chemistry, University of Texas at El Paso, 500 W. University Ave., Chemistry and Computer Science Building 2.0202, 121 A Spiel Paso, El Paso, TX, 79968, USA. mnarayan@utep.edu.

Document Type

Article

Abstract

Elevated levels of mitochondrial nitrosative stress have been associated with the pathogenesis of both Parkinson's and Alzheimer's diseases. The mechanism involves catalytic poisoning of the endoplasmic reticulum (ER)-resident oxidoreductase chaperone, protein disulfide isomerase (PDI), and the subsequent accumulation of ER-processed substrate proteins. Using a model system to mimic mitochondrial oxidative and nitrosative stress, we demonstrate a PDI-independent mechanism whereby reactive oxygen species (ROS) compromise regeneration rates of disulfide bond-containing ER-processed proteins. Under ROS-duress, the secretion-destined traffic adopts disulfide-exposed structures making the protein flux retrotranslocation biased. We also demonstrate that ROS-compromised protein maturation rates can be rescued by the polyphenol ellagic acid (EA). Our results are significant in that they reveal an additional mechanism which could promote neurodegenerative disorders. Furthermore, our data reveal that EA possesses therapeutic potential as a lead prophylactic agent against oxidative/nitrosative stress-related neurodegenerative diseases.

Medical Subject Headings

Animals; Biphenyl Compounds (metabolism); Cattle; Disulfides (chemistry); Endoplasmic Reticulum (metabolism); Oxidative Stress; Picrates (metabolism); Protein Processing, Post-Translational; Reactive Oxygen Species (metabolism); Ribonuclease, Pancreatic (chemistry, metabolism)

Publication Date

6-1-2016

Publication Title

Cell biochemistry and biophysics

E-ISSN

1559-0283

Volume

74

Issue

2

First Page

213

Last Page

20

PubMed ID

26983927

Digital Object Identifier (DOI)

10.1007/s12013-016-0726-9

Recommended Citation

Khalil, Mahmoud F.; Valenzuela, Carlos; Sisniega, Daniella; Skouta, Rachid; and Narayan, Mahesh, "ER Protein Processing Under Oxidative Stress: Implications and Prevention" (2016). Neurology. 1903.
https://scholar.barrowneuro.org/neurology/1903