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ER Protein Processing Under Oxidative Stress: Implications and Prevention

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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.

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Acknowledgments

The authors would like to express special thanks to the staff of the Cytometry, Screening, and Imaging Core Facility of the Border Biomedical Research Center at The University of Texas at El Paso (UTEP). This facility is supported by Grant # 2G12MD007592 and Grant # 5G12MD007592 from the Research Centers in Minority Institutions program of the National Institutes on Minority Health and Health Disparities. In addition, M.N. would like to thank Dr. Eddie Vazquez and Mrs. Holly Vazquez (The El Paso Pain Center) for their financial support.

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    Authors and Affiliations

    1. 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

      Mahmoud F. Khalil, Carlos Valenzuela, Rachid Skouta & Mahesh Narayan

    2. Boston University School of Medicine, 72 E Concord St, Boston, MA, 02118, USA

      Daniella Sisniega

    3. Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX, 79968, USA

      Rachid Skouta

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    1. Mahmoud F. Khalil
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    2. Carlos Valenzuela
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    Correspondence to Rachid Skouta or Mahesh Narayan.

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    Carlos Valenzuela and Daniella Sisniega have been contributed equally to this work.

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    Khalil, M.F., Valenzuela, C., Sisniega, D. et al. ER Protein Processing Under Oxidative Stress: Implications and Prevention. Cell Biochem Biophys 74, 213–220 (2016). https://doi.org/10.1007/s12013-016-0726-9

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    • DOI: https://doi.org/10.1007/s12013-016-0726-9

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