CRIF1 deficiency induces p66shc-mediated oxidative stress and endothelial activation

Harsha Nagar; Saet-byel Jung; Sun Kwan Kwon; Jung-Bum Park; Minho Shong; Hee-Jung Song; Byeong Hwa Jeon; Kaikobad Irani; Cuk-Seong Kim

doi:10.1371/journal.pone.0098670

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CRIF1 deficiency induces p66shc-mediated oxidative stress and endothelial activation

Journal article

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Peer reviewed

CRIF1 deficiency induces p66shc-mediated oxidative stress and endothelial activation

Harsha Nagar, Saet-byel Jung, Sun Kwan Kwon, Jung-Bum Park, Minho Shong, Hee-Jung Song, Byeong Hwa Jeon, Kaikobad Irani and Cuk-Seong Kim

PloS one, Vol.9(6), pp.e98670-e98670

2014

DOI: 10.1371/journal.pone.0098670

PMCID: PMC4048193

PMID: 24906005

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Abstract

Mitochondrial dysfunction has been implicated in the pathophysiology of various cardiovascular diseases. CRIF1 is a protein present in the mitochondria associated with large mitoribosomal subunits, and CRIF1 knockdown induces mitochondrial dysfunction and promotes ROS production. p66shc is a redox enzyme implicated in mitochondrial ROS generation and translation of oxidative signals and, therefore, is a key factor for oxidative stress in endothelial cells. In this study, we investigated whether mitochondrial dysfunction induced by CRIF1 knockdown induces p66shc stimulation and plays any role in mitochondrial dysfunction-induced endothelial activation. Knockdown of CRIF1 decreased the expression of mitochondrial oxidative phosphorylation (OXPHOS) complexes I, III and IV, leading to increased mitochondrial ROS (mtROS) and hyperpolarization of the mitochondrial membrane potential. Knockdown of CRIF1 also stimulated phosphorylation of p66shc and increased cytosolic ROS in endothelial cells. Furthermore, the expression of vascular cell adhesion molecule-1 and endoplasmic reticulum stress proteins were increased upon CRIF1 knockdown in endothelial cells. However, p66shc knockdown blunted the alteration in mitochondrial dynamics and ROS production in CRIF1 knockdown endothelial cells. In addition, p66shc knockdown reduced the CRIF1 knockdown-induced increases in adhesion between monocytes and endothelial cells. Taken together, these results suggest that CRIF1 knockdown partially induces endothelial activation via increased ROS production and phosphorylation of p66shc.

Shc Signaling Adaptor Proteins - metabolism

Reactive Oxygen Species - metabolism

Oxidative Stress

Endothelial Cells - metabolism

Monocytes - cytology

Humans

Oxidative Phosphorylation

Cell Cycle Proteins - deficiency

Mitochondria - metabolism

Cell Adhesion

Gene Knockdown Techniques

Animals

Src Homology 2 Domain-Containing, Transforming Protein 1

Endothelial Cells - cytology

Endoplasmic Reticulum Stress

Human Umbilical Vein Endothelial Cells - cytology

Nuclear Proteins - deficiency

Cell Cycle Proteins - genetics

Mice

Nuclear Proteins - genetics

Vascular Cell Adhesion Molecule-1 - metabolism

Details

Title: Subtitle: CRIF1 deficiency induces p66shc-mediated oxidative stress and endothelial activation
Creators: Harsha Nagar - Department of physiology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea
Saet-byel Jung - Department of Endocrinology, Chungnam National University Hospital, Daejeon, Republic of Korea
Sun Kwan Kwon - Department of physiology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea
Jung-Bum Park - Department of physiology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea
Minho Shong - Department of Endocrinology, Chungnam National University Hospital, Daejeon, Republic of Korea
Hee-Jung Song - Department of neurology, Chungnam National University Hospital, Daejeon, Republic of Korea
Byeong Hwa Jeon - Department of physiology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea
Kaikobad Irani - Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America
Cuk-Seong Kim - Department of physiology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea
Resource Type: Journal article
Publication Details: PloS one, Vol.9(6), pp.e98670-e98670
DOI: 10.1371/journal.pone.0098670
PMID: 24906005
PMCID: PMC4048193
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science; United States
Language: English
Date published: 2014
Academic Unit: Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984047887502771

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