Redox Regulation of Mitochondrial Fission Protein Drp1 by Protein Disulfide Isomerase Limits Endothelial Senescence

Young-Mee Kim,Seock-Won Youn,Varadarajan Sudhahar,Archita Das,Reyhaan Chandhri,Henar Cuervo Grajal,Junghun Kweon,Silvia Leanhart,Lianying He,Peter T Toth,Jan Kitajewski,Jalees Rehman,Yisang Yoon,Jaehyung Cho,Tohru Fukai,Masuko Ushio-Fukai

doi:10.1016/j.celrep.2018.05.054

Young-Mee Kim, Seock-Won Youn + Show 14 more

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https://doi.org/10.1016/j.celrep.2018.05.054

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Abstract

In BriefKim et al. demonstrate a molecular link between PDIA1 and Drp1 oxidoreduction, which protects against mitochondrial fragmentation and ROS elevation, limiting endothelial senescence. This study provides insights into restoring endothelial PDIA1 function or targeting Drp1 Cys oxidation as potential therapeutic strategies for treating diabetes-associated vascular and metabolic diseases.

Highlights

Endothelial cells (ECs) with senescence impair the integrity of the endothelium in blood vessels, which contributes to vascular aging and cardiovascular and metabolic diseases with unknown mechanisms (Erusalimsky, 2009)
protein disulfide isomerase A1 (PDIA1) Knockdown Induces Senescence and Endothelial Dysfunction To determine the function of endogenous PDIA1 in ECs, we examined the effect of PDIA1 knockdown using small interfering RNAs in human umbilical vein endothelial cells (HUVECs)
Silencing of PDIA1 induced significant morphological changes, such as round, flattened, or di- and/or multi-nucleustype cells (Figure S1A), and increased b-galactosidase activity at pH 6 (Figure 1A), demonstrating a senescence-like phenotype. This was further confirmed by increased expression of the senescence markers p16, p21, and p53 (Figure 1B) as well as decreased cell growth (Figure 1C), cell proliferation (Figure 1D), and induced cell cycle arrest at G0/G1 phase (Figure 1E) in PDIA1-depleted ECs compared with control small interfering RNAs (siRNAs)-transfected ECs

Summary

Introduction

Endothelial cells (ECs) with senescence impair the integrity of the endothelium in blood vessels, which contributes to vascular aging and cardiovascular and metabolic diseases with unknown mechanisms (Erusalimsky, 2009). In ECs, mitochondria are not the main source of ATP (Vandekeere et al, 2015); they function as reactive oxygen species (ROS) signaling organelles, maintaining EC homeostasis (Kluge et al, 2013). Mitochondrial dynamics are tightly regulated by fusion and fission. Mitochondrial fission is involved in physiological function, mitochondrial fragmentation induces excess mitochondrial ROS (mtROS), which results in endothelial dysfunction in pathological conditions such as diabetes (Kluge et al, 2013; Shenouda et al, 2011). Mitochondrial morphology, ROS levels, and endothelial (dys)function are interconnected; the mechanism of how redox signals regulate coupling between mitochondrial dynamics and EC function in normal and pathological conditions is poorly understood

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