The Mitochondrial Antioxidant SS-31 Modulates Oxidative Stress, Endoplasmic Reticulum Stress, and Autophagy in Type 2 Diabetes.

Irene Escribano-López,Nadezda Apostolova,Pedro Díaz,Eva Solá,Víctor M Víctor,Zaida Abad-Jiménez,Sandra López-Domènech,Francesca Iannantuoni,Milagros Rocha,Aranzazu M de Marañon

doi:10.3390/jcm8091322

Abstract

Mitochondrial dysfunction has been shown to play a central role in the pathophysiology of type 2 diabetes (T2D), and mitochondria-targeted agents such as SS-31 are emerging as a promising strategy for its treatment. We aimed to study the effects of SS-31 on leukocytes from T2D patients by evaluating oxidative stress, endoplasmic reticulum (ER) stress and autophagy. Sixty-one T2D patients and 53 controls were included. Anthropometric and analytical measurements were performed. We also assessed reactive oxygen species (ROS) production, calcium content, the expression of ER stress markers GRP78, CHOP, P-eIF2α, and autophagy-related proteins Beclin1, LC3 II/I, and p62 in leukocytes from T2D and control subjects treated or not with SS-31. Furthermore, we have evaluated the action of SS-31 on leukocyte-endothelium interactions. T2D patients exhibited elevated ROS concentration, calcium levels and presence of ER markers (GRP78 and CHOP gene expression, and GRP78 and P-eIF2α protein expression), all of which were reduced by SS-31 treatment. SS-31 also led to a drop in BECN1 gene expression, and Beclin1 and LC3 II/I protein expression in T2D patients. In contrast, the T2D group displayed reduced p62 protein levels that were restored by SS-31. SS-20 (with non-antioxidant activity) did not change any analyzed parameter. In addition, SS-31 decreased rolling flux and leukocyte adhesion, and increased rolling velocity in T2D patients. Our findings suggest that SS-31 exerts potentially beneficial effects on leukocytes of T2D patients modulating oxidative stress and autophagy, and ameliorating ER stress.

Highlights

Type 2 diabetes (T2D) represents a serious global problem with a worryingly high rate worldwide, constituting one of the main public health challenges of the 21st century
Given that body mass index (BMI) was significantly different in T2D patients, data were adjusted for this variable, but statistical differences remained similar
A study by Sage et al demonstrated that levels of endoplasmic reticulum (ER) stress markers such as glucose-regulated protein 78 kDa (GRP78), sXBP1 and CHOP correlated positively with glucose levels in leukocytes from patients with metabolic syndrome [54]. In line with such data, we have shown in previous studies that leukocytes from T2D patients exhibit increased ER stress markers which display enhanced GRP78, P-eIF2α and ATF6 protein levels [35]

Summary

Introduction

Type 2 diabetes (T2D) represents a serious global problem with a worryingly high rate worldwide, constituting one of the main public health challenges of the 21st century. T2D is a metabolic disruption characterized by insulin resistance (IR) and β cell failure In those affected, the persistent exposure to a hyperglycemic environment promotes excessive generation of reactive oxygen species (ROS) and it leads to the imbalance of antioxidant defenses [1], inducing oxidative stress, which contributes to IR and the activation of pro-inflammatory signaling pathways [2], both thought to play key roles in the complications associated with T2D. It is known that antioxidant production is one of the restorative functions of the UPR, which coordinates the activation of the trans-membrane ER resident protein (PERK) signaling pathway, allowing the cell to adapt to oxidative and ER stress [7,8]. The onset of autophagy involves the formation of an autophagosome, a process in which several autophagy-related genes coordinate to engulf the defective material in a double membrane. We have studied these processes by analyzing general markers for their activation

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