Study of mitochondrial dynamics and function and autophagy and their relationship with cardiovascular complications in type 2

Laburpena

Type 2 diabetes (T2D) is a chronic metabolic disease with an inflammatory basis and whose incidence has been increasing over recent years. This metabolic disease also increases the predisposition to suffer cardiovascular complications, which endanger the life of the patient. Hence, delving into the cellular and molecular origin of T2D would facilitate its early prevention and the delay of the cardiovascular complications. In this context, this doctoral thesis aims to describe some of the homeostatic pathways involved in the physiopathology of T2D in human leukocytes. Specifically, the focus is set on studying the alterations on mitochondrial function, inflammation, autophagy and endoplasmic reticulum stress and their impact on leukocyte-endothelium interactions and markers of early atherosclerotic lesions. We hypothesize that the different pathophysiologic alterations in T2D affect the leuckocyte function by disturbing mitochondrial function and generating oxidative stress, endoplasmic reticulum stress and activating autophagy. Moreover, we address the influence of different therapeutic approaches, as glycaemic control, metformin treatment or the novel mitochondria-targeted antioxidant peptide SS-31, in those mechanisms. Initially, we describe that autophagy, mitochondrial ROS production and leukocyte-endothelium interactions are enhanced in leukocytes from T2D patients. Interestingly, we found correlations between Beclin-1 and the leukocyte-endothelium interactions, which points to an autophagy-dependent regulation of inflammation. Next, we analysed how glycaemic control influences the carotid intima-media thickness, an early atherosclerosis development marker, and its association with the leukocyte-endothelium interactions and inflammation in T2D patients. Glycaemic control is measured by the percentage of glycated haemoglobin in peripheral blood, and is employed in usual clinical practice to assess the patients’ evolution since T2D onset. We observed that a tight glycaemic control is beneficial for all measured parameters, representing an easy and useful therapeutic strategy for prevention of atherosclerotic events. In parallel, we described that metformin treatment can mitigate the alterations in mitochondrial dynamics in leukocytes from T2D patients. Metformin is one of the most prescribed and best described treatments of type 2 diabetes. Among its known pleiotropic effects, it inhibits the function of mitochondrial complex I. Our results are in line with this knowledge, and suggest that metformin exerts a protective effect on mitochondria, beyond its known hypoglycaemic effect. As tackling mitochondrial dysfunction seems to be a promising therapy, we aimed to determine the effect of SS-31. SS-31 is a mitochondria-targeted antioxidant peptide that can quench the excess of reactive oxygen species thanks to its diphenylphosphonium residue. The treatment of leukocytes from T2D patients with this antioxidant reduced the activation of autophagy, endoplasmic reticulum stress and improved the mitochondrial dysfunction. SS-31 treatment also diminished the interactions of the leukocytes with the endothelium, pointing to a possible preventive action of SS-31 against atherosclerotic events. Altogether, these results contribute to untangle the mechanisms that contribute to the physiopathology of T2D and its cardiovascular comorbidities. We also dive into the possible beneficial effects of different therapeutic approaches as the tight monitoring of glycaemic control or pharmacological treatments with metformin or SS-31 on mitochondrial function and the cellular homeostatic pathways, proposing them as possible early anti-atherosclerotic treatments.