New signalling pathways in reproductive tissues associated with mitochondrial dysfunction induced by metabolic diseases

• Autor(a) principal: Diniz, Antónia Teixeira
• Data de Publicação: 2018
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.6/10220
• topic: Biogénese Mitocondrial; Diabetes Mellitus; Epidídimo; Fertilidade Masculina; Stress Oxidativo; Testículos; Domínio/Área Científica::Ciências Naturais::Ciências Químicas

Diabetes mellitus is a metabolic disease and its incidence is reaching epidemic proportions. Classically it can be divided into two types: type 1 diabetes mellitus, characterized by an insulin-dependent state, and type 2 diabetes mellitus (T2DM), where there is a resistance to the action of the hormone. External factors associated with lifestyle, such as eating behaviors, in particular, the excessive consumption of high caloric diets in combination with other factors, such as sedentary lifestyle, are the main causes for the increased incidence of T2DM. The metabolic deregulation associated with T2DM leads to the emergence of other comorbidities, notably a deregulation of male fertility. The hypothalamus-pituitary-testicle axis, also known as a reproductive axis, is sensitive to the metabolic changes induced by T2DM. Recent studies have shown that endocrine and metabolic alterations associated with T2DM affect the physiology of reproductive organs, mainly their mitochondrial bioenergetics. Maintaining mitochondrial function in reproductive organs is imperative for the maintenance of the reproductive capacity of the individual. Thus, we aimed to study the impact of T2DM on the molecular pathways underlying the control of the testicular and epididymal mitochondrial function. For this, we used an animal model of T2DM, in which we evaluated the expression of key proteins involved in the regulation of mitochondrial biogenesis and in mitochondrial function. We measured the activity of the enzymes of the antioxidant defense system. We also evaluated the effects of T2DM on the number of mitochondrial DNA copies and on the expression of the levels of the mitochondrial respiratory chain complexes in both tissues. Finally, we evaluated the parameters of oxidative stress (OS), such as carbonylation and proteins nitration, as well as lipid peroxidation. Our results showed that T2DM decreased the expression of sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3) in the testicular tissue. There was also a decrease in the expression of complexes III and V of the mitochondrial respiratory chain, but the content of mitochondrial DNA (mtDNA) remained unchanged in the testicular tissue. There were no alterations on the activities of the antioxidant enzymes, however, these results were accompanied by an increase in lipid peroxidation and nitrate of proteins. In the epididymal tissue, a decrease was observed on the expression of the key regulator of mitochondrial biogenesis, the peroxisome proliferator activated receptor ? co-activator 1 a (PGC-1a), as well as on the SIRT1 and SIRT3 expression levels. Although there were no changes in the mtDNA content, DMT2 has induced a significant decrease in the expression of complexes II, III and V in the epididymis. There were also decreases in the activities of the enzymes involved in the system of antioxidant defenses, which were accompanied by an increase of protein nitration. The results suggested that T2DM disrupted the expression of key regulators of the mitochondrial biogenesis of the reproductive organs, thereby compromising the molecular pathways involved in the regulation of the mitochondrial function and, consequently in the maintenance of the antioxidant defense system. In this way, it is essential to deepen the knowledge in mitochondrial bioenergetics in order to develop possible therapeutic approaches to attenuate the increased decline of male fertility, especially in developed countries where the prevalence of metabolic diseases is a major public health concern.