Nitric oxide and mitochondria in metabolic syndrome

Abstract

Metabolic syndrome (MS) is a cluster of metabolic disorders that collectively increase the risk of cardiovascular disease. Nitric oxide (NO) plays a crucial role in the pathogeneses of MS components and is involved in different mitochondrial signaling pathways that control respiration and apoptosis. The present review summarizes the recent information regarding the interrelations of mitochondria and NO in MS. Changes in the activities of different NO synthase isoforms lead to the formation of metabolic disorders and therefore are highlighted here. Reduced endothelial NOS activity and NO bioavailability, as the main factors underlying the endothelial dysfunction that occurs in MS, are discussed in this review in relation to mitochondrial dysfunction. We also focus on potential therapeutic strategies involving NO signaling pathways that can be used to treat patients with metabolic disorders associated with mitochondrial dysfunction. The article may help researchers develop new approaches for the diagnosis, prevention and treatment of MS.

Keywords: metabolic syndrome; mitochondrial dysfunction; mitochondrial nitric oxide synthase; nitric oxide; nitric oxide synthase; nitric oxide synthase type I; nitric oxide synthase type II; oxide synthase type III.

Figure 1

Interrelation between nitric oxide and mitochondria in the pathophysiology of metabolic syndrome (a, in the vascular wall; b, in an adipocyte; c, in a hepatocyte). a: Insulin resistance contributes to decreased activities of signaling molecules, which leads to decreased eNOS activity. Superoxide generated in mitochondria can modestly, and peroxynitrite can strongly, oxidize BH4–BH2, leading to uncoupling of eNOS, increased production of ROS and endothelial dysfunction. Moreover, mtNOS becomes “uncoupled”; it switches from a NO-generating enzyme to a superoxide-producing enzyme. Increased production of peroxynitrite and superoxide anions generated from uncoupled mtNOS and eNOS damage mitochondrial ETC complexes, leading to mitochondrial dysfunction. eNOS then generates superoxide rather than NO, which contributes to vascular oxidative stress and further reduces NO bioavailability. Excessive mtNOS-derived NO can produce reactive nitrogen species, such as peroxynitrite, which may cause tyrosine nitration of mitochondrial components and may play a key role in apoptosis. Under the conditions of oxidative stress, the enhanced activity of iNOS, with less contribution of nNOS, in vascular smooth muscle cells induces the development of chronic metabolic inflammation.

Figure 2

Interrelation between nitric oxide and mitochondria in adipose tissue in metabolic syndrome. The proinflammatory microenvironment of adipose tissue induces the iNOS activity in MS that increases peroxynitrite synthesis, thus contributing to oxidative stress and chronic inflammation. Under the influence of these conditions the reduced expression of the mitochondrial protein UCP-2 promotes the formation of MS components through decreased NO bioavailability and increased ROS generation. Reduction in the expression of mitochondrial transcription factor A also contributes to the development of MS components.

Figure 3

Interrelation between nitric oxide and mitochondria in hepatocytes in metabolic syndrome. The enhanced activities of mtNOS and iNOS in hepatocytes during insulin resistance promote peroxynitrite production and cytochrome c release, which are associated with the peroxidation of mitochondrial lipids and apoptosis. Reduced SIRT3 activity contributes to mitochondrial dysfunction, which in turn promotes oxidative stress and chronic inflammation in MS. Taken together, the reviewed studies suggest that NO and the different NOS isoforms play an important role in critical pathological states such as endothelial dysfunction and peroxynitrite-induced cytotoxicity.