Increased Protein Nitration in Mitochondrial Diseases: Evidence for Vessel Wall Involvement

Abstract

Mitochondrial diseases (MD) are heterogeneous disorders because of impairment of respiratory chain function leading to oxidative stress. We hypothesized that in MD the vascular endothelium may be affected by increased oxidative/ nitrative stress causing a reduction of nitric oxide availability. We therefore, investigated the pathobiology of vasculature in MD patients by assaying the presence of 3-nitrotyrosine in muscle biopsies followed by the proteomic identification of proteins which undergo tyrosine nitration. We then measured the flow-mediated vasodilatation as a proof of altered nitric oxide generation/bioactivity. Here, we show that 3-nitrotyrosine staining is specifically located in the small vessels of muscle tissue and that the reaction is stronger and more evident in a significant percentage of vessels from MD patients as compared with controls. Eleven specific proteins which are nitrated under pathological conditions were identified; most of them are involved in energy metabolism and are located mainly in mitochondria. In MD patients the flow-mediated vasodilatation was reduced whereas baseline arterial diameters, blood flow velocity and endothelium-independent vasodilatation were similar to controls. The present results provide evidence that in MD the vessel wall is a target of increased oxidative/nitrative stress.

Citrulline and arginine utility in treating nitric oxide deficiency in mitochondrial disorders

“…Another study has demonstrated that sarcoplasmic NOS activity is reduced in cytochrome c oxidase (COX) deficient fibers of muscle biopsies obtained from patients with chronic progressive external ophthalmoplegia (CPEO), mitochondrial myopathy, and MELAS syndrome [2]. Flow-mediated vasodilation (FMD), which is a function of NO synthesized by endothelial cells in response to re-perfusion, was found to be impaired in patients with mitochondrial myopathy, MELAS, MERRF (myoclonic epilepsy with ragged red fibers), MIDD (maternally inherited diabetes and deafness), and CPEO, providing further evidence of NO deficiency in mitochondrial diseases [4,6].…”

“…Increased protein nitration has been reported to occur in endothelial cells of small blood vessels in muscle tissues from subjects with different mitochondrial diseases including mitochondrial myopathy, MELAS, MERRF, MIDD, and CPEO [6]. Based on these findings it was suggested that oxidative stress in mitochondrial diseases results in decreased NO availability by shunting NO into reactive nitrogen species formation [6]. Therefore, NO deficiency can result from post-production scavenging of NO by COX and/or the diversion of NO to reactive nitrogen species formation.…”

“…Disturbed mitochondrial function in various tissues and organs can explain the multi-organ manifestations of mitochondrial diseases including epilepsy, intellectual disability, skeletal and cardiac myopathy, diabetes, sensorineural hearing loss, and renal impairment [1]. In addition to reduced energy production, there is growing evidence that nitric oxide (NO) deficiency occurs in mitochondrial diseases and can play a major role in the pathogenesis of several complications observed in mitochondrial diseases including stroke-like episodes, myopathy, diabetes, and lactic acidosis [2][3][4][5][6][7]. The amino acids arginine and citrulline act as NO precursors and can be used to restore NO production and may be of therapeutic utility in treating NO deficiency-related manifestations of mitochondrial diseases [7].…”

Late onset MELAS with m.3243A > G mutation and its association with aneurysm formation

“…However, several hypotheses have been proposed; the most commonly accepted is an aberrant vascular tone caused by abnormalities in the vascular smooth muscle and endothelium. A study by Vattemi et al (Vattemi et al 2011) suggested that in MELAS patients, the vessel wall is a target of oxidative stress and that the degree of endothelial dysfunction is related to age and oxidative stress. First, regarding endothelial dysfunction, nitric oxide (NO) synthesis by endothelial nitric oxide synthase (eNOS) was decreased.…”

Decreased exhaled nitric oxide levels in patients with mitochondrial disorders

“…There is growing evidence that NO deficiency occurs in at least some MD and can play a major role in the pathogenesis of stroke-like episodes, myopathy, diabetes mellitus, and lactic acidosis [3,[5][6][7][8][9][10]. As such, NO measurements in patients with mitochondrial disease could be an important tool for understanding the pathogenesis and stages of the disease, assisting in the diagnosis, and monitoring response to treatment.…”