Protein Nitration in Patients with Mitochondrial Diseases.

Abstract

Mitochondrial diseases are complex disorders caused by nuclear or mitochondrial DNA mutations, leading to oxidative phosphorylation deficiency and excessive production of reactive oxygen species (ROS). While ROS have been well established in the pathogenesis of these diseases, the role of reactive nitrogen species (RNS) remains unclear. In this study, we performed a quantitative analysis of muscle fibers to investigate the relationship between protein nitration and mitochondrial abnormalities (mitochondrial proliferation and cytochrome-c oxidase (COX) deficiency) and factors like genotype, muscle damage, and age. A total of 1961 muscle fibers (303 from 4 controls and 1658 from 29 patients with mitochondrial diseases) were analyzed by immunostaining for nitro-tyrosine. Contrary to previous findings, which identified nitro-tyrosine only in small muscle vessels, we observed a broader distribution affecting the sarcolemma and sarcoplasm. Using multivariate techniques, we identified a significant correlation between protein nitration and mitochondrial proliferation but found no associations with COX deficiency, age, muscle damage, or genotype. These findings suggest that nitrative stress may contribute to mitochondrial dysfunction or play a role in signaling processes that induce mitochondrial biogenesis. Our results provide new insights into the molecular mechanisms of mitochondrial diseases and highlight the potential relevance of protein nitration.