L-Arginine Reduces Nitro-Oxidative Stress in Cultured Cells with Mitochondrial Deficiency.

Camila D S Barros,Margaret G Mouro,Elisa Mieko Suemitsu Higa,Carlos T Moraes,Celia Harumi Tengan,Jomênica B Livramento

doi:10.3390/nu13020534

Camila D S Barros, Margaret G Mouro + Show 4 more

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https://doi.org/10.3390/nu13020534

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Abstract

L-Arginine (L-ARG) supplementation has been suggested as a therapeutic option in several diseases, including Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like syndrome (MELAS), arguably the most common mitochondrial disease. It is suggested that L-ARG, a nitric oxide (NO) precursor, can restore NO levels in blood vessels, improving cerebral blood flow. However, NO also participates in mitochondrial processes, such as mitochondrial biogenesis, the regulation of the respiratory chain, and oxidative stress. This study investigated the effects of L-ARG on mitochondrial function, nitric oxide synthesis, and nitro-oxidative stress in cell lines harboring the MELAS mitochondrial DNA (mtDNA) mutation (m.3243A>G). We evaluated mitochondrial enzyme activity, mitochondrial mass, NO concentration, and nitro-oxidative stress. Our results showed that m.3243A>G cells had increased NO levels and protein nitration at basal conditions. Treatment with L-ARG did not affect the mitochondrial function and mass but reduced the intracellular NO concentration and nitrated proteins in m.3243A>G cells. The same treatment led to opposite effects in control cells. In conclusion, we showed that the main effect of L-ARG was on protein nitration. Lowering protein nitration is probably involved in the mechanism related to L-ARG supplementation benefits in MELAS patients.

Highlights

L-Arginine (L-ARG) supplementation has been considered as a therapeutic option in different conditions, such as immunological dysfunctions, cardiovascular diseases [1], obesity [2], diabetes [3,4], and mitochondrial diseases [5,6]
Because C-IV has subunits encoded by the mitochondrial DNA (mtDNA), whereas C-II is exclusively coded by the nuclear DNA, we expected to see a defect in COX only [26]
The C-IV activity (C-IV/Citrate Synthase (CS)) was 64% lower than that of controls and the C-II was 57% higher, but we did not observe any significant changes with L-ARG treatment in m.3243A>G and 143B cells (Figure 1)

Summary

Introduction

L-Arginine (L-ARG) supplementation has been considered as a therapeutic option in different conditions, such as immunological dysfunctions, cardiovascular diseases [1], obesity [2], diabetes [3,4], and mitochondrial diseases [5,6]. Good clinical responses were observed after L-ARG supplementation in patients with MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes), a mitochondrial disease with stroke-like episodes as the most typical manifestation [5] This common syndrome among patients with mitochondrial diseases is frequently caused by a mitochondrial DNA (mtDNA) mutation (m.3243A>G) in the tRNALeu(UUR) gene and is associated with oxidative phosphorylation (OXPHOS) deficiency and decreased ATP production [7]. It is hypothesized that L-ARG can increase NO synthesis, promoting vasodilation due to NO action in vascular smooth muscle [8,9,10] This hypothesis is supported by results showing the improvement of microvascular cerebral flux and reduction in tissue damage caused by stroke-like episodes in these patients [11]. L-ARG supplementation is supported by the finding of L-ARG deficiency in these patients [8,12]

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