Chagas Disease Megaesophagus Patients Carrying Variant MRPS18B P260A Display Nitro-Oxidative Stress and Mitochondrial Dysfunction in Response to IFN-γ Stimulus

Abstract

Chagas disease (CD), caused by the protozoan parasite Trypanosoma cruzi, affects 8 million people, and around 1/3 develop chronic cardiac (CCC) or digestive disease (megaesophagus/megacolon), while the majority remain asymptomatic, in the indeterminate form of Chagas disease (ASY). Most CCC cases in families with multiple Chagas disease patients carry damaging mutations in mitochondrial genes. We searched for exonic mutations associated to chagasic megaesophagus (CME) in genes essential to mitochondrial processes. We performed whole exome sequencing of 13 CME and 45 ASY patients. We found the damaging variant MRPS18B 688C > G P230A, in five out of the 13 CME patients (one of them being homozygous; 38.4%), while the variant appeared in one out of 45 ASY patients (2.2%). We analyzed the interferon (IFN)-γ-induced nitro-oxidative stress and mitochondrial function of EBV-transformed lymphoblastoid cell lines. We found the CME carriers of the mutation displayed increased levels of nitrite and nitrated proteins; in addition, the homozygous (G/G) CME patient also showed increased mitochondrial superoxide and reduced levels of ATP production. The results suggest that pathogenic mitochondrial mutations may contribute to cytokine-induced nitro-oxidative stress and mitochondrial dysfunction. We hypothesize that, in mutation carriers, IFN-γ produced in the esophageal myenteric plexus might cause nitro-oxidative stress and mitochondrial dysfunction in neurons, contributing to megaesophagus.

Inflammation and mitochondria in the pathogenesis of chronic Chagas disease cardiomyopathy

“…Genetic alterations with direct implications to mitochondrial function and immune response can therefore be important components for CD cardiomyopathy and megaesophagus susceptibility and progression. 80,83…”

“…Significantly, 30–40% of mitochondriopathy patients evolve with cardiomyopathy, heart conduction abnormalities and severe arrhythmia, 81,82 and 15% to gastrointestinal motility disorders, including megaesophagus and megacolon, with denervation of myoenteric nervous plexi, and autonomic nervous system disturbances. The similarity in the proportions of clinical outcomes with those of CD (30% CCC, 10% digestive form motility disorders 83 ) is impressive and made us hypothesize that heterozygous pathogenic variants, which may cause a partial reduction in mitochondrial function, may play a role in differential progression for CD in a two-hit phenomenon where cytokine-induced mitochondrial damage is the second hit. Genetic alterations with direct implications to mitochondrial function and immune response can therefore be important components for CD cardiomyopathy and megaesophagus susceptibility and progression.…”