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

Karla Deysiree Alcântara Silva (1) , João Paulo Silva Nunes (1) , Pauline Andrieux (2) , Pauline Brochet (2) , Rafael Ribeiro Almeida (1) , Andréia Cristina Kazue Kuramoto Takara (1) , Natalia Bueno Pereira (1) , Laurent Abel (3, 4) , Aurelie Cobat (3, 4) , Ricardo Costa Fernandes Zaniratto (1) , Débora Levy (1) , Sergio Paulo Bydlowski (1) , Ivan Cecconello (1) , Francisco Carlos Bernal da Costa Seguro (1) , Jorge Kalil (1) , Christophe Chevillard (2) , Edecio Cunha-Neto (1)

1 USP - Universidade de São Paulo = University of São Paulo
2 TAGC - Theories and Approaches of Genomic Complexity
3 Rockefeller University [New York]
4 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)

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.

Mots clés: chagasic megaesophagus; mitochondrial mutation; mitochondrial dysfunction; interferon-gamma; Chagas disease; Trypanosoma cruzi

Domaines: Sciences du Vivant [q-bio]; Médecine humaine et pathologie

Karla Deysiree Alcântara Silva, João Paulo Silva Nunes, Pauline Andrieux, Pauline Brochet, Rafael Ribeiro Almeida, et al.. Chagas Disease Megaesophagus Patients Carrying Variant MRPS18B P260A Display Nitro-Oxidative Stress and Mitochondrial Dysfunction in Response to IFN-γ Stimulus. Biomedicines, 2022, 10 (9), pp.2215. ⟨10.3390/biomedicines10092215⟩. ⟨hal-03831899⟩