Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Silva, Karla Deysiree Alcântara, Nunes, João Paulo Silva, Andrieux, Pauline, Brochet, Pauline, Almeida, Rafael Ribeiro, Kuramoto Takara, Andréia Cristina Kazue, Pereira, Natalia Bueno, Abel, Laurent, Cobat, Aurelie, Zaniratto, Ricardo Costa Fernandes, Levy, Débora, Bydlowski, Sergio Paulo, Cecconello, Ivan, Seguro, Francisco Carlos Bernal da Costa, Kalil, Jorge, Chevillard, Christophe, Cunha-Neto, Edecio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9496350/
https://www.ncbi.nlm.nih.gov/pubmed/36140315
http://dx.doi.org/10.3390/biomedicines10092215
_version_ 1784794247377977344
author Silva, Karla Deysiree Alcântara
Nunes, João Paulo Silva
Andrieux, Pauline
Brochet, Pauline
Almeida, Rafael Ribeiro
Kuramoto Takara, Andréia Cristina Kazue
Pereira, Natalia Bueno
Abel, Laurent
Cobat, Aurelie
Zaniratto, Ricardo Costa Fernandes
Levy, Débora
Bydlowski, Sergio Paulo
Cecconello, Ivan
Seguro, Francisco Carlos Bernal da Costa
Kalil, Jorge
Chevillard, Christophe
Cunha-Neto, Edecio
author_facet Silva, Karla Deysiree Alcântara
Nunes, João Paulo Silva
Andrieux, Pauline
Brochet, Pauline
Almeida, Rafael Ribeiro
Kuramoto Takara, Andréia Cristina Kazue
Pereira, Natalia Bueno
Abel, Laurent
Cobat, Aurelie
Zaniratto, Ricardo Costa Fernandes
Levy, Débora
Bydlowski, Sergio Paulo
Cecconello, Ivan
Seguro, Francisco Carlos Bernal da Costa
Kalil, Jorge
Chevillard, Christophe
Cunha-Neto, Edecio
author_sort Silva, Karla Deysiree Alcântara
collection PubMed
description 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.
format Online
Article
Text
id pubmed-9496350
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-94963502022-09-23 Chagas Disease Megaesophagus Patients Carrying Variant MRPS18B P260A Display Nitro-Oxidative Stress and Mitochondrial Dysfunction in Response to IFN-γ Stimulus Silva, Karla Deysiree Alcântara Nunes, João Paulo Silva Andrieux, Pauline Brochet, Pauline Almeida, Rafael Ribeiro Kuramoto Takara, Andréia Cristina Kazue Pereira, Natalia Bueno Abel, Laurent Cobat, Aurelie Zaniratto, Ricardo Costa Fernandes Levy, Débora Bydlowski, Sergio Paulo Cecconello, Ivan Seguro, Francisco Carlos Bernal da Costa Kalil, Jorge Chevillard, Christophe Cunha-Neto, Edecio Biomedicines Article 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. MDPI 2022-09-07 /pmc/articles/PMC9496350/ /pubmed/36140315 http://dx.doi.org/10.3390/biomedicines10092215 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Silva, Karla Deysiree Alcântara
Nunes, João Paulo Silva
Andrieux, Pauline
Brochet, Pauline
Almeida, Rafael Ribeiro
Kuramoto Takara, Andréia Cristina Kazue
Pereira, Natalia Bueno
Abel, Laurent
Cobat, Aurelie
Zaniratto, Ricardo Costa Fernandes
Levy, Débora
Bydlowski, Sergio Paulo
Cecconello, Ivan
Seguro, Francisco Carlos Bernal da Costa
Kalil, Jorge
Chevillard, Christophe
Cunha-Neto, Edecio
Chagas Disease Megaesophagus Patients Carrying Variant MRPS18B P260A Display Nitro-Oxidative Stress and Mitochondrial Dysfunction in Response to IFN-γ Stimulus
title Chagas Disease Megaesophagus Patients Carrying Variant MRPS18B P260A Display Nitro-Oxidative Stress and Mitochondrial Dysfunction in Response to IFN-γ Stimulus
title_full Chagas Disease Megaesophagus Patients Carrying Variant MRPS18B P260A Display Nitro-Oxidative Stress and Mitochondrial Dysfunction in Response to IFN-γ Stimulus
title_fullStr Chagas Disease Megaesophagus Patients Carrying Variant MRPS18B P260A Display Nitro-Oxidative Stress and Mitochondrial Dysfunction in Response to IFN-γ Stimulus
title_full_unstemmed Chagas Disease Megaesophagus Patients Carrying Variant MRPS18B P260A Display Nitro-Oxidative Stress and Mitochondrial Dysfunction in Response to IFN-γ Stimulus
title_short Chagas Disease Megaesophagus Patients Carrying Variant MRPS18B P260A Display Nitro-Oxidative Stress and Mitochondrial Dysfunction in Response to IFN-γ Stimulus
title_sort chagas disease megaesophagus patients carrying variant mrps18b p260a display nitro-oxidative stress and mitochondrial dysfunction in response to ifn-γ stimulus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9496350/
https://www.ncbi.nlm.nih.gov/pubmed/36140315
http://dx.doi.org/10.3390/biomedicines10092215
work_keys_str_mv AT silvakarladeysireealcantara chagasdiseasemegaesophaguspatientscarryingvariantmrps18bp260adisplaynitrooxidativestressandmitochondrialdysfunctioninresponsetoifngstimulus
AT nunesjoaopaulosilva chagasdiseasemegaesophaguspatientscarryingvariantmrps18bp260adisplaynitrooxidativestressandmitochondrialdysfunctioninresponsetoifngstimulus
AT andrieuxpauline chagasdiseasemegaesophaguspatientscarryingvariantmrps18bp260adisplaynitrooxidativestressandmitochondrialdysfunctioninresponsetoifngstimulus
AT brochetpauline chagasdiseasemegaesophaguspatientscarryingvariantmrps18bp260adisplaynitrooxidativestressandmitochondrialdysfunctioninresponsetoifngstimulus
AT almeidarafaelribeiro chagasdiseasemegaesophaguspatientscarryingvariantmrps18bp260adisplaynitrooxidativestressandmitochondrialdysfunctioninresponsetoifngstimulus
AT kuramototakaraandreiacristinakazue chagasdiseasemegaesophaguspatientscarryingvariantmrps18bp260adisplaynitrooxidativestressandmitochondrialdysfunctioninresponsetoifngstimulus
AT pereiranataliabueno chagasdiseasemegaesophaguspatientscarryingvariantmrps18bp260adisplaynitrooxidativestressandmitochondrialdysfunctioninresponsetoifngstimulus
AT abellaurent chagasdiseasemegaesophaguspatientscarryingvariantmrps18bp260adisplaynitrooxidativestressandmitochondrialdysfunctioninresponsetoifngstimulus
AT cobataurelie chagasdiseasemegaesophaguspatientscarryingvariantmrps18bp260adisplaynitrooxidativestressandmitochondrialdysfunctioninresponsetoifngstimulus
AT zanirattoricardocostafernandes chagasdiseasemegaesophaguspatientscarryingvariantmrps18bp260adisplaynitrooxidativestressandmitochondrialdysfunctioninresponsetoifngstimulus
AT levydebora chagasdiseasemegaesophaguspatientscarryingvariantmrps18bp260adisplaynitrooxidativestressandmitochondrialdysfunctioninresponsetoifngstimulus
AT bydlowskisergiopaulo chagasdiseasemegaesophaguspatientscarryingvariantmrps18bp260adisplaynitrooxidativestressandmitochondrialdysfunctioninresponsetoifngstimulus
AT cecconelloivan chagasdiseasemegaesophaguspatientscarryingvariantmrps18bp260adisplaynitrooxidativestressandmitochondrialdysfunctioninresponsetoifngstimulus
AT segurofranciscocarlosbernaldacosta chagasdiseasemegaesophaguspatientscarryingvariantmrps18bp260adisplaynitrooxidativestressandmitochondrialdysfunctioninresponsetoifngstimulus
AT kaliljorge chagasdiseasemegaesophaguspatientscarryingvariantmrps18bp260adisplaynitrooxidativestressandmitochondrialdysfunctioninresponsetoifngstimulus
AT chevillardchristophe chagasdiseasemegaesophaguspatientscarryingvariantmrps18bp260adisplaynitrooxidativestressandmitochondrialdysfunctioninresponsetoifngstimulus
AT cunhanetoedecio chagasdiseasemegaesophaguspatientscarryingvariantmrps18bp260adisplaynitrooxidativestressandmitochondrialdysfunctioninresponsetoifngstimulus