Chagas Disease Megaesophagus Patients Carrying Variant <i>MRPS18B</i> P260A Display Nitro-Oxidative Stress and Mitochondrial Dysfunction in Response to IFN-γ Stimulus
Chagas disease (CD), caused by the protozoan parasite <i>Trypanosoma cruzi</i>, 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)...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-09-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/10/9/2215 |
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| author | Karla Deysiree Alcântara Silva João Paulo Silva Nunes Pauline Andrieux Pauline Brochet Rafael Ribeiro Almeida Andréia Cristina Kazue Kuramoto Takara Natalia Bueno Pereira Laurent Abel Aurelie Cobat Ricardo Costa Fernandes Zaniratto Débora Levy Sergio Paulo Bydlowski Ivan Cecconello Francisco Carlos Bernal da Costa Seguro Jorge Kalil Christophe Chevillard Edecio Cunha-Neto |
| author_facet | Karla Deysiree Alcântara Silva João Paulo Silva Nunes Pauline Andrieux Pauline Brochet Rafael Ribeiro Almeida Andréia Cristina Kazue Kuramoto Takara Natalia Bueno Pereira Laurent Abel Aurelie Cobat Ricardo Costa Fernandes Zaniratto Débora Levy Sergio Paulo Bydlowski Ivan Cecconello Francisco Carlos Bernal da Costa Seguro Jorge Kalil Christophe Chevillard Edecio Cunha-Neto |
| author_sort | Karla Deysiree Alcântara Silva |
| collection | DOAJ |
| description | Chagas disease (CD), caused by the protozoan parasite <i>Trypanosoma cruzi</i>, 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 <i>MRPS18B</i> 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. |
| first_indexed | 2024-03-10T00:39:45Z |
| format | Article |
| id | doaj.art-e9ad316eeb1a4187ae3d708e74938924 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T00:39:45Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-e9ad316eeb1a4187ae3d708e749389242023-11-23T15:11:02ZengMDPI AGBiomedicines2227-90592022-09-01109221510.3390/biomedicines10092215Chagas Disease Megaesophagus Patients Carrying Variant <i>MRPS18B</i> P260A Display Nitro-Oxidative Stress and Mitochondrial Dysfunction in Response to IFN-γ StimulusKarla Deysiree Alcântara Silva0João Paulo Silva Nunes1Pauline Andrieux2Pauline Brochet3Rafael Ribeiro Almeida4Andréia Cristina Kazue Kuramoto Takara5Natalia Bueno Pereira6Laurent Abel7Aurelie Cobat8Ricardo Costa Fernandes Zaniratto9Débora Levy10Sergio Paulo Bydlowski11Ivan Cecconello12Francisco Carlos Bernal da Costa Seguro13Jorge Kalil14Christophe Chevillard15Edecio Cunha-Neto16Laboratory of Immunology, Heart Institute (Incor) Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, BrazilLaboratory of Immunology, Heart Institute (Incor) Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, BrazilInstitut MarMaRa, INSERM, UMR_1090, Aix Marseille Université, TAGC Theories and Approaches of Genomic Complexity, 13288 Marseille, FranceInstitut MarMaRa, INSERM, UMR_1090, Aix Marseille Université, TAGC Theories and Approaches of Genomic Complexity, 13288 Marseille, FranceLaboratory of Immunology, Heart Institute (Incor) Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, BrazilLaboratory of Immunology, Heart Institute (Incor) Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, BrazilLaboratory of Immunology, Heart Institute (Incor) Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, BrazilLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, FranceLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, FranceLaboratory of Immunology, Heart Institute (Incor) Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, BrazilLaboratory of Immunology, Heart Institute (Incor) Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, BrazilLaboratory of Immunology, Heart Institute (Incor) Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, BrazilHospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, BrazilHospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, BrazilLaboratory of Immunology, Heart Institute (Incor) Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, BrazilInstitut MarMaRa, INSERM, UMR_1090, Aix Marseille Université, TAGC Theories and Approaches of Genomic Complexity, 13288 Marseille, FranceLaboratory of Immunology, Heart Institute (Incor) Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, BrazilChagas disease (CD), caused by the protozoan parasite <i>Trypanosoma cruzi</i>, 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 <i>MRPS18B</i> 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.https://www.mdpi.com/2227-9059/10/9/2215chagasic megaesophagusmitochondriamitochondrial mutationmitochondrial dysfunctioninterferon-gammaMRPS18B |
| spellingShingle | Karla Deysiree Alcântara Silva João Paulo Silva Nunes Pauline Andrieux Pauline Brochet Rafael Ribeiro Almeida Andréia Cristina Kazue Kuramoto Takara Natalia Bueno Pereira Laurent Abel Aurelie Cobat Ricardo Costa Fernandes Zaniratto Débora Levy Sergio Paulo Bydlowski Ivan Cecconello Francisco Carlos Bernal da Costa Seguro Jorge Kalil Christophe Chevillard Edecio Cunha-Neto Chagas Disease Megaesophagus Patients Carrying Variant <i>MRPS18B</i> P260A Display Nitro-Oxidative Stress and Mitochondrial Dysfunction in Response to IFN-γ Stimulus Biomedicines chagasic megaesophagus mitochondria mitochondrial mutation mitochondrial dysfunction interferon-gamma MRPS18B |
| title | Chagas Disease Megaesophagus Patients Carrying Variant <i>MRPS18B</i> P260A Display Nitro-Oxidative Stress and Mitochondrial Dysfunction in Response to IFN-γ Stimulus |
| title_full | Chagas Disease Megaesophagus Patients Carrying Variant <i>MRPS18B</i> P260A Display Nitro-Oxidative Stress and Mitochondrial Dysfunction in Response to IFN-γ Stimulus |
| title_fullStr | Chagas Disease Megaesophagus Patients Carrying Variant <i>MRPS18B</i> P260A Display Nitro-Oxidative Stress and Mitochondrial Dysfunction in Response to IFN-γ Stimulus |
| title_full_unstemmed | Chagas Disease Megaesophagus Patients Carrying Variant <i>MRPS18B</i> P260A Display Nitro-Oxidative Stress and Mitochondrial Dysfunction in Response to IFN-γ Stimulus |
| title_short | Chagas Disease Megaesophagus Patients Carrying Variant <i>MRPS18B</i> P260A Display Nitro-Oxidative Stress and Mitochondrial Dysfunction in Response to IFN-γ Stimulus |
| title_sort | chagas disease megaesophagus patients carrying variant i mrps18b i p260a display nitro oxidative stress and mitochondrial dysfunction in response to ifn γ stimulus |
| topic | chagasic megaesophagus mitochondria mitochondrial mutation mitochondrial dysfunction interferon-gamma MRPS18B |
| url | https://www.mdpi.com/2227-9059/10/9/2215 |
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