Mitochondrial carrier homolog 2 is important for mitochondrial functionality and non-small cell lung cancer cell growth
Abstract Discovering new molecular targets for non-small cell lung cancer (NSCLC) is critically important. Enhanced mitochondrial function can promote NSCLC progression by enabling metabolic reprogramming, resistance to apoptosis, and increased cell proliferation. Mitochondrial carrier homolog 2 (MT...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-02-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07419-0 |
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| author | Yong Zhao Siyang Wu Guohong Cao Peidong Song Chang-gong Lan Lin Zhang Yong-hua Sang |
| author_facet | Yong Zhao Siyang Wu Guohong Cao Peidong Song Chang-gong Lan Lin Zhang Yong-hua Sang |
| author_sort | Yong Zhao |
| collection | DOAJ |
| description | Abstract Discovering new molecular targets for non-small cell lung cancer (NSCLC) is critically important. Enhanced mitochondrial function can promote NSCLC progression by enabling metabolic reprogramming, resistance to apoptosis, and increased cell proliferation. Mitochondrial carrier homolog 2 (MTCH2), located in the outer mitochondrial membrane, is pivotal in regulating mitochondrial activities. This study examines MTCH2 expression and its functional role in NSCLC. Bioinformatic analysis showed that MTCH2 is overexpressed in NSCLC tissues, correlating with poor prognosis and other key clinical parameters of the patients. In addition, single-cell sequencing data revealed higher MTCH2 expression levels in cancer cells of NSCLC tumor mass. Moreover, MTCH2 is also upregulated in locally-treated NSCLC tissues and multiple primary/established human NSCLC cells. In various NSCLC cells, silencing MTCH2 via targeted shRNA or knockout (KO) using the CRISPR/Cas9 method significantly hindered cell proliferation, migration and invasion, while inducing apoptosis. MTCH2 knockdown or KO robustly impaired mitochondrial function, as indicated by reduced mitochondrial respiration, decreased complex I activity, lower ATP levels, lower mitochondrial membrane potential (mitochondrial depolarization), and increased reactive oxygen species (ROS) production. Conversely, ectopic overexpression of MTCH2 in primary NSCLC cells enhanced mitochondrial complex I activity and ATP production, promoting cell proliferation and migration. In vivo, the intratumoral injection of MTCH2 shRNA adeno-associated virus (aav) impeded the growth of subcutaneous xenografts of primary NSCLC cells in nude mice. In MTCH2 shRNA aav-injected NSCLC xenograft tissues, there was decreases in MTCH2 expression, mitochondrial complex I activity, ATP content, and the glutathione (GSH)/glutathione disulfide (GSSG) ratio, but increase in thiobarbituric acid reactive substances (TBAR) activity. Additionally, MTCH2 silencing led to reduced Ki-67 staining but increased apoptosis in NSCLC xenografts. Collectively, these findings demonstrate that overexpressed MTCH2 promotes NSCLC cell growth potentially through the maintenance of mitochondrial hyper-function, highlighting MTCH2 as a novel and promising therapeutic target for treating this disease. |
| format | Article |
| id | doaj-art-2fafb3bbc2cd4604bae8d4c753c31c40 |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-2fafb3bbc2cd4604bae8d4c753c31c402025-08-20T02:48:16ZengNature Publishing GroupCell Death and Disease2041-48892025-02-0116111510.1038/s41419-025-07419-0Mitochondrial carrier homolog 2 is important for mitochondrial functionality and non-small cell lung cancer cell growthYong Zhao0Siyang Wu1Guohong Cao2Peidong Song3Chang-gong Lan4Lin Zhang5Yong-hua Sang6Department of Thoracic Surgery, Affiliated Hospital of Jiangnan UniversityRespiratory Intensive Care Unit, Affiliated Hospital of YouJiang Medical University for NationalitiesDepartment of Respiratory and Critical Care Medicine, Binzhou Medical University Hospital, Binzhou Medical UniversityDepartment of Cardiothoracic Surgery, the Second Affiliated Hospital of Soochow UniversityGuangxi Key Laboratory of basic and translational research of Bone and Joint Degenerative Diseases, Guangxi Biomedical Materials Engineering Research Center for Bone and Joint Degenerative DiseasesDepartment of Thoracic Surgery, Suzhou Ninth People’s Hospital Affiliated to Soochow UniversityDepartment of Cardiothoracic Surgery, the Second Affiliated Hospital of Soochow UniversityAbstract Discovering new molecular targets for non-small cell lung cancer (NSCLC) is critically important. Enhanced mitochondrial function can promote NSCLC progression by enabling metabolic reprogramming, resistance to apoptosis, and increased cell proliferation. Mitochondrial carrier homolog 2 (MTCH2), located in the outer mitochondrial membrane, is pivotal in regulating mitochondrial activities. This study examines MTCH2 expression and its functional role in NSCLC. Bioinformatic analysis showed that MTCH2 is overexpressed in NSCLC tissues, correlating with poor prognosis and other key clinical parameters of the patients. In addition, single-cell sequencing data revealed higher MTCH2 expression levels in cancer cells of NSCLC tumor mass. Moreover, MTCH2 is also upregulated in locally-treated NSCLC tissues and multiple primary/established human NSCLC cells. In various NSCLC cells, silencing MTCH2 via targeted shRNA or knockout (KO) using the CRISPR/Cas9 method significantly hindered cell proliferation, migration and invasion, while inducing apoptosis. MTCH2 knockdown or KO robustly impaired mitochondrial function, as indicated by reduced mitochondrial respiration, decreased complex I activity, lower ATP levels, lower mitochondrial membrane potential (mitochondrial depolarization), and increased reactive oxygen species (ROS) production. Conversely, ectopic overexpression of MTCH2 in primary NSCLC cells enhanced mitochondrial complex I activity and ATP production, promoting cell proliferation and migration. In vivo, the intratumoral injection of MTCH2 shRNA adeno-associated virus (aav) impeded the growth of subcutaneous xenografts of primary NSCLC cells in nude mice. In MTCH2 shRNA aav-injected NSCLC xenograft tissues, there was decreases in MTCH2 expression, mitochondrial complex I activity, ATP content, and the glutathione (GSH)/glutathione disulfide (GSSG) ratio, but increase in thiobarbituric acid reactive substances (TBAR) activity. Additionally, MTCH2 silencing led to reduced Ki-67 staining but increased apoptosis in NSCLC xenografts. Collectively, these findings demonstrate that overexpressed MTCH2 promotes NSCLC cell growth potentially through the maintenance of mitochondrial hyper-function, highlighting MTCH2 as a novel and promising therapeutic target for treating this disease.https://doi.org/10.1038/s41419-025-07419-0 |
| spellingShingle | Yong Zhao Siyang Wu Guohong Cao Peidong Song Chang-gong Lan Lin Zhang Yong-hua Sang Mitochondrial carrier homolog 2 is important for mitochondrial functionality and non-small cell lung cancer cell growth Cell Death and Disease |
| title | Mitochondrial carrier homolog 2 is important for mitochondrial functionality and non-small cell lung cancer cell growth |
| title_full | Mitochondrial carrier homolog 2 is important for mitochondrial functionality and non-small cell lung cancer cell growth |
| title_fullStr | Mitochondrial carrier homolog 2 is important for mitochondrial functionality and non-small cell lung cancer cell growth |
| title_full_unstemmed | Mitochondrial carrier homolog 2 is important for mitochondrial functionality and non-small cell lung cancer cell growth |
| title_short | Mitochondrial carrier homolog 2 is important for mitochondrial functionality and non-small cell lung cancer cell growth |
| title_sort | mitochondrial carrier homolog 2 is important for mitochondrial functionality and non small cell lung cancer cell growth |
| url | https://doi.org/10.1038/s41419-025-07419-0 |
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