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한국생명공학연구원

Biomaterials, Sep 26 2024, 314 S0142-9612(24)00376-4 | https://doi.org/10.1016/j.biomaterials.2024.122842 Helicobacter pylori VacA-induced mitochondrial damage in the gastric pit cells of the antrum and therapeutic rescue

Ye Seul Son a,1, Yong Hwan Kwon b,1, Moo-Seung Lee a,c,1, Ohman Kwon a, Yu-Jin Jeong a, Seon Ju Mun a, Sojeong Jeon a,c, Ji Hye Park b, Man-Hoon Han d, Jae-sung Bae e, Keun Hur f, Ah-Ra Jang g, Jong-Hwan Park g, Hyun-Soo Cho a,c, Cho-Rok Jung a,c, Choong-Min Ryu a,c, Myung Jin Son a,c, Doo-Sang Park a,h, Mi-Young Son a,c,i

^aKorea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea

^bDepartment of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea

^cKRIBB School of Bioscience, Korea University of Science and Technology, Daejeon, 34113, Republic of Korea

^dDepartment of Pathology, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea

^eDepartment of Physiology, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea

^fDepartment of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea

^gLaboratory Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju, 61186, Republic of Korea

^hKorean Collection for Type Cultures, Biological Resource Center, Korea Research Institute of Bioscience and Biotechnology, Jeongeup, 56212, Republic of Korea

ⁱDepartment of Biological Science, Sungkyunkwan University, Suwon, 16419, Republic of Korea

¹These authors contributed equally to this work.

Corresponding authors: Myung Jin Son, Doo-Sang Park, Mi-Young Son

Abstract

Exploring host cell specificity, pathogenicity, and molecular mechanisms of the vacuolating cytotoxin A (VacA), secreted by Helicobacter pylori (Hp) is crucial for developing novel treatment strategies. VacA affects subcellular events, particularly mitochondria, at a cell-type-specific level. However, the lack of reliable models that mimic VacA-induced subcellular damages and enable novel drug screening linked to the human stomach clinically limits our understanding of the mitochondrial networks in vivo. Here, human antrum gastric organoids (hAGOs) and tissue samples from Hp-infected patients were used to show the toxic effects of VacA-induced mitochondrial damage mainly in mucus-producing gastric pit cells by employing transcriptional, translational, and functional analyses. In VacA-intoxicated or Hp-infected hAGOs, robust mitochondrial fragmentation in gastric pit cells reduced ATP production during respiration, and loss of mucosal barrier integrity was first demonstrated experimentally. Using hAGOs, clinically relevant small molecules were screened for efficacy, and MLN8054, an Aurora kinase A inhibitor, reversed VacA-induced mitochondrial damage and loss of gastric epithelium integrity. MLN8054 was effective in VacA-treated and Hp-infected hAGOs and mice, highlighting hAGOs as a promising drug-screening model. These findings suggest that mitochondrial quality control may serve as a promising therapeutic target for Hp VacA-mediated toxicity and disease progression.

논문정보

형식Research article
게재일2024년 09월 (BRIC 등록일 2024-10-10)
연구진국내 연구진
분야 생명과학 > 세포생물학

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