Metabolism: clinical and experimental · 2026
SEC62 at mitochondria-associated membranes drives MASH progression by suppressing ATAD3B-mediated mitochondrial quality control.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Lin Junchao, Wu Tong, Wang Chen, Zhou Wei, Liu Yutong, Yang Gang, Zhou He, Luo Jingyan, Fan Zhenzhen, Da Yu, He Jie, Xu Bing, Jiang Mingzhuo, Fan Daiming, Wu Kaichun, Liang Jie
Аннотация
BACKGROUND: The progression of metabolic dysfunction-associated steatohepatitis (MASH) involves chronic, irreversible inflammatory responses linked to intracellular organelle dysfunction. While endoplasmic reticulum (ER) stress and mitochondrial impairment are recognized as critical drivers, the precise molecular mechanisms governing inter-organelle communication in this disease context remain incompletely understood.
AIM: This study aimed to investigate the role of the ER transmembrane protein SEC62 in MASH pathogenesis. Specifically, it sought to determine whether SEC62 expression is altered in MASH, define its functional impact on disease phenotypes, and elucidate the mechanistic pathway through which it regulates mitochondrial homeostasis and inflammation.
RESULTS: SEC62 was upregulated in both human and mouse MASH livers. Hepatocyte-specific SEC62 overexpression worsened hepatic steatosis, inflammation, and mitochondrial damage, whereas SEC62 knockout ameliorated these features. Mechanistically, SEC62 interacted directly with ATAD3B at the mitochondria-associated membranes (MAMs) interface, leading to the significant downregulation of ATAD3B expression. This SEC62-ATAD3B axis resulted in defective mitophagy, increased mitochondrial reactive oxygen species (ROS) production, and amplified inflammatory responses.
CONCLUSION: Our results demonstrate that SEC62 is a novel regulator of MAMs that drives MASH progression. By interacting with and suppressing ATAD3B, SEC62 disrupts mitochondrial quality control, leading to oxidative stress and inflammation. Together, these findings define a specific molecular mechanism of organelle interplay in MASH and position SEC62 as a potential therapeutic target for intervention.
AIM: This study aimed to investigate the role of the ER transmembrane protein SEC62 in MASH pathogenesis. Specifically, it sought to determine whether SEC62 expression is altered in MASH, define its functional impact on disease phenotypes, and elucidate the mechanistic pathway through which it regulates mitochondrial homeostasis and inflammation.
RESULTS: SEC62 was upregulated in both human and mouse MASH livers. Hepatocyte-specific SEC62 overexpression worsened hepatic steatosis, inflammation, and mitochondrial damage, whereas SEC62 knockout ameliorated these features. Mechanistically, SEC62 interacted directly with ATAD3B at the mitochondria-associated membranes (MAMs) interface, leading to the significant downregulation of ATAD3B expression. This SEC62-ATAD3B axis resulted in defective mitophagy, increased mitochondrial reactive oxygen species (ROS) production, and amplified inflammatory responses.
CONCLUSION: Our results demonstrate that SEC62 is a novel regulator of MAMs that drives MASH progression. By interacting with and suppressing ATAD3B, SEC62 disrupts mitochondrial quality control, leading to oxidative stress and inflammation. Together, these findings define a specific molecular mechanism of organelle interplay in MASH and position SEC62 as a potential therapeutic target for intervention.