Prevention and regression of megamitochondria and steatosis by blocking mitochondrial fusion in the liver.
Prevention and regression of megamitochondria and steatosis by blocking mitochondrial fusion in the liver.
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DOI：
10.1016/j.isci.2022.103996
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发表时间：
2022-04-15
期刊：
影响因子：
5.8
通讯作者：
Sesaki H
中科院分区：
文献类型：
--
作者：
Yamada T;Murata D;Kleiner DE;Anders R;Rosenberg AZ;Kaplan J;Hamilton JP;Aghajan M;Levi M;Wang NY;Dawson TM;Yanagawa T;Powers AF;Iijima M;Sesaki H
非酒精性脂肪性肝炎（NASH）是一种最常见的慢性肝病，表现为脂肪变性、炎症、纤维化和组织损伤。NASH患者的肝细胞产生称为巨线粒体的巨大线粒体。研究表明，在蛋氨酸胆碱缺乏（MCD）饮食诱导的NASH小鼠模型中，OPA 1（一种介导线粒体融合的线粒体动力蛋白相关GT3）的基因敲除可预防巨线粒体形成和肝损伤。然而，阻断线粒体融合是否减轻NASH病理尚不清楚。在这里，我们在巨线粒体形成之前或之后，在NASH小鼠模型中使用反义寡核苷酸急性耗尽OPA 1。当在疾病发作时应用OPA 1 ASO时，它们有效地防止了MCD模型中的巨线粒体形成和肝脏病理。值得注意的是，即使在小鼠强烈发展NASH病理后应用，OPA 1靶向也有效地使巨线粒体和疾病表型消退。因此，我们的数据显示了线粒体动力学作为巨线粒体相关肝病的独特疗法的功效。由MCD饮食诱导的NASH小鼠模型在肝细胞中产生巨线粒体巨线粒体减少线粒体自噬通过靶向OPA 1阻断线粒体融合减轻NASH病理靶向OPA 1改善MCD模型中的SDH活性肝脏学;细胞生物学
Non-alcoholic steatohepatitis (NASH) is a most common chronic liver disease that is manifested by steatosis, inflammation, fibrosis, and tissue damage. Hepatocytes produce giant mitochondria termed megamitochondria in patients with NASH. It has been shown that gene knockout of OPA1, a mitochondrial dynamin-related GTPase that mediates mitochondrial fusion, prevents megamitochondria formation and liver damage in a NASH mouse model induced by a methionine-choline-deficient (MCD) diet. However, it is unknown whether blocking mitochondrial fusion mitigates NASH pathologies. Here, we acutely depleted OPA1 using antisense oligonucleotides in the NASH mouse model before or after megamitochondria formation. When OPA1 ASOs were applied at the disease onset, they effectively prevented megamitochondria formation and liver pathologies in the MCD model. Notably, even when applied after mice robustly developed NASH pathologies, OPA1 targeting effectively regressed megamitochondria and the disease phenotypes. Thus, our data show the efficacy of mitochondrial dynamics as a unique therapy for megamitochondria-associated liver disease. A NASH mouse model induced by the MCD diet produces megamitochondria in hepatocytes Megamitochondria decrease mitophagy Blocking mitochondrial fusion by targeting OPA1 mitigates NASH pathologies Targeting OPA1 improves the SDH activity in the MCD model Hepatology; Cell biology
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