The outcome of boosting mitochondrial activity in alcohol-associated liver disease is organ-dependent.
The outcome of boosting mitochondrial activity in alcohol-associated liver disease is organ-dependent.
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DOI：
10.1097/hep.0000000000000303
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发表时间：
2023-09-01
期刊：
影响因子：
13.5
通讯作者：
Martinez-Chantar, Maria Luz
中科院分区：
文献类型：
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作者：
Goikoetxea-Usandizaga, Naroa;Bravo, Miren;Egia-Mendikute, Leire;Abecia, Leticia;Serrano-Macia, Marina;Urdinguio, Rocio G.;Clos-Garcia, Marc;Rodriguez-Agudo, Ruben;Araujo-Legido, Raquel;Lopez-Bermudo, Lucia;Delgado, Teresa C.;Lachiondo-Ortega, Sofia;Gonzalez-Recio, Irene;Gil-Pitarch, Claudia;Pena-Cearra, Ainize;Simon, Jorge;Benede-Ubieto, Raquel;Arino, Silvia;Herranz, Jose M.;Azkargorta, Mikel;Salazar-Bermeo, Julio;Marti, Nuria;Varela-Rey, Marta;Falcon-Perez, Juan M.;Lorenzo, Oscar;Nogueiras, Ruben;Elortza, Felix;Nevzorova, Yulia A.;Cubero, Francisco J.;Saura, Domingo;Martinez-Cruz, Luis Alfonso;Sabio, Guadalupe;Palazon, Asis;Sancho-Bru, Pau;Elguezabal, Natalia;Fraga, Mario F.;Avila, Matias A.;Bataller, Ramon;Marin, Jose J. G.;Martin, Franz;Martinez-Chantar, Maria Luz
在欧洲，酒精相关性肝病 (ALD) 占肝脏相关死亡的 70%，且尚无有效的获批治疗方法。尽管线粒体功能障碍是酒精引起的损伤的最早表现之一，但由于氧化应激，恢复线粒体活性仍然是一个有问题的策略。在这里，我们确定甲基化控制的 J 蛋白 (MCJ) 作为 ALD 进展的介质，并假设靶向 MCJ 可能有助于恢复线粒体健康，而不会产生附带的氧化损伤。 C57BL/6 小鼠 [野生型 (Wt)] Mcj 敲除和 Mcj 肝脏特异性沉默 (MCJ-LSS) 接受 NIAAA 饮食方案（含有 5%（体积/体积）乙醇的 Lieber-DeCarli 饮食 10 天，加上第 11 天单次暴食乙醇喂养）。为了评估线粒体活性恢复对 ALD 的影响，对肝脏、肠道和胰腺进行了表征，重点关注脂质代谢、葡萄糖稳态、肠道通透性和微生物群组成。 MCJ 是一种作为线粒体呼吸的内源性负调节因子的蛋白质，在 ALD 的早期阶段表达下调，并随着疾病的严重程度而表达增加。全身 MCJ 缺乏在 ALD 期间是有害的，因为它会通过改变肠道通透性、增加内毒素血症和胰腺功能失调而加剧酒精滥用的全身影响，从而总体上加重肝损伤。另一方面，肝脏特异性 Mcj 沉默可以防止 ALD 的主要特征，即线粒体功能障碍、脂肪变性、炎症和氧化应激，因为它可以恢复 NAD+/NADH 比例和 SIRT1 功能，从而防止从头脂肪生成并改善脂质氧化。通过肝脏特异性 Mcj 沉默改善线粒体呼吸可能成为治疗 ALD 的一种新方法。
Alcohol-associated liver disease (ALD) accounts for 70% of liver-related deaths in Europe, with no effective approved therapies. Although mitochondrial dysfunction is one of the earliest manifestations of alcohol-induced injury, restoring mitochondrial activity remains a problematic strategy due to oxidative stress. Here, we identify methylation-controlled J protein (MCJ) as a mediator for ALD progression and hypothesize that targeting MCJ may help in recovering mitochondrial fitness without collateral oxidative damage. C57BL/6 mice [wild-type (Wt)] Mcj knockout and Mcj liver-specific silencing (MCJ-LSS) underwent the NIAAA dietary protocol (Lieber-DeCarli diet containing 5% (vol/vol) ethanol for 10 days, plus a single binge ethanol feeding at day 11). To evaluate the impact of a restored mitochondrial activity in ALD, the liver, gut, and pancreas were characterized, focusing on lipid metabolism, glucose homeostasis, intestinal permeability, and microbiota composition. MCJ, a protein acting as an endogenous negative regulator of mitochondrial respiration, is downregulated in the early stages of ALD and increases with the severity of the disease. Whole-body deficiency of MCJ is detrimental during ALD because it exacerbates the systemic effects of alcohol abuse through altered intestinal permeability, increased endotoxemia, and dysregulation of pancreatic function, which overall worsens liver injury. On the other hand, liver-specific Mcj silencing prevents main ALD hallmarks, that is, mitochondrial dysfunction, steatosis, inflammation, and oxidative stress, as it restores the NAD+/NADH ratio and SIRT1 function, hence preventing de novo lipogenesis and improving lipid oxidation. Improving mitochondrial respiration by liver-specific Mcj silencing might become a novel therapeutic approach for treating ALD.