Differential requirements for mitochondrial electron transport chain components in the adult murine liver.
Differential requirements for mitochondrial electron transport chain components in the adult murine liver.
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DOI：
10.7554/elife.80919
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发表时间：
2022-09-26
期刊：
影响因子：
7.7
通讯作者：
Mishra P
中科院分区：
文献类型：
--
作者：
Lesner NP;Wang X;Chen Z;Frank A;Menezes CJ;House S;Shelton SD;Lemoff A;McFadden DG;Wansapura J;DeBerardinis RJ;Mishra P
由于核或线粒体基因组中的突变引起的线粒体电子传递链（ETC）功能障碍是人类代谢疾病的常见原因，并且根据受影响的基因显示出惊人的组织特异性。组织特异性表型的机制尚不清楚。复合物I（cI）通常被认为是电子进入ETC的入口点，体外实验表明cI是基础呼吸和维持NAD+/NADH比率（细胞氧化还原状态的指标）所必需的。这一发现在很大程度上没有在体内进行过测试。在这里，我们报告说，线粒体复合物I是维持稳态的成年小鼠肝脏;动物肝细胞特异性丧失cI功能显示没有明显的表型或肝损伤的迹象，并保持肝功能，氧化还原和氧状态。进一步分析cI缺乏的肝脏没有发现显着的蛋白质组学或代谢的变化，表明很少或没有补偿是需要在设置复杂的I损失。相比之下，成年肝细胞中的复合物IV（cIV）功能障碍导致肝功能降低、氧处理受损、脂肪变性和肝损伤，伴随显著的代谢组学和蛋白质组学扰动。我们的结果支持了一种模型，即小鼠肝脏可以耐受复合物I的丢失，因为肝细胞使用替代电子供体来为线粒体等提供燃料。线粒体是细胞内的专门结构，有助于将营养物质转化为能量。它们从营养物质中获取电子，并利用它们为提供化学燃料的生化反应提供动力。之前对实验室培养的细胞的研究发现，电子通过线粒体中称为复合物I的蛋白质大集合进入这一过程。了解能量产生的机制很重要，因为线粒体的问题可能导致各种代谢疾病。然而，目前还不清楚I在活体动物中的行为有多复杂。Lesner等人通过从小鼠肝脏中的复合物I中遗传去除一种关键蛋白质来解决这一知识缺口。令人惊讶的是，这些动物没有出现任何可检测到的症状，并保持健康的肝功能。小鼠似乎没有通过以不同的方式制造能量来补偿，这表明复合物I通常不被小鼠肝脏用于这一过程。这项研究表明，生物学家应该重新考虑线粒体为动物细胞提供动力的机制。虽然复合物I在电子转移中的作用在实验室培养的细胞和一些器官（如大脑）中得到了很好的证实，但不能假设这适用于整个身体。了解特定器官的能量产生可以帮助研究人员开发基于营养的代谢疾病疗法。
Mitochondrial electron transport chain (ETC) dysfunction due to mutations in the nuclear or mitochondrial genome is a common cause of metabolic disease in humans and displays striking tissue specificity depending on the affected gene. The mechanisms underlying tissue-specific phenotypes are not understood. Complex I (cI) is classically considered the entry point for electrons into the ETC, and in vitro experiments indicate that cI is required for basal respiration and maintenance of the NAD+/NADH ratio, an indicator of cellular redox status. This finding has largely not been tested in vivo. Here, we report that mitochondrial complex I is dispensable for homeostasis of the adult mouse liver; animals with hepatocyte-specific loss of cI function display no overt phenotypes or signs of liver damage, and maintain liver function, redox and oxygen status. Further analysis of cI-deficient livers did not reveal significant proteomic or metabolic changes, indicating little to no compensation is required in the setting of complex I loss. In contrast, complex IV (cIV) dysfunction in adult hepatocytes results in decreased liver function, impaired oxygen handling, steatosis, and liver damage, accompanied by significant metabolomic and proteomic perturbations. Our results support a model whereby complex I loss is tolerated in the mouse liver because hepatocytes use alternative electron donors to fuel the mitochondrial ETC. Mitochondria are specialised structures inside cells that help to convert nutrients into energy. They take electrons from nutrients and use them to power biochemical reactions that supply chemical fuel. Previous studies of cells grown in the laboratory have found that electrons enter this process via a large assembly of proteins in mitochondria called complex I. Understanding the mechanism of energy production is important, as issues with mitochondria can lead to a variety of metabolic diseases. However, it is still unclear how complex I acts in living animals. Lesner et al. addressed this knowledge gap by genetically removing a key protein from complex I in the liver of mice. Surprisingly, the animals did not develop any detectable symptoms and maintained healthy liver function. Mice did not seem to compensate by making energy in a different way, suggesting that complex I is not normally used by the mouse liver for this process. This research suggests that biologists should reconsider the mechanism that mitochondria use to power cells in animals. While the role of Complex I in electron transfer is well established in laboratory-grown cells and some organs, like the brain, it cannot be assumed this applies to the whole body. Understanding energy production in specific organs could help researchers to develop nutrient-based therapies for metabolic diseases.