Dynamic adaptation of liver mitochondria to alcohol

摘要 这一建议的首要目标是阐明肝脏线粒体重塑在 酒精性肝病(ALD)。我们最近令人兴奋的发现表明，长期饮酒会导致动力 肝脏线粒体重塑增强线粒体生物能量活性以适应 酒精。我们观察到饮酒后线粒体重塑的两种主要类型：1)增加 关键线粒体成分的生物发生(例如，呼吸复合体蛋白、吡啶的表达 核苷酸水平)以及，2)通过线粒体的改变改变肝脏线粒体的形态 聚变率。我们的发现为ALD主要涉及的既定教条增加了新的见解 线粒体功能障碍。虽然ALD的这种线粒体功能障碍的范例已经被广泛接受 几十年来，它代表了一幅不完整的肝脏线粒体动力学图景。长期饮酒 会导致一些线粒体功能障碍，但也会导致肝脏中大量的线粒体重塑 作为对饮酒引起的压力的一种适应。 在这个方案中，我们将通过调节两个基因来研究ALD中线粒体重塑的意义。 肝脏中的不同路径。过氧化物酶体增殖物激活受体-1辅活化子-1α(pGC-1α)是 线粒体生物发生的主要调节者，我们的初步数据表明，它在酒精中发挥作用- 诱导线粒体生物发生，特别是肝脏中呼吸复合体的发生。因此，我们将 使用反义(ASO)沉默pGC-1α以确定线粒体生物发生是否起到有益的作用(即 适应)或长期饮酒对肝脏的有害作用。在ALD期间，就像在许多病理学中一样， 线粒体融合-裂变改变以增加线粒体的异质性，从而产生亚群 线粒体可能有不同的性质(呼吸作用、活性氧生成、JNK结合)。 我们将使用ASO(例如，MFN-2-产生片段)来调节线粒体融合-裂变速率 线粒体；OpA-1-产生更大的线粒体)来改变线粒体的异质性，以确定其 在ALD发病机制中的意义。该提案有两个具体目标：1)确定 线粒体生物发生在ALD发病机制中的作用，以及2)决定ALD的程度和意义 在酒精喂养的肝脏中出现的线粒体异质性。总体而言，通过调制两个不同的 关于线粒体重塑(生物发生和融合-裂变)的各个方面，我们的建议应该提供新的见解 线粒体重塑在ALD中的作用。尽管我们的提案重点是酒精，但我们认为 这项研究的发现将对肝脏病理生理学产生更广泛的影响，因为许多肝脏疾病，如 非酒精性脂肪性肝病，也与线粒体重塑有关。

ABSTRACT The overarching goal of this proposal is to elucidate the role that mitochondrial remodeling in the liver plays in alcoholic liver disease (ALD). Our recent exciting findings suggest that chronic alcohol feeding causes dynamic mitochondrial remodeling in the liver that enhances mitochondrial bioenergetic activity as an adaptation to alcohol. We observed two major types of mitochondrial remodeling following alcohol feeding: 1) increased biogenesis of key mitochondrial constituents (e.g. expression of respiratory complex proteins, pyridine nucleotide levels) and, 2) alterations in liver mitochondrial morphology through changes in mitochondrial fusion-fission rates. Our findings add new insights to the established dogma that ALD primarily involves mitochondrial dysfunction. While this paradigm of mitochondrial dysfunction in ALD has been widely accepted for decades, it represents an incomplete picture of mitochondrial dynamics in the liver. Chronic alcohol feeding causes some mitochondrial dysfunction, but it also induces a great deal of mitochondrial remodeling in the liver as an adaptation to the stress induced by alcohol intake. In this proposal, we will examine the significance of mitochondrial remodeling in ALD by modulating two distinct pathways in the liver. Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) is the master regulator of mitochondrial biogenesis, and our preliminary data suggests that it plays a role in alcohol- induced mitochondrial biogenesis, particularly of respiratory complexes in the liver. Consequently, we will silence PGC-1α using antisense (ASO) to determine if mitochondrial biogenesis plays a beneficial (i.e. adaptation) or deleterious role in the liver with chronic alcohol feeding. During ALD, like in many pathologies, mitochondrial fusion-fission alters to increase mitochondrial heterogeneity, which produces subpopulations of mitochondria that may have different properties (respiration, reactive oxygen species generation, JNK binding). We will modulate mitochondrial fusion-fission rates using ASO (e.g. Mfn-2 - produces fragmented mitochondria; Opa-1 - produces larger mitochondria) to alter mitochondrial heterogeneity to determine its significance in the pathogenesis of ALD. The proposal has two specific aims: 1) Determine the significance of mitochondrial biogenesis in the pathogenesis of ALD, and 2) Determine the extent and significance of mitochondrial heterogeneity that occurs in the liver with alcohol feeding. Overall, by modulating two different aspects of mitochondrial remodeling (biogenesis and fusion-fission), our proposal should provide new insights on the role mitochondrial remodeling plays in ALD. Although our proposal focuses on alcohol, we believe the findings of this study will have broader implications in liver pathophysiology, since many liver diseases, such as non-alcoholic fatty liver disease, are also associated with mitochondrial remodeling.