Dynamic adaptation of liver mitochondria to alcohol

肝线粒体对酒精的动态适应

• 批准号: 10002157
• 负责人: DERICK S HAN
• 金额: $ 18.2万
• 依托单位: KECK GRADUATE INST OF APPLIED LIFE SCIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10002157
• 关键词: Acetylation; Affect; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Apoptosis; Binding; Bioenergetics; Biogenesis; Cessation of life; Chronic; Clinical; Collaborations; Complex; Data; Disease; Dissection; Dynamin; Enzymes; Ethanol Metabolism; Functional disorder; Generations; Goals; Guanosine Triphosphate Phosphohydrolases; Hepatocyte; Heterogeneity; Human; Injury; Lasers; Lead; Letters; Liver; Liver Mitochondria; Liver diseases; MAPK8 gene; Maps; Mediating; Membrane Fusion; Mitochondria; Morphology; Natural regeneration; Necrosis; Optic Atrophy; Oral; Outcome; PPAR gamma; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmacologic Substance; Physiology; Play; Property; Reactive Oxygen Species; Reporting; Respiration; Role; Stress; Technology; Time; United States; cytochrome c; feeding; insight; liver injury; mitochondrial dysfunction; non-alcoholic fatty liver disease; oxidation; problem drinker; protein complex; pyridine nucleotide; respiratory

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.

摘要 这项建议的首要目标是阐明肝脏线粒体重塑在肝脏中的作用， 酒精性肝病（ALD）我们最近令人兴奋的发现表明，慢性酒精喂养会导致动态 肝脏中的线粒体重塑，增强线粒体生物能量活动，作为适应 酒精我们观察到两种主要类型的线粒体重塑酒精喂养后：1）增加 关键线粒体成分的生物发生（例如呼吸复合蛋白、吡啶 核苷酸水平）和，2）通过线粒体的变化改变肝脏线粒体形态 聚变-裂变速率我们的发现为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中线粒体功能障碍的这种模式已被广泛接受， 几十年来，它代表了肝脏中线粒体动力学的不完整画面。慢性酒精喂养 导致一些线粒体功能障碍，但它也诱导了肝脏中大量的线粒体重塑 作为对酒精摄入引起的压力的适应。 在这个建议中，我们将通过调节两个细胞因子来研究ALD中线粒体重塑的意义。 肝脏中的不同通路。过氧化物酶体增殖物激活受体γ共激活因子-1 α（PGC-1α）是一种 线粒体生物发生的主要调节器，我们的初步数据表明它在酒精中起作用， 诱导线粒体生物合成，特别是肝脏中的呼吸复合物。因此，我们将 使用反义（阿索）沉默PGC-1α，以确定线粒体生物发生是否发挥有益的（即， 适应）或慢性酒精喂养对肝脏的有害作用。在ALD期间，像许多病理一样， 线粒体融合-分裂改变增加线粒体异质性，从而产生 线粒体可能具有不同的特性（呼吸、活性氧产生、JNK结合）。 我们将使用阿索调节线粒体融合-分裂速率（例如，Mfn-2 -产生片段化的 线粒体; Opa-1 -产生更大的线粒体）来改变线粒体异质性，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 线粒体生物合成在ALD发病机制中的作用，以及2）确定线粒体生物合成的程度和意义， 线粒体异质性，发生在肝脏与酒精喂养。总的来说，通过调节两种不同的 线粒体重塑（生物发生和融合-裂变）方面，我们的建议应该提供新的见解 线粒体重塑在ALD中的作用虽然我们的建议侧重于酒精，但我们认为， 这项研究的结果将在肝脏病理生理学方面具有更广泛的意义，因为许多肝脏疾病，如 非酒精性脂肪肝也与线粒体重塑有关。