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.

抽象的 该提案的总体目标是阐明肝脏中线粒体重塑的作用 我们最近令人兴奋的发现表明，长期饮酒会导致动态变化。 肝脏中的线粒体重塑增强了线粒体生物能活性，以适应 我们观察到酒精喂养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（例如呼吸复合蛋白、吡啶的表达） 核苷酸水平）和，2）通过线粒体的变化改变肝脏线粒体形态 我们的研究结果为 ALD 主要涉及的既定教条增添了新的见解。 虽然 ALD 中线粒体功能障碍的这种范例已被广泛接受。 几十年来，它代表了肝脏中慢性酒精喂养的线粒体动力学的不完整图景。 导致一些线粒体功能障碍，但它也会引起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。 在本提案中，我们将通过调节两个参数来研究线粒体重塑在 ALD 中的重要性 肝脏中的独特途径是过氧化物酶体增殖物激活受体 γ 辅激活因子-1α (PGC-1α)。 线粒体生物合成的主要调节因子，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，特别是在肝脏中测试呼吸复合物。 使用反义 (ASO) 沉默 PGC-1α 以确定线粒体生物发生是否发挥有益作用（即 在 ALD 期间，就像在许多病理情况下一样， 线粒体融合裂变的改变增加了线粒体的异质性，从而产生了亚群 线粒体可能具有不同的特性（呼吸、活性氧生成、JNK 结合）。 我们将使用 ASO 调节线粒体融合裂变速率（例如 Mfn-2 - 产生碎片 线粒体；Opa-1 - 产生更大的线粒体）以改变线粒体异质性以确定其 该提案有两个具体目标： 1) 确定 ALD 发病机制的重要性。 线粒体生物发生在 ALD 发病机制中的作用，以及 2) 确定线粒体生物发生的程度和意义 总体而言，通过调节两种不同的方式，肝脏中发生的线粒体异质性。 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 尽管我们的建议主要针对酒精，但我们相信线粒体重塑在 ALD 中的作用。 这项研究的结果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，例如 非酒精性脂肪肝也与线粒体重塑有关。