Mitochondrial depolarization, mitophagy, and mitochondrial DAMPs in ALD

ALD 中的线粒体去极化、线粒体自噬和线粒体 DAMP

• 批准号: 10155373
• 负责人: John J Lemasters
• 金额: $ 33.64万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155373
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acetaldehyde; Acute; Acute Alcoholic Hepatitis; Agonist; Alcohol dehydrogenase; Alcoholic Hepatitis; Alcoholic Liver Diseases; Autophagosome; Biological Markers; CYP2E1 gene; Cardiolipins; Cessation of life; Characteristics; Cholesterol; Chronic; Cirrhosis; Development; Electron Microscopy; Ethanol; Ethanol Metabolism; FK506; Fasting; Fibrosis; GLP-I receptor; Genetic; Glucagon; Goals; Hepatic; Hepatocyte; Impairment; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Lead; Link; Liver; Liver Mitochondria; Liver diseases; Lysosomes; Mediator of activation protein; Mitochondria; Mitochondrial DNA; Modality; Modeling; Molecular; Molecular Analysis; Monitor; Mus; Neuromuscular Depolarizing Agents; Pathogenesis; Pattern; Pharmacology; Pioglitazone; Prevention; Prevention strategy; Process; Role; Serum; Severities; Severity of illness; Testing; Therapeutic Agents; Transgenic Mice; Work; alcohol exposure; aldehyde dehydrogenases; binge drinking; cytochrome c; disorder prevention; experimental study; extracellular; feeding; hepatocellular injury; in vivo; innovation; intravital microscopy; liver development; liver injury; mortality; multiphoton microscopy; new therapeutic target; nonalcoholic steatohepatitis; novel; novel marker; oxidation; parkin gene/protein; prevent; response

Alcoholic liver disease (ALD) accounts for ~50% of deaths due to cirrhosis and ~30% of all liver-related deaths in the US. How ethanol damages the liver remains poorly understood, and therapies are lacking or unproven. Our goal is to understand the pathogenesis of ALD. We observed widespread, reversible hepatic mitochondrial depolarization (mtDepo), increased mitophagic burden and elevated serum mitochondrial DNA (mtDNA) in mice after ethanol treatment. We propose to test the novel hypothesis that ethanol metabolism induces mtDepo, which in turn stimulates mitophagy. Markedly increased mitophagic burden overwhelms the capacity of lysosomes to process autophagosomes, particularly when processing of depolarized mitochondria into mitophagosomes and then into lysosomes is compromised after chronic ethanol exposure, leading to extracellular release of damaged mitochondria, mitophagosomes and/or autolysosomes containing mitochondrial damage-associated molecular pattern (mtDAMP) molecules to cause a profibrotic inflammatory response and liver injury. In Specific Aim 1 using intravital multiphoton microscopy, we will explore if mtDepo occurs in living mice after chronic ethanol and is exacerbated by superimposed binge drinking and in an unique fibrosis-inducing ethanol/cholesterol model we developed. We will determine the relation of mtDepo to hepatic injury, inflammation and fibrosis. We will also explore if inhibition of acetaldehyde (AcAld) formation by alcohol dehydrogenase and CYP2E1 deficiency, accelerated AcAld oxidation by Alda-1, and FK506 (blocker of depolarization) decrease mtDepo and liver injury/inflammation/fibrosis after chronic ethanol. In Aim 2, we will determine the relation of mtDepo to mitophagy. Using genetic and pharmacological interventions in combination with intravital and electron microscopy and analyses of molecular indicators of mitophagic flux, we will elucidate if ethanol-induced mtDepo initiates mitophagy or if mitophagy causes mtDepo. We will determine if mitophagy/mitophagosome processing is blunted by chronic, chronic plus cholesterol and chronic plus binge ethanol and further explore if inhibition of autophagic processing exacerbates liver injury/inflammation/fibrosis after chronic ethanol. In Aim 3, we will characterize how mtDepo and compromised mitophagy/processing contribute to mtDAMP release after ethanol. We will characterize release into serum of mtDAMPs after acute ethanol and chronic, chronic plus cholesterol and chronic plus binge ethanol to determine the relationship of mtDAMP release to liver injury/inflammation/fibrosis. We will also determine how up and down-modulation of mtDepo, mitophagy and processing of mitophagosomes alters mtDAMP release after ethanol. This study will elucidate a novel link between early mitochondrial changes associated with ethanol metabolism and the later development of liver injury/inflammation/fibrosis and thus fill a critical gap in understanding ALD pathogenesis. This study should also identify new therapeutic targets of ALD and novel biomarkers for monitoring ALD severity/progression.

酒精性肝病（ALD）占肝硬化死亡的约50%，占所有肝脏相关死亡的约30%