Epigenetic Regulation of Mitochondrial Homeostasis and Energy Metabolism

线粒体稳态和能量代谢的表观遗传调控

• 批准号: 10469401
• 负责人: Qin Yang
• 金额: $ 39.25万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-21 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10469401
• 关键词: Adhesions; Adipocytes; Adipose tissue; Adult; Aging; Applications Grants; Biology; Brown Fat; Cells; Complement 1q; Complex; Cyclic AMP; DNA; Data; Development; Diabetes Mellitus; Disease; Energy Metabolism; Enhancers; Enzymes; Epigenetic Process; Excision; Fatty Liver; G-Protein-Coupled Receptors; GDF15 gene; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Hepatic; Hepatocyte; High Fat Diet; Histones; Homeostasis; Housekeeping; KDM1A gene; Knock-out; Laboratories; Ligands; Liver; Liver Mitochondria; Longevity; Lysine; Mediating; Metabolic; Metabolism; Methylation; Mitochondria; Modeling; Molecular; Mus; Nicotinamide-Nucleotide Adenylyltransferase; Nuclear; Nuclear Proteins; Obese Mice; Obesity; Organ; Organelles; Oxidative Phosphorylation; Pathway interactions; Phosphorylation; Physiological; Play; Positioning Attribute; Production; Proteins; Proteomics; Recombinant Proteins; Regulation; Research; Role; SIRT1 gene; Signal Transduction; Stress; System; Tissues; adiponectin; aged; epigenetic regulation; feeding; fibroblast growth factor 21; fly; gene function; glucose metabolism; glucose tolerance; histone demethylase; histone methylation; humanin; improved; insight; knock-down; member; metabolic phenotype; mitochondrial dysfunction; non-histone protein; novel; obesity treatment; overexpression; synthetic enzyme; transcription factor; transcriptome sequencing

Mitochondria are powerhouses regulating cellular and systemic energy metabolism. Although mitochondria have their own DNA encoding 13 oxidative phosphorylation proteins, mitochondrial function is mainly regulated by more than 1,000 proteins encoded by the “mitochondrial genes” in the nuclear genome. While transcription factors have been the focus of research on mitochondrial gene regulation, major gaps exist in understanding how epigenetic factors are integrated into the transcriptional networks. Here the applicant proposes that lysine-specific demethylase-1 (LSD1) in liver serves as a novel housekeeping mechanism coordinating histone methylation and NAD+-modulated transcription factors to control mitochondrial gene expression and function and to regulate systemic energy metabolism. LSD1 catalyzes the removal of mono- and di-methylation of lysine 4 and 9 on histone 3 (H3K4/9). LSD1 also targets non-histone proteins to regulate their activity. Hepatic LSD1 was reduced in aged and obese mice. As LSD1 is essential to development, the applicant’s laboratory generated liver-specific LSD1 knockout in adult mice (LSD1-LKO). RNA-seq analysis revealed that LSD1 knockout in liver decreased approximately one-third of all known mitochondrial genes. Preliminary mechanistic studies showed that H3K9 methylation contributed to mitochondrial gene reduction. LSD1 did not directly target mitochondrial transcription factors, but rather targeted NAD+-synthetic enzyme NMNAT1 to regulate the activity of Sirt1 and Sirt7, which are positioned upstream of the mitochondrial transcription factors. Surprisingly, despite the reduced hepatic mitochondrial gene expression and function, LSD1-LKO mice showed improved metabolic phenotype including increased energy expenditure and reduced adiposity. We identified complement C1q like 4 (C1ql4), a member of adiponectin superfamily, as a potential novel mitochondrial stress-induced hepatic mitokine that regulates systemic energy expenditure. The applicant therefore hypothesizes that LSD1 modulates histone and NMNAT1 methylation to control mitochondrial gene expression and hepatic mitokine production for regulating systemic energy metabolism. Aim 1 is to determine the mechanisms for LSD1-regulated hepatic mitochondrial gene expression, focusing on 1) LSD1 demethylase activity and histone methylation; 2) NMNAT1 methylation and NAD+-mediated transcription factor activation. Aim 2 is to elucidate the mechanisms by which hepatic LSD1 regulates systemic energy metabolism. We will focus on C1ql4 and study 1) regulation of C1ql4 expression by mitochondrial stress and histone methylation; 2) effects of C1ql4 on obesity; 3) mechanism of C1ql4 action for increasing energy expenditure; 4) role of C1ql4 induction in the improved systemic energy metabolism in the LSD1-LKO mice. Overall, the proposal will provide molecular, cellular and physiological insights into the housekeeping roles of LSD1 in controlling mitochondrial gene expression and function. Furthermore, the identification of C1ql4 as a novel hepatic mitokine not only highlights the significance of mitokines in regulating systemic energy metabolism, but may also provide a novel target for obesity treatment.

线粒体是调节细胞和全身能量代谢的动力室。虽然线粒体有自己的DNA编码13种氧化磷酸化蛋白，但线粒体功能主要由核基因组中的"线粒体基因"编码的1,000多种蛋白质调节。虽然转录因子一直是线粒体基因调控研究的重点，但在理解表观遗传因子如何整合到转录网络中方面存在重大差距。在此，申请人提出，肝脏中的赖氨酸特异性脱甲基酶-1（LSD 1）作为一种新的管家机制，协调组蛋白甲基化和NAD+调节的转录因子，以控制线粒体基因表达和功能，并调节全身能量代谢。LSD 1催化组蛋白3（H3K4/9）上赖氨酸4和9的单甲基化和二甲基化的去除。LSD1还靶向非组蛋白蛋白以调节其活性。在老年和肥胖小鼠中，肝脏LSD 1降低。由于LSD 1对发育至关重要，申请人的实验室在成年小鼠中产生了肝脏特异性LSD 1敲除（LSD 1-LKO）。RNA-seq分析显示，肝脏中的LSD1敲除减少了所有已知线粒体基因的约三分之一。初步机制研究表明，H3K9甲基化有助于线粒体基因减少。LSD 1不直接靶向线粒体转录因子，而是靶向NAD+合成酶NMNAT 1，以调节位于线粒体转录因子上游的Sirt1和Sirt7的活性。令人惊讶的是，尽管肝脏线粒体基因表达和功能降低，但LSD1-LKO小鼠显示出改善的代谢表型，包括增加的能量消耗和减少的肥胖。我们确定补体C1q样4（C1ql4），脂联素超家族的成员，作为一个潜在的新的线粒体应激诱导的肝细胞有丝分裂因子，调节全身能量消耗。因此，申请人假设LSD 1调节组蛋白和NMNAT 1甲基化，以控制线粒体基因表达和肝脏丝裂因子产生，从而调节全身能量代谢。目的1：探讨LSD 1调控肝线粒体基因表达的机制，包括LSD 1去甲基化酶活性和组蛋白甲基化; NMNAT 1甲基化和NAD+介导的转录因子激活。目的二是阐明肝脏LSD 1调节全身能量代谢的机制。我们将重点关注C1ql4并研究1）线粒体应激和组蛋白甲基化对C1ql4表达的调节; 2）C1ql4对肥胖的影响; 3）C1ql4增加能量消耗的作用机制; 4）C1ql4诱导在LSD1-LKO小鼠中改善全身能量代谢中的作用。总的来说，该提案将为LSD 1在控制线粒体基因表达和功能中的管家作用提供分子，细胞和生理学见解。此外，C1ql4作为一种新的肝细胞分裂因子的鉴定不仅突出了细胞分裂因子在调节全身能量代谢中的重要性，而且还可能为肥胖治疗提供新的靶点。