Control of beta cell identity by the mitochondrial life cycle

通过线粒体生命周期控制 β 细胞身份

• 批准号: 10619610
• 负责人: Scott Soleimanpour
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10619610
• 关键词: Address; Anabolism; Antioxidants; Back; Beta Cell; Biogenesis; Biosensor; Blood Glucose; Cell Survival; Cells; Characteristics; Chromatin; Chronic Disease; DNA; Data; Defect; Diabetes Mellitus; Diabetes prevention; Ensure; Environment; Equilibrium; Etiology; Exhibits; Failure; Feedback; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Glucose; Goals; Health; Human; Hyperglycemia; Impairment; Insulin; Lead; Life Cycle Stages; Maintenance; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Pancreas; Patients; Peripheral; Physiological; Power Plants; Quality Control; Reporting; Respiration; Role; Signal Induction; Signal Pathway; Signal Transduction; Spirometry; Structure; Structure of beta Cell of islet; Techniques; Testing; Veterans; biological adaptation to stress; diabetes pathogenesis; endocrine pancreas development; euglycemia; fatty acid metabolism; functional restoration; genetic approach; improved; in vivo; insight; insulin secretion; islet; metabolomics; mitochondrial dysfunction; novel; oxidative damage; pharmacologic; preservation; programs; response; stem cells; tool; transcriptomics

Diabetes results from insufficient functional pancreatic β-cell mass to meet peripheral insulin demands. β-cell failure can occur in T2D due to loss of β-cell identity or de-differentiation, with recent studies suggesting that loss of the mitochondrial gene expression program heralds the immature β-cell state. β-cells rely upon mitochondrial respiration to generate the energy necessary for the metabolic demands of insulin biosynthesis, processing, and secretion. Indeed, defects in mitochondrial structure, function, and DNA levels have been reported in the β-cells of patients with type 2 diabetes (T2D). Defects in mitochondrial structure and function are characteristic of impairments in the mitochondrial life cycle, which maintains functional mitochondrial mass via a balance of biogenesis and turnover. It is not clear, however, if impaired mitochondria are necessary and sufficient to directly induce β-cell immaturity. Interestingly, our preliminary data suggest that genetic loss of biogenesis or mitophagy reduces β-cell maturity and mass, which is not due to impaired β-cell replication or survival. Therefore, our goal is to dissect the mechanistic contribution of mitochondrial biogenesis and turnover to β-cell maturity and elucidate their contribution to diabetes pathogenesis. The central hypothesis to be tested is that defects in the mitochondrial life cycle induce a retrograde signaling cascade that impairs β-cell identity. We will test this hypothesis by the following approach: Specific Aim 1 will elucidate the effect of metabolic overload on the mitochondrial life cycle and its control of β-cell identity. Specific Aim 2 will determine the contribution of mitochondria derived oxidative damage to the development of β-cell immaturity. Specific Aim 3 will delineate the role of the integrated stress response to consolidate retrograde signals inducing β-cell immaturity following mitochondrial dysfunction. We anticipate obtaining a clear understanding of the importance and translational relevance of the mitochondrial life cycle by revealing the key effectors that mediate mito-nuclear crosstalk and impact β-cell identity. These results should re-define the role of mitochondria in diabetes pathogenesis and could open new possibilities to re-program immature β-cells back to a mature state to treat diabetes in Veterans.

糖尿病是由于功能性胰腺β细胞量不足以满足外周胰岛素需求而引起的。 β细胞 由于 β 细胞身份丧失或去分化，T2D 患者可能会出现失败，最近的研究表明，β 细胞丧失 线粒体基因表达程序的异常预示着β细胞的不成熟状态。 β细胞依赖线粒体 呼吸作用产生胰岛素生物合成、加工和代谢所需的能量 分泌。事实上，β 细胞中线粒体结构、功能和 DNA 水平的缺陷已被报道 2 型糖尿病 (T2D) 患者。线粒体结构和功能缺陷的特征 线粒体生命周期受损，通过平衡维持功能性线粒体质量 生物发生和周转。然而，尚不清楚线粒体受损是否是直接影响线粒体的必要和充分条件。 诱导β细胞不成熟。有趣的是，我们的初步数据表明生物发生或线粒体自噬的遗传损失 降低 β 细胞成熟度和​​质量，这并不是由于 β 细胞复制或存活受损所致。因此，我们的目标 是剖析线粒体生物发生和周转对 β 细胞成熟的机制贡献并阐明 它们对糖尿病发病机制的贡献。要检验的中心假设是 线粒体生命周期诱导逆行信号级联反应，损害 β 细胞身份。我们将测试这个 通过以下方法进行假设：具体目标 1 将阐明代谢超负荷对 线粒体生命周期及其对 β 细胞身份的控制。具体目标 2 将确定的贡献 线粒体衍生的氧化损伤导致β细胞发育不成熟。具体目标 3 将描述 整合应激反应在巩固逆行信号中诱导β细胞不成熟的作用 线粒体功能障碍。我们期望对重要性和转化有一个清晰的理解 通过揭示介导线粒体核串扰的关键效应器来研究线粒体生命周期的相关性 影响β细胞身份。这些结果应该重新定义线粒体在糖尿病发病机制中的作用，并可能 开辟新的可能性，将未成熟的β细胞重新编程回成熟状态，以治疗退伍军人的糖尿病。